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Perioperative anaphylaxis: Clinical manifestations, etiology, and management

Perioperative anaphylaxis: Clinical manifestations, etiology, and management
Literature review current through: Aug 2023.
This topic last updated: Sep 23, 2022.

INTRODUCTION — Patients undergoing general anesthesia and surgery can experience complex physiologic changes, which may complicate recognition of an allergic reaction.

The prevalence, etiology, risk factors, clinical manifestations, and acute diagnosis of anaphylaxis during general anesthesia are reviewed here. The evaluation of a patient who has experienced perioperative anaphylaxis, skin testing to the drugs that cause immunoglobulin E (IgE)-mediated reactions, and prevention of recurrent reactions, as well as the treatment of anaphylaxis from any cause, are discussed separately. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions" and "Anaphylaxis: Emergency treatment".)

INCIDENCE — Estimates of the incidence of anaphylaxis during general anesthesia have ranged from 1:350 to 1:20,000, with more recent studies narrowing this range to 1 case for every 1000 to 10,000 episodes of anesthesia [1-8]. The wide variability in estimates of prevalence and incidence reflects the difficulties in determining the denominator (or the total number of anesthesia cases), as well as limitations in diagnosing perianesthetic anaphylaxis.

Perioperative anaphylaxis occurs in children less frequently than in adults (ie, approximately 1 in 37,000 cases), but clinical manifestations and culprit drugs are similar [9,10]. The incidence is equal in prepubertal girls and boys but greater in adult females than males [1].

MECHANISMS OF ANAPHYLAXIS — Anaphylaxis is an acute, potentially lethal, multisystem syndrome almost always resulting from the sudden release of mast cell- and basophil-derived mediators into the circulation [11-15]. (See "Pathophysiology of anaphylaxis".)

In this review (and increasingly in the literature), the term "anaphylaxis" applies to all of the following mechanisms of acute reactions (table 1) [16]:

IgE-dependent mechanisms, which account for approximately 60 percent of perioperative anaphylaxis [17].

Non-IgE-dependent immunologic mechanisms (formerly called anaphylactoid); included in this category are reactions mediated by IgG or IgM antibodies or by antigen-antibody complexes and complement.

Nonimmunologic mechanisms (formerly called anaphylactoid) involving direct release of histamine and other mediators from mast cells and basophils [18-22]. The receptor MRGPRX2 was identified in 2015 and may be responsible for reactions to quinolone medications (eg, ciprofloxacin), icatibant, general anesthetics (eg, rocuronium, atracurium), vancomycin, and other drugs with the central tetrahydroisoquinoline (THIQ) motif [21,23,24].

The various mechanisms leading to activation of mast cells and basophils are increasingly grouped together under the term "anaphylaxis" because the initial management of these reactions is the same, regardless of the trigger or mechanism involved, and the clinical severity of the reactions may be similar [11,12]. In addition, several of the agents that are commonly implicated in perioperative anaphylaxis, such as neuromuscular-blocking agents, are capable of causing reactions through more than one mechanism (table 2).

Despite the similarities, there are important differences in the evaluation, prevention, and prognosis of the various types of reactions (table 1):

Immediate-type skin testing methods (ie, prick-puncture and intradermal techniques) are only useful in evaluating IgE-mediated reactions.

The severity of immunologically-mediated reactions may increase with subsequent administration of the causal agent, while the severity of repeat reactions arising from nonimmunologic mechanisms usually remains similar.

The severity of anaphylaxis associated with specific IgE to the culprit agent is often more severe than anaphylaxis in which specific IgE cannot be identified [1,25].

Some IgE