Version May 2024
INTRODUCTION — Anaphylaxis is a severe multisystem allergic reaction that may cause death. Perioperative anaphylaxis tends to be more severe than anaphylaxis in other settings, with respiratory or cardiovascular compromise at presentation. This topic will discuss the evaluation of an adult or child who has experienced perioperative anaphylaxis and strategies to prevent recurrence. The prevalence, etiologies, clinical manifestations, diagnosis, and differential diagnosis of perioperative anaphylaxis are discussed separately (see "Perioperative anaphylaxis: Clinical manifestations, etiology, and management"). The treatment of anaphylaxis is reviewed elsewhere. (See "Anaphylaxis: Emergency treatment".)
Terminology — Some clinical investigators use the term "hypersensitivity reactions" or "systemic reactions" to include milder forms of perioperative allergic reactions, reserving anaphylaxis only for those with severe cardiovascular or respiratory compromise. In this topic review, we will consider these terms interchangeable. In addition, we will use "anaphylaxis" to refer to both immunoglobulin (Ig)E-mediated and non-IgE-mediated reactions. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Mechanisms of anaphylaxis'.)
EVALUATION — The evaluation of a patient who has experienced suspected perioperative or perianesthetic anaphylaxis involves a clinical history, review of records of the event, analysis of laboratory tests obtained at the time, and skin testing or in vitro serum-specific IgE testing if the reaction was believed to be IgE mediated. The complexity of medications used for anesthesia and surgery present challenges when attempting to identify the cause, but critical interpretation of clinical information and select testing leads to better recognition of culprit drugs [1,2].
There are three goals of this evaluation:
●Collection of evidence to support or refute that the adverse perioperative event was mast-cell mediated (ie, anaphylaxis).
●Identification of the culprit agent so that the agent can be avoided in the future. Not identifying the responsible agent necessitates the use of multiple second-line agents, a strategy that is not without risk to the patient.
●Identification of alternative agents to which the patient has no evidence of hypersensitivity.
Referral — Skin testing and challenge procedures to identify drug allergy should be performed by allergy specialists and/or anesthesiologists trained in the safe performance and accurate interpretation of these tests and challenges.
History — Patients usually cannot provide much information about reactions that occurred during anesthesia. However, questioning the patient about prior anesthesia may be helpful in identifying previous exposures as well as agents that were tolerated in the past.
An initial step in evaluating a patient with suspected perioperative anaphylaxis is verification that the reaction was clinically consistent with anaphylaxis. Wheezing and urticaria are helpful in distinguishing anaphylaxis from other disorders. The characteristic signs and symptoms of perioperative anaphylaxis are reviewed separately. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management".)
Records of the procedure — In many cases, the evaluating allergy specialist must rely solely upon anesthesia and perioperative records and perhaps a verbal account from clinicians who were present. A review of drug administration records is essential to determine temporal relationships between the administration of various agents and the onset of symptoms or signs. Operative notes may be helpful for identifying potential exposures to latex (eg, symptoms that began shortly after an internal organ was extensively manipulated and handled).
Tests for mast cell mediators — Serum or plasma tryptase and/or histamine elevations measured during or shortly after the reaction should be analyzed. If serum tryptase is elevated, a repeat measurement should be performed when the patient has recovered to assure that levels are not persistently elevated. An increase from baseline is highly suggestive of anaphylaxis, although a normal tryptase level does not exclude anaphylaxis. A serum tryptase of 1.2 x baseline + 2 ng/mL immediately after the reaction is considered sufficient to determine that mast cell/basophil degranulation occurred and that the episode was indeed anaphylaxis, although it does not provide information about the mechanism (eg, IgE mediated or other) of anaphylaxis or the culprit trigger.
In fatal cases, blood collected before death should be analyzed but interpreted with caution, as nonspecific increases in these mediators can occur immediately after death. The interpretation of these tests is discussed in detail elsewhere. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)
If these tests were not obtained at the time of the event, but blood samples were drawn for other purposes, it may still be possible to measure serum tryptase (although not histamine), as tryptase is stable in frozen serum for up to one year or up to five days when stored at 8°C [3].
The utility of elevated tryptase in perioperative anaphylaxis is illustrated in the following studies:
●In one large series, the estimated positive predictive value of tryptase elevations in 259 subjects with anesthesia-associated anaphylaxis was 93 percent, and the estimated negative predictive value of normal tryptase levels was 54 percent [4,5].
●Another study compared 75 subjects who were resuscitated for perioperative-allergic cardiopulmonary arrest and 25 control subjects who were resuscitated for nonallergic cardiopulmonary arrest [6]. The sensitivity and specificity of an elevated tryptase or histamine were 90 to 92 percent for identifying an allergic cause. The cutoff values were 7.35 mcg/L (7.35 ng/mL) for tryptase and 6.35 nmol/L for histamine.
●A survey from Belgium identified 180 subjects with tryptase data from a total of 532 subjects with perioperative anaphylaxis, collected over 15 years at a single academic medical center. Of the 180 subjects, 139 (77 percent) with anaphylaxis and tryptase data showed an increase of tryptase greater than 1.2 x baseline + 2 mcg/L. Subjects with increased tryptase were more likely to have experienced severe anaphylaxis and to have detectable specific IgE to the culprit drug. Absence of an increase in tryptase did not exclude specific IgE as the cause of the anaphylaxis [7].
Patients with persistent elevations above 20 ng/mL, even after completely recovery from the reaction, should be evaluated for the rare disorder systemic mastocytosis. Patients with systemic mastocytosis may react to multiple unrelated drugs and agents. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "Mast cell disorders: An overview".)
Skin testing
Important concepts — Skin testing may be considered if the suspect agent is known to cause IgE-mediated reactions (table 1) [8,9]. Skin testing is more sensitive than in vitro testing in most cases, although the negative and positive predictive values of skin testing for drugs other than penicillin are unknown.
Immediate prick/percutaneous and intradermal skin testing has no utility in the evaluation of anaphylaxis resulting from non-IgE mechanisms, although other forms of skin testing, such as patch and delayed intradermal testing, may be of value in assessment of non-anaphylactic, delayed adverse reactions to materials and drugs used at the time of surgery (eg, contact dermatitis and delayed-onset drug eruptions). These reactions typically develop in the days following exposure and do not present clinically as perioperative anaphylaxis. (See "Patch testing".)
The groups of agents that have most often been implicated in IgE-mediated perioperative anaphylaxis include:
●Neuromuscular-blocking agents (NMBAs)
●Certain antibiotics (particularly beta-lactam antibiotics, such as penicillin or cephalosporins)
●Latex (approved in vitro testing is available in the United States and other parts of the world; approved skin test reagents are not available in the United States but are in other countries)
●Blue dyes (also called supravital dyes, including isosulfan blue, patent blue V, and methylene blue)
Skin testing has also been described for streptokinase, chymopapain, barbiturates, and insulin, although these agents are rarely implicated in anaphylaxis [8]. Chlorhexidine, an antiseptic commonly used in dental rinses, surgical scrubs, and sterilizing solutions, may cause anaphylaxis, and skin testing as well as in vitro-specific IgE testing are described in the literature [10].
Suggested concentrations for intradermal skin testing of the most commonly implicated agents are provided below and are generally consistent with a 2019 European guideline [2,11]. Nonspecific irritant reactions are possible with some drugs, although these should be less likely if the recommended intradermal concentrations are not exceeded. Testing with higher concentrations may result in nonspecific positive responses, even in people who have not had adverse reactions to the drug, making the test of no value. (See 'Skin testing to specific agents' below.)
We generally test a patient with each of the medications that were administered prior to or during the adverse reaction, placing priority on those agents most likely to cause anaphylaxis. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Etiologies'.)
For those agents that have been implicated in causing anaphylaxis through multiple mechanisms (table 1), particularly NMBAs, we also perform skin testing for one or two potential alternative drugs that are available to the anesthesiologist involved in the case. Alternative agents may be the only option if challenges cannot be performed with agents producing a positive test, since the testing has not been validated for anesthetic drugs. Challenges can be problematic, particularly with agents restricted to the operating room, such as neuromuscular blocking agents or induction drugs. Test negative alternatives may assist in planning for future anesthesia. (See 'Neuromuscular-blocking agents' below.)
Timing of skin testing — Skin testing is usually delayed for four to eight weeks after the reaction, since false-negative results may be more likely immediately following anaphylaxis [12-16]. It is hypothesized that mast cells in the skin may be relatively unresponsive immediately after an episode of widespread hives or flushing, for reasons that are not fully defined. However, testing may be performed sooner if repeat anesthesia is necessary, as positive tests are still meaningful. This approach is supported by a study that compared the results of skin testing at two time points in patients with perioperative anaphylaxis; the first within four days of the reaction and, the second, four to eight weeks after the reaction [17]. Of patients with positive skin test results implicating a specific drug, 15 had positive results at the first testing, 22 at the second testing, 12 at both, 3 at only the first testing, and 10 at only the second testing. Until an evaluation has been completed, the agents statistically more likely to have caused the reaction should be avoided.
Beyond the initial four to eight weeks after the reaction, skin testing should be performed as promptly as possible, as sensitization to some drugs can be transient, and skin testing years after a reaction is less likely to reveal a culprit drug. However, if the patient is referred years after a reaction, we perform the same evaluation but with the understanding that the sensitivity of retrospective identification of culprits may be lower.
Techniques and safety — Allergy skin testing ideally should only be performed by allergy specialists with training in the technique. Skin testing is considered safe for most patients, although it is not without risk. It is recommended that emergency equipment and medications, including epinephrine (1 mg/mL), be available for treatment of the rare yet potentially life-threatening anaphylaxis that can arise from the testing. A general review of skin testing techniques is found separately. (See "Overview of skin testing for IgE-mediated allergic disease".)
Prick-puncture testing (also called epicutaneous or skin prick testing [SPT]) is safer than intradermal testing (IDT) and is preferred for the initial testing. If SPT is negative, IDT can safely proceed, although it is important to understand that there are rare reports of IDT resulting in anaphylaxis even when SPT was negative, which has been noted with testing with macrogols (eg, polyethylene glycol) or emulsifiers (eg, polysorbates) [18]. IDT is more sensitive than SPT and thus provides maximal reassurance that the agent in question was not responsible for the adverse event. In general, the maximal concentration used for IDT is 10- to 1000-fold more dilute than that used for SPT. However, these concentrations are often arbitrary. If the concentration is too high, testing can induce either an irritant response or anaphylaxis. Both of these adverse outcomes are more likely with IDT, so a reduction in concentration from that of the SPT is employed. The concentration(s) chosen are dependent upon prior experience, perceived risk of anaphylaxis or published case series, and rarely on controlled trials.
●If the literature provides a nonirritating concentration for IDT, the same concentration can be used for initial SPT as a safety precaution, since it is roughly equivalent to IDT at 1:100 to 1:000 dilution. If SPT is negative, then IDT can be performed, as IDT is more sensitive.
●If there is no recommended testing concentration available in the literature, we begin SPT with a 1:100 to 1:100,000 dilution of the concentration associated with the original reaction. The initial test concentration is based upon the severity of the reaction and the likelihood that the drug in question was responsible. A more dilute concentration may be used for the initial steps of testing if the patient's reaction was particularly severe. Repeat testing is performed with 10-fold increases in concentration until a positive SPT result or the clinically utilized concentration is reached. If all SPTs are negative, then IDT is performed starting at 1:100 to 1:1000 of the maximum SPT concentration [19]. Dilutions should be made with saline or phosphate-buffered saline (PBS) with added human albumin to preserve isotonicity and solubility. Serial tests with 10-fold progressive increases in concentration are subsequently performed. The time required for testing may be reduced by using fewer dilutions (eg, 1:100, 1:10, and undiluted) first for SPT, followed by the same dilutions for IDT. Some experts are comfortable with this efficiency, while others prefer the additional safety of using more dilute starting solutions.
●Appropriate positive and negative controls are always required. (See "Overview of skin testing for IgE-mediated allergic disease".)
●A false-positive irritant reaction may occur with both SPT and IDT but is more likely with the latter. If a positive SPT or IDT result is obtained with a substance for which there are no specific published concentration recommendations, we advise testing several controls (eg, the clinician and a few volunteers) to verify that the concentration does not cause a nonspecific, irritant response. The positive and negative predictive values are very limited when performing testing with drugs not rigorously studied, but this is often the only option to provide some guidance with respect to safety if no alternative choices for anesthesia are available.
Accuracy and interpretation — The interpretation of skin testing requires clinical expertise, because the positive and negative predictive values for skin testing with most medications have not been systematically defined, with the notable exception of penicillin. (See "Penicillin allergy: Immediate reactions".)
Despite these limitations, a positive skin test to an agent that is known to cause IgE-mediated reactions, with appropriate positive (histamine) and negative (saline) controls, is usually interpreted as indicative of allergic sensitization.
A negative skin test to an agent that is known to cause IgE-mediated reactions means that the patient is either not sensitized to that agent (if skin testing protocols are well-defined) or that testing is not able to demonstrate the sensitization (if the agent is less commonly implicated or is not well-studied). In cases in which the culprit is not clearly identified, drug challenge could be performed, but this is often difficult outside of specialty centers due to the unique physiologic actions of drugs used in anesthesia, the limited availability of these agents in outpatient settings, and the limited experience of most allergists in administering them [1,2].
Limited role of in vitro testing — In vitro tests are limited in availability for drugs in general.
●IgE immunoassays – Immunoassays for allergen-specific IgE (the current form of in vitro testing using enzyme-linked methodology [ELISA] and historically performed with radioallergosorbent testing [RAST]) may be helpful in identifying the causative agent in IgE-mediated anaphylaxis, although these are available commercially only for a limited number of allergens: penicillin and a limited number of other beta-lactam antibiotics, latex, gelatin, and alpha-gal. (See 'Latex' below and 'Colloids' below.)
Of note, some tests that are offered commercially are not validated and/or involve drugs that have never been shown to induce IgE antibodies. Thus, skin testing is usually more reliable, in part because skin testing is more sensitive for detecting specific IgE. Neither type of testing has utility in the evaluation of anaphylaxis resulting from mechanisms other than IgE.
●Basophil activation test – The basophil activation test (BAT) is an in vitro method of assaying the effects of mixing blood-containing basophils with suspected culprit agents. This test is not widely utilized in the United States, although its application is growing in the medical literature as an aid in the diagnosis of allergy and anaphylaxis. Use of the BAT is more common in European countries and is usually combined with skin testing for confirmation or assessment of cross reactivity [1].
The methodology involves flow cytometry of blood cells after mixing with potential allergens and labeling with monoclonal antibodies for total basophils (CCR3, CD123, or IgE) and for activated basophils (CD63 or CD203c). The BAT was performed in 14 subjects with perioperative anaphylaxis, and the results indicated that the BAT was specific but not highly sensitive and could be used to complement the results of inconclusive skin testing. This test is not generally commercially available, but this may change in the future [20]. A detailed discussion of in vitro testing for allergic disease is presented elsewhere. (See "Overview of in vitro allergy tests".)
SKIN TESTING TO SPECIFIC AGENTS — Certain agents have been repeatedly implicated in perioperative and perianesthesia anaphylaxis, including neuromuscular-blocking agents (NMBAs), antibiotics, barbiturate induction agents, latex, blood products, blue dyes, and possibly analgesics (opioids or nonsteroidal anti-inflammatory drugs [NSAIDs]). The list of causative medications is similar in adults and children [21].
Perioperative anaphylaxis can result from more than one mechanism, and it is important to understand which mechanisms are associated with commonly implicated agents (table 2). The pathophysiology of these reactions is reviewed separately. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Mechanisms of anaphylaxis'.)
Neuromuscular-blocking agents — In a large case series from Europe, 50 to 70 percent of anaphylaxis related to anesthesia is attributed to NMBAs (also referred to as muscle relaxants or paralytics). In series from the United States, antibiotics are the most common cause of perioperative anaphylaxis, followed by NMBAs. NMBAs can cause anaphylaxis through both IgE-mediated and direct mast cell activation, although severe, life-threatening reactions are usually IgE mediated (table 2) [19]. The epidemiology and risk factors of hypersensitivity to NMBAs are discussed separately. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Neuromuscular-blocking agents'.)
The explanation for the difference in prevalence of NMBA-associated anaphylaxis in Europe versus the United States may be a result of false-positive results when skin testing for NMBA allergy is performed. Some of the NMBAs (those derived from steroids) may induce a wheal-and-flare skin test response due to direct action on blood vessels. This has been confirmed by almost 50 percent of normal volunteers showing a positive skin response. Since skin tests may be used to document NMBAs as a cause of anaphylaxis, the false-positive rate with certain agents may result in an exaggeration of the risk, particularly if more concentrated solutions are used for intradermal testing [22,23].
Alternatively, there may be epidemiologic differences between Europe and the United States that explain the difference. The use of cough suppressants containing pholcodine, available in many countries in Europe but not in the United States, may be associated with the development of IgE antibodies to pholcodine, morphine, and/or suxamethonium and other NMBAs. Furthermore, suspected NMBA-associated anaphylaxis is 10 times more common in Norway, a country in which pholcodine products are more commonly used, than in Sweden [24]. However, other substances may lead to IgE sensitization to NMBAs and pholcodine, since IgE to pholcodine can be detected in vitro, albeit less frequently, in the serum of patients in countries where pholcodine is not used, such as the United States [25].
The NMBAs most commonly implicated in anaphylaxis are succinylcholine (also known as suxamethonium), rocuronium, atracurium, vecuronium, pancuronium, mivacurium (where available), and cisatracurium. Atracurium can cause nonimmunologic release of histamine from mast cells and false-positive skin tests [22], and some other drugs with this property (metocurine and tubocurarine) were removed from the United States market. Mivacurium is seldom used. However, they are mentioned here because they may still be in use in other parts of the world. A national survey in the United Kingdom showed that reactions to succinylcholine were more likely to result in bronchospasm and those to atracurium to result in hypotension [26].
Cross-reactivity has been documented among NMBAs, meaning that patients who react to one NMBA may react to others. This phenomenon has been most often reported with pancuronium and vecuronium and with succinylcholine (suxamethonium) and gallamine [27,28]. The shared quaternary ammonium groups in all NMBAs may underlie this phenomenon. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Neuromuscular-blocking agents'.)
Testing for IgE-mediated reactions — Skin testing with NMBAs is not standardized. We begin with prick-puncture testing, performed as described above and accompanied by a positive and negative control. If there is no reaction to the drug, we then proceed to intradermal testing (IDT) with concentrations no higher than those listed below [9,29]. Some experts limit the number of tests by using undiluted NMBA for skin prick testing (SPT) and using 1:100 dilution for initial IDT. (See 'Skin testing' above.)
We simultaneously test the patient to one or more alternative drugs, which we obtain from the anesthesiologist involved in the case. This facilitates the selection of an alternative agent for future use, particularly if a positive test occurs.
As mentioned previously, this approach may be altered for patients with a very severe past reaction. (See 'Techniques and safety' above.)
Maximal nonirritating concentrations for SPT and IDT skin testing in the literature are [2,11,14,30]:
●Succinylcholine (suxamethonium) – maximal SPT 10 to 20 mg/mL; maximal IDT 0.01 to 0.8 mg/mL
●Rocuronium – maximal SPT 10 mg/mL; intradermal 0.01 to 0.05 mg/mL
●Pancuronium – maximal SPT 2 to 20 mg/mL; intradermal 0.02 to 2 mg/mL
●Vecuronium – maximal SPT 1 mg/mL; intradermal 0.01 to 0.4 mg/mL
●Mivacurium (where available) – maximal SPT 0.2 to 1 mg/mL; intradermal 0.002 to 0.01 mg/mL
●Atracurium – maximal SPT 1 mg/mL; intradermal 0.01 mg/mL
●Cisatracurium – maximal SPT 2 mg/mL; intradermal 0.02 mg/mL
A range of concentrations is provided for some agents because the literature varies as to the maximum nonirritating concentration. The use of concentrations at the higher end of the range provides the clinician with more confidence that the drug is not the cause of the IgE-mediated reaction, although there is an increased risk of false-positive results. If the test is positive, we usually perform the test on control individuals (the clinician or associates) to be sure the positive is not a nonspecific irritant reaction. Dilutions are usually made with normal saline or PBS with human albumin when pH or solubility is an issue (eg, vancomycin).
In vitro assays for IgE specific to NMBAs are available in some countries, including the United States. Reported assays have up to 88 percent sensitivity but a false-positive rate of 5 to 10 percent. If available, these in vitro tests may be of use if skin testing cannot be performed or interpreted, since provocative challenging with NMBAs is not generally feasible.
Evaluation of non-IgE-mediated reactions — If the skin test to one of these agents is negative and there is concern that a non-IgE-mediated reaction caused by an NMBA may have been responsible, then a challenge protocol would be the only definitive means of excluding this possibility. However, this is not generally feasible due to the paralytic effects of NMBAs and limited access to this class of drugs for challenge. Thus, alternative strategies are available and described in the next section.
Alternatives — For patients with IgE-mediated reactions to NMBAs, we recommend an alternative agent to which the patient has been skin tested and found to be negative. Challenge/desensitization to an IgE-mediated reaction to NMBA is generally not feasible, so the suspected NMBA must be avoided.
If there is no alternative agent with a negative skin test, then the suspect agent could be used again following premedication with antihistamine and possibly glucocorticoid. However, many studies document that no premedication regimen can reliably prevent all, or even most, cases of IgE-dependent anaphylaxis, and the clinician should take all possible precautions to minimize the severity of a reaction (eg, lowest possible dose) and must be prepared to treat an adverse event. A shared decision-making discussion with the patient, anesthesiologist, surgeon, and allergist/immunologist outlining the risks and benefits of various options as well as the limitations of the testing strategy should be documented prior to repeat drug administration. (See 'General precautions' below.)
Antibiotics — Antibiotics are frequently administered before, during, or immediately after anesthesia. Beta-lactam antibiotics (specifically cephalosporins and penicillins) and vancomycin are the most common causes of antibiotic-induced anaphylaxis or reactions that resemble anaphylaxis in the perioperative setting.
Testing — Beta-lactam antibiotics cause IgE-mediated reactions that can be evaluated with appropriate skin testing. Clavulanate is a rare cause of reactions but should be considered when testing to penicillin is negative and the patient received a preparation containing clavulanate. (See "Penicillin skin testing" and "Penicillin allergy: Immediate reactions".)
Most vancomycin reactions are non-IgE-mediated and related to the rate of infusion [31,32]. Skin testing is usually not performed. However, rare IgE-mediated reactions to vancomycin are reported and should be suspected in patients who have received repeated administrations. If an IgE-mediated reaction is suspected, then skin testing with a maximum intradermal testing concentration of 10 micrograms/mL is appropriate. (See "Vancomycin hypersensitivity".)
Options for retreatment — Patients with IgE-mediated allergies to antibiotics are generally managed by avoidance of the specific culprit drug and closely related drugs. Desensitization can be performed if the culprit antibiotic is required in the future and no acceptable alternative is available. Desensitization is a process by which temporary tolerance to an agent is achieved by administering progressively increasing doses, starting at a dose less than that required to provoke symptoms.
Antibiotic desensitization by the oral route is associated with fewer risks than intravenous desensitization and is therefore preferred if an oral preparation is available. However, even oral administration may require intensive care observation if the prior reaction was life-threatening.
Since many antibiotics do not have an oral formulation, antibiotic desensitizations are often administered intravenously in an intensive care setting under the supervision of an allergy specialist. The procedure is usually accomplished over several hours. Desensitization protocols for penicillin are reviewed separately. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)
Vancomycin reactions are rarely IgE mediated, and the management of patients with non-IgE-mediated reactions is based upon the use of antihistamine premedication and slower rates of infusion. Most patients are able to tolerate repeat administration using these procedures. The use of desensitization protocols is an option for patients with recurrent reactions despite slower rates and premedication. (See "Vancomycin hypersensitivity".)
Sugammadex — Sugammadex is a synthetic compound, first introduced in 2008, which is used to rapidly reverse neuromuscular blockade (specifically rocuronium or vecuronium) after surgery is completed. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Sugammadex'.)
Sugammadex hypersensitivity reactions (HSRs) typically begin within one minute of intravenous infusion, although sometimes up to several minutes later. Hypersensitivity can occur with a first-time exposure. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Sugammadex'.)
The mechanism of sugammadex HSRs is unclear:
●Studies of healthy adult volunteers given repeated doses of sugammadex did not find consistent evidence of drug-specific IgE or IgG, direct mast cell activation, or complement activation in individuals who developed HSRs [33,34]. In addition, skin testing did not reliably identify the patients with HSRs.
●Despite the above, case reports of patients with immediate reactions, including severe anaphylaxis, demonstrated markedly positive skin testing to sugammadex and negative results to all other medications to which they were exposed, indicating that immediate-type reactions are possible [35-37].
●There is some evidence that the complex of sugammadex and rocuronium, which involves high-affinity, molecule-to-molecule binding, may become allergenic when the individual components are not [38,39]. Sugammadex binds most avidly to rocuronium and vecuronium and less avidly to pancuronium. Strategies to test for this possibility are discussed below.
Testing — The literature regarding skin testing to sugammadex is preliminary and evolving in parallel with an understanding of possible mechanisms. Until the mechanism(s) of these reactions are clear, a positive skin test to sugammadex should be interpreted as evidence of hypersensitivity, but a negative result does not exclude hypersensitivity. Testing with both sugammadex along with the sugammadex-NMBA mixture is suggested. If sugammadex is believed to be the most likely culprit in a patient with perioperative anaphylaxis, it should not be given again.
●To test for sensitization to sugammadex, SPT can be performed with the stock solution (100 mg/mL) [11,37]. European guidelines recommend IDT concentrations up to 10 mg/mL [2]. A different group identified a nonirritating concentration of 50 mg/mL for IDT [11]. Dilutions are made with normal saline.
●To test for sensitization to the combination of sugammadex and rocuronium, one group has proposed using a molar equivalent mixture of sugammadex and rocuronium. They demonstrated the minimal nonirritating concentration of the sugammadex-rocuronium mixture to be 35.71 mg/mL + 10 mg/mL for SPT and 7.14 + 2 mg/mL for IDT [11].
●In Japan, where sugammadex is used much more frequently for NMBA reversal than in most countries, a retrospective series of 49,532 patients who received anesthesia reported that 18 patients experienced anaphylaxis [40]. Six of these 18 episodes of perioperative anaphylaxis were attributed to sugammadex, whereas there were no occurrences with neostigmine. The authors concluded that neostigmine may be a safe option in subjects with a history of anaphylaxis associated with sugammadex. Other studies show sugammadex to be superior to neostigmine as a reversal agent with respect to efficacy and general tolerance [41,42]. Thus, the selection of a NMBA reversal agent in a patient with a history of perioperative anaphylaxis should be made by a shared decision involving the anesthesiologist, patient, and allergist.
Latex — Anaphylaxis to latex is an IgE-mediated process resulting from the formation of specific IgE against proteins from natural rubber latex. The incidence of latex reactions is currently much lower than in the 1990s. A 2018 national survey in the United Kingdom reported zero cases of latex anaphylaxis among 268 subjects with perioperative anaphylaxis [26]. Compared with reactions to induction agents or NMBAs, latex reactions tend to occur later in procedures (eg, 30 minutes or more after the start of the intervention and often shortly after there has been extensive contact between the surgeon's gloves and the patient's tissues).
The risk factors for developing latex allergy, the sources of latex that are found in the intraoperative setting, and the diagnosis of latex allergy are reviewed separately. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Latex' and "Latex allergy: Epidemiology, clinical manifestations, and diagnosis".)
Strategies for future care — Patients with IgE-mediated latex allergy are usually managed with strict latex avoidance and must undergo all future procedures and surgeries in latex-free environments, which are available at most hospitals. (See "Latex allergy: Management".)
Hypnotic induction agents — Induction agents historically have accounted for up to 5 percent of perioperative anaphylaxis. However, since the removal of Cremophor ER (polyethoxylated castor oil) as a solvent for many of these agents, the incidence of induction agent anaphylaxis has decreased significantly.
There are two types of induction agents: barbiturates (eg, thiopental and methohexital) and nonbarbiturates (eg, benzodiazepines, propofol, etomidate, and ketamine). Reactions caused by barbiturates can be IgE-mediated, although direct mast cell/basophil activation has also been described (table 1) [9,43-45]. Barbiturates are less commonly used than in the past. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Hypnotic induction agents'.)
Nonbarbiturate induction agents can cause direct mast cell/basophil activation in vitro [44,46]. Formation of specific IgE to these agents is rare, and skin testing is generally not recommended. Skin testing has been reported for etomidate but is of unknown value for ketamine [47]. A case report of very rare anaphylaxis to propofol was associated with a positive skin test to the phenol constituent of the preparation [48].
Cross-reactivity — The following is known about cross-reactivity among different types of hypnotic induction agents:
●Immunologic cross-reactivity among the barbiturates is possible, and skin testing may be used to select an agent less likely to result in reactions with subsequent procedures [9].
●Barbiturates may cross-react with NMBAs due to shared quaternary amine chemical structures. Caution is recommended with use of NMBAs in subjects with confirmed IgE-mediated reactions to barbiturates. Some experts recommend screening for NMBA sensitivity in subjects with IgE-mediated barbiturate reactions [19].
●There is no evidence for cross-reactivity between the barbiturate and nonbarbiturate groups.
●Cross-reactivity between benzodiazepines and propofol, the other commonly used nonbarbiturate, has not been reported.
Testing — IgE-mediated reactions to barbiturate agents are well-described. However, skin testing for barbiturate induction agents is not standardized. We begin with SPT using the diluted or undiluted drug (depending on the severity of the patient's reaction), accompanied by a positive and negative control. If there is no reaction to the drug, we then proceed to serial IDT with concentrations no higher than those listed below [2,14,29,30]. The concentrations cited below are maximal concentrations for SPT and IDT from a 2019 European guideline, except a methohexital SPT concentration was not provided and our recommendation is listed [2].
Barbiturate agents:
●Methohexital – maximal SPT 1 mg/mL; IDT 0.1 mg/mL
●Thiopental – maximal SPT 25 mg/mL; maximal IDT 2.5 mg/mL
Nonbarbiturate agents (skin testing is indicated if an IgE-mediated reaction is suspected):
●Propofol – maximal SPT 10 mg/mL; maximal IDT 1 mg/mL
●Midazolam – maximal SPT 5 mg/mL; maximal IDT 0.05 mg/mL
●Etomidate – maximal SPT 2 mg/mL; maximal IDT 0.2 mg/mL
Alternatives — For patients with either IgE-mediated or non-IgE mediated reaction to barbiturate, a non-barbiturate hypnotic agent is recommended. If a suspected reaction occurred to a non-barbiturate hypnotic, we would base the alternative on negative skin tests or switch to alternative class (eg, benzodiazepine instead of propofol). Desensitization to hypnotics is not feasible due to side effects of prolonged exposure to a sedating drug.
If a non-IgE-mediated reaction is suspected and there is no suitable alternative agent, then we generally recommend using the suspect agent again and pretreating the patient with antihistamines and possibly glucocorticoids. However, pretreatment regimens may not prevent all recurrent reactions.
Opioids — Opioids used in anesthesia are common causes of flushing and urticaria following intravenous or intramuscular administration, although these agents rarely cause life-threatening anaphylaxis. Reactions to orally administered opioids are less common and not as severe. There may be an association with the use of cough suppressants containing pholcodine and the development of IgE that cross-reacts with morphine and NMBAs [25]. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Opioids'.)
Testing — Reactions to opioids are almost always non-IgE mediated. We do not perform skin testing with opioids, since nonspecific positive responses are expected due to the nonimmunologic degranulation of dermal mast cells or nonspecific vasodilation with testing (eg, fentanyl and sufentanil). Suggested concentrations have been published if testing is desired [1,2].
Strategies to prevent recurrent reactions — Multiple preparations of opioids are available, and repeat exposure to the culprit agent is rarely necessary. We prefer the use of a different agent administered slowly. We have found that premedication is unnecessary for most patients using this approach. However, some patients will have similar reactions to other opioids. In such patients, premedication with antihistamines, with or without glucocorticoids, may help reduce the frequency and severity of recurrent symptoms [49,50].
Fentanyl is unique among opioids in its lack of mast cell-/basophil-stimulating properties. It is therefore a good option for pain management in patients who developed cutaneous reactions with other opioids [44,46,51]. However, it should be noted that fentanyl has been implicated in anaphylaxis, albeit rarely [52]. A supervised drug challenge may be considered in patients who appear to be very sensitive to opioids.
Nonsteroidal anti-inflammatory drugs — Individuals with preexisting asthma, especially if there is coexisting hyperplastic rhinosinusitis with or without nasal polyps, are at increased risk of experiencing nonallergic responses that may resemble anaphylaxis, also called pseudoallergic reactions, after administration of nonsteroidal anti-inflammatory drugs (NSAIDs). These reactions are characterized by asthma exacerbations with increased upper airway congestion and rhinorrhea. The respiratory response may be very severe and life-threatening. Generally, these reactions do not occur or have diminished severity with agents that are weak cyclooxygenase 1 inhibitors, for example acetaminophen or salsalate, or selective cyclooxygenase 2 inhibitors (celecoxib) [53]. Urticaria may also occur with certain NSAIDs, but this is not usually associated with other features of anaphylaxis, such as decrease in blood pressure or respiratory symptoms. Reactions may occur with low-dose aspirin used for antiplatelet effects. Very rarely, IgE sensitivity to NSAIDs may result in allergic reactions [54]. Allergic and pseudoallergic reactions to NSAIDs are discussed separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)
Testing — There are no reliable skin or in vitro tests to detect NSAID-induced exacerbations of chronic respiratory disease. Graded challenges with NSAIDs, such as aspirin or intranasal ketorolac compounded solution or ophthalmic solution, will detect this sensitivity, but these procedures have risk if not performed under controlled conditions. The best option is to avoid NSAIDs in the perioperative period. Challenge procedures for NSAID-pseudoallergic reactions are described elsewhere. (See "Diagnostic challenge and desensitization protocols for NSAID reactions".)
Blood products — Administration of blood products common in the perioperative period can result in a variety of immunologic reactions, including anaphylaxis. One study observed that 1.3 percent of all transfusion reactions were anaphylaxis [23]. Other complex adverse effects resemble anaphylaxis but are nonimmunologic, immunologic though not IgE dependent, or a mixture of the two. These include fluid overload, hemolytic reactions, and transfusion-related acute lung injury (TRALI) [23]. TRALI is likely the result of antibodies in the transfused material reacting with determinants on blood cells of the recipient. TRALI can mimic anaphylaxis as it results in acute shortness of breath, hypoxemia, and hypotension within one to six hours of a transfusion. It has been reported to be the third most common cause of transfusion-associated death [23]. (See "Immunologic transfusion reactions".)
Colloids — Colloid plasma expanders, such as dextran or hydroxyethyl starch (HES), are solutions of high molecular weight polysaccharides. Anaphylaxis to these agents is uncommon, with reported rates of <0.1 percent for each [23,43,55,56].
●HES is used in battle-related trauma and can also cause persistent pruritus that is refractory to therapy and can last for months [57].
●Dextran is uncommonly used, and the reaction to it is believed to be IgG mediated, so skin testing is not informative [2].
●Gelatin in plasma expanders (eg, gelofusine) has been implicated in IgE-mediated anaphylaxis [58,59]. Gelatin reactions may also be due to alpha-gal (galactose-alpha-1,3-galactose) allergy [60].
●Albumin has been implicated in rare perioperative anaphylactic reactions, although the mechanisms have not been explored [27,61].
Testing — There is limited experience with skin testing to colloids [58,59]. One case report described testing by SPT method with undiluted preparations [43], although we would suggest additional IDT with 1:100 or 1:10 dilutions if the SPT is negative. If the results are positive, we would perform the test on control individuals (the clinician and a few volunteers) to be sure the positive is not a nonspecific irritant reaction.
Published skin testing concentrations are available for HES:
●Maximal SPT 60 mg/mL; maximal IDT 6 mg/mL
In vitro tests for IgE specific to gelatin and alpha-gal are commercially available, and skin testing is also possible, as reviewed elsewhere. (See "Allergic reactions to vaccines", section on 'Testing for vaccine constituents' and "Allergy to meats", section on 'Available tests'.)
Radiocontrast agents — The management of patients with past reactions to radiocontrast agents is reviewed separately. (See "Patient evaluation prior to oral or iodinated intravenous contrast for computed tomography", section on 'Patients with past reactions to contrast'.)
Blue dyes — Blue or aniline dyes, particularly isosulfan blue, patent blue V, and methylene blue, are used to identify sentinel lymph nodes that are associated with specific anatomic areas with confirmed or suspected malignancy. This technique is used especially with breast cancer. Isosulfan blue has a warning in the package insert of a risk of anaphylaxis of 1 to 3 percent, and sustained and biphasic reactions have also been described [62]. A single-center, retrospective review reported that 2 of 1163 subjects (0.17 percent) exposed to isosulfan blue during surgery experienced a reaction. No life-threatening reactions occurred, and the two subjects experienced urticaria [63]. The risk of anaphylaxis is probably similar with the chemically related supravital dye patent blue V and lower with methylene blue [62,64-68].
Testing — SPT and IDT may identify the cause of prior anaphylaxis or assess subjects at increased risk for subsequent procedures [2,62,69]. Although additional information is needed to evaluate the positive and negative predictive value of such testing, including the threshold for nonspecific skin irritation, skin testing has been reported with the following concentrations:
●Patent blue V [2,14,69]:
•Maximal SPT: 1:10 dilution, increasing if negative to undiluted (25 mg/mL)
•Maximal IDT: 1:100 dilution or a 1:10 dilution (2.5 mg/mL)
●Methylene blue [2,14]:
•Maximal SPT: Undiluted (10 mg/mL)
•Maximal IDT: 0.1 mg/mL
●Isosulfan blue [64,70]:
•Maximal SPT: 1:10 dilution (particularly if prior reaction was very severe), followed by undiluted (1 percent stock)
•Maximal IDT: 1:1000, 1:100, and then 1:10 dilution
Alternatives — Subjects with past history of reaction to isosulfan blue could be assessed for sensitivity to methylene blue or vice versa, but the predictive value of allergy skin testing is not established. Methylene blue is less likely to result in HSRs [66]. Radioactive colloid may be used as an alternative to sentinel node detection, but the inability of the surgeon to visually confirm the node limits this approach. Antihistamine and glucocorticoid pretreatment is not supported by specific evidence but may be helpful with mild or atypical reactions.
Antiseptics — Chlorhexidine and povidone iodine (Betadine) are topical agents used as surgical preparations to reduce bacteria on cutaneous or mucosal surfaces. Both antiseptics can cause anaphylaxis. The likelihood of a reaction is increased if these solutions are applied to a disrupted or injured surface. The solvent for the antiseptic may also influence the likelihood of a reaction, as alcohol solutions of chlorhexidine are associated with more reactions than chlorhexidine in other solvents. Chlorhexidine is found in a wide variety of commercial cosmetic products used largely by females [71]. One study found positive IgE chlorhexidine tests in 9.6 percent of 228 cases of perioperative anaphylaxis [72].
Testing — Recommendations are based upon case reports or small case series [72-76]. Skin testing and/or in vitro testing are possible. There are no validated provocation protocols for antiseptics.
●Chlorhexidine [2,74,76]:
•Maximal SPT: 5 mg/mL or 0.5 percent
•Maximal IDT: 0.002 mg/mL of a sterile, uncolored, alcohol-free solution [2]
•An in vitro IgE test using an enzyme-linked immunosorbent assay (ELISA) methodology is available [77]; histamine release assays are available commercially in some countries [72]
•Maximal SPT: 100 mg/mL; IDT is not recommended
Alternatives — Subjects with a history of anaphylaxis and/or positive testing with an antiseptic should be treated with an alternative antiseptic. There is no cross-reactivity between chlorhexidine and povidone iodine, so a patient with an allergy to one could make use of the other.
OUTCOMES OF REPEAT ANESTHESIA AFTER ALLERGY EVALUATION — Several studies have examined recurrence rates in patients with perioperative anaphylaxis who subsequently underwent an allergy evaluation and then required repeat anesthesia [78-82]. In these studies, between 1 and 8 percent of patients experienced recurrent perioperative anaphylaxis.
In a representative retrospective analysis, 70 patients with perioperative anaphylaxis were evaluated at a single drug allergy clinic and subsequently required repeat anesthesia (63 underwent general anesthesia), during which three patients experienced repeat anaphylaxis [78]. Following the initial reaction, patients were evaluated with a combination of skin testing and drug-specific IgE testing (when available), and a culprit drug was identified in 55 of 70 cases. As in other studies, neuromuscular-blocking agents (NMBAs) and beta-lactam antibiotics were the most common causes. If a culprit drug could not be identified, a plan was formulated for avoidance of drugs with the highest probability of causing anaphylaxis. In two of the three cases with repeat anaphylaxis, inadequate information had been supplied in the initial anesthesia report, and the evaluation had not included the culprit agents (the disinfectant chlorhexidine and the colloid gelofusine). The third patient was eventually diagnosed with systemic mastocytosis (with normal baseline serum tryptase) after a total of three reactions to unrelated medications. Mast cell disorders are a known risk factor for perioperative anaphylaxis. These data again emphasize the importance of accurate, thorough historical information and the consideration of mast cell disorders when evaluating subjects with perioperative anaphylaxis. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Risk factors'.)
APPROACH TO FUTURE ANESTHESIA — The safest approach for managing future anesthesia in a patient who suffered perioperative anaphylaxis is avoidance of the culprit agent [83,84]. Therefore, every effort should be made to identify the responsible trigger. Unfortunately, even a very thorough evaluation may reveal no evidence of allergy to one specific agent. In these cases, future management involves avoidance of high-risk agents and adherence to the general precautions discussed in this section. The disadvantage of this approach is that the patient is restricted to receiving multiple second-line agents. In other cases, a positive skin test result may be obtained to more than one agent, raising the possibility that one or more results are false positives. This is a particular concern with the neuromuscular-blocking agents (NMBAs) or opioids. Future use of alternate NMBAs with negative skin tests is likely safe.
General precautions — For any patient with a history of perioperative anaphylaxis, there are several general precautions that should be applied to future procedures requiring anesthesia. A 2018 national survey in the United Kingdom found the risk for serious perioperative anaphylaxis to be increased by obesity, chronic pulmonary disease, beta-blocker therapy, angiotensin-converting enzyme (ACE) inhibitor therapy, and greater preoperative physiologic dysfunction as defined by the American Society of Anesthesiology's physical status classification system [26]. A more detailed discussion of risk factors is found separately. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Risk factors'.)
●Patients with asthma should have respiratory symptoms as well controlled as possible prior to receiving anesthesia. (See "Evaluation of perioperative pulmonary risk".)
●Beta-blockers should be avoided, if possible, especially if the culprit agent could not be conclusively identified. Beta-blockers may increase the severity of anaphylaxis and reduce responsiveness to epinephrine. However, some patients may have cardiovascular conditions for which beta-blockade is critical, and these cases require multidisciplinary consideration. (See "Anaphylaxis: Acute diagnosis", section on 'Concurrent medications'.)
●Angiotensin-converting enzyme (ACE) inhibitors may interfere with compensatory physiologic responses to anaphylaxis and exaggerate bradykinin-induced vascular changes, although these data are not robust. The decision to discontinue these medications prior to repeat anesthesia depends upon the severity of the reaction and on whether a specific cause could be implicated. (See "Anaphylaxis: Acute diagnosis", section on 'Concurrent medications'.)
●Drugs that can cause direct histamine release from mast cells and basophils (eg, morphine, vancomycin, quaternary NMBAs) should be administered as slowly as possible, particularly if they are infused in close temporal proximity to each other (table 1). Drugs that do not have these properties (if available) should be given instead.
●Intraoperative antibiotics should be administered slowly, with careful hemodynamic monitoring. When possible, loading or initial doses should be given prior to induction of anesthesia while the patient is awake and not concomitantly with multiple other anesthetic agents.
●Verification that baseline total serum tryptase is not elevated may be helpful to identify subjects at increased risk of anaphylaxis due to clonal mast cell disorders (>11 ng/mL) or mastocytosis (>20 ng/mL). Additional precautions should be implemented in such individuals, as they are at increased risk of anaphylaxis in general.
●Documentation of a shared decision-making discussion with the patient is important, since there are limited, validated testing options to facilitate a decision for the best course of action in repeat surgery. The discussion should include the risks, the limitations of the risk assessment, and options for surgery. Ideally, the process should involve the allergist and the surgical team.
Alternate forms of anesthesia — Alternate forms of anesthesia have the potential advantage of avoiding the use of NMBAs and hypnotic induction agents. In addition, patients are awake and able to communicate symptoms, such as pruritus or dyspnea. However, these forms of anesthesia may not be appropriate for many surgeries.
●Local anesthesia or nerve blocks may be adequate in a few situations. If the patient has a history of reacting to local anesthetic agents, then skin testing and challenge can be performed in advance to the drug that will be used to ensure that there is no evidence of IgE-mediated allergy. Preservatives in some local anesthetic preparations can result in positive skin tests but very rarely cause anaphylaxis [85]. (See "Allergic reactions to local anesthetics".)
●Spinal or epidural anesthesia can be used for relatively minor surgeries below the diaphragm, although perioperative anaphylaxis has been reported in patients receiving these forms of anesthesia [86]. The rate of recurrent reactions in patients who initially reacted during general anesthesia and later received spinal anesthesia is unstudied. In addition, the clinician should be mindful that the patient is essentially sympathectomized (below the level at which the anesthesia is introduced), reducing the baseline blood pressure and decreasing responsiveness to epinephrine and other sympathomimetic agents that would be needed if anaphylaxis were to recur. This is particularly concerning in cases in which a culprit drug could not be identified. Thus, the general precautions noted above must still be applied.
SOCIETY GUIDELINE LINKS — The approach outlined in this topic is consistent with guidelines from various professional societies around the world [1,2,87,88]. Links to society and government-sponsored anaphylaxis guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anaphylaxis".)
SUMMARY AND RECOMMENDATIONS
●Evaluation – The evaluation of perioperative anaphylaxis involves a clinical history, review of records of the event, and review of any tests for mast cell mediators that were obtained at the time. If an immunoglobulin (Ig)E-mediated reaction is suspected or likely, skin testing (or, far less commonly, in vitro testing) for allergen-specific IgE should be considered. (See 'Evaluation' above.)
●Consider mast cell disorders – A elevated serum tryptase level obtained at the time of the reaction can be invaluable in identifying the episode as anaphylaxis. Serum total tryptase should be repeated when the patient has fully recovered as a screen for rare mast cell disorders. An elevated tryptase level after recovery, when the patient is in their baseline state, should prompt referral to an allergist for evaluation of a possible mast cell disorder. Patients with mast cell disorders may react to multiple unrelated drugs and agents. (See 'Tests for mast cell mediators' above.)
●Skin testing for agents that cause IgE-mediated reactions – Perioperative anaphylaxis can result from more than one mechanism, and it is important to understand which mechanisms are associated with each agent, as well as what type of testing is relevant for that mechanism (table 1). IgE-mediated reactions are most common with neuromuscular-blocking agents (NMBAs) (muscle relaxants), antibiotics (particularly penicillins and cephalosporins), latex, blue dyes, and barbiturate induction agents. Skin tests can be performed for each of these agents. Skin testing should be performed by allergy specialists. (See 'Skin testing' above and 'Skin testing to specific agents' above and 'Referral' above.)
●Limited role of in vitro tests – In vitro tests for allergen-specific IgE are available for latex and a very limited number of other agents (eg, penicillin and NMBAs in some countries). In vitro testing is generally less sensitive than skin testing. (See 'Limited role of in vitro testing' above.)
●Utility of allergy evaluations – In several series of patients with perioperative anaphylaxis who subsequently underwent an allergy evaluation and then required anesthesia again, repeat anaphylaxis occurred in up to 8 percent of individuals. (See 'Outcomes of repeat anesthesia after allergy evaluation' above.)
●Options for future anesthesia – The safest management approach for a patient with past anaphylaxis is the definitive identification and complete avoidance of the trigger. However, sometimes evaluation is not possible or a culprit drug/agent cannot be identified. In these situations, future management is based upon avoidance of high-risk agents and implementation of several precautionary measures. Precautionary measures for future anesthesia include optimal preoperative control of asthma, slow administration of antibiotics and other high-risk agents, and avoidance (when possible) of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and drugs that cause direct histamine release from mast cells/basophils. Spinal or epidural anesthesia may be an option in some cases. (See 'Approach to future anesthesia' above.)
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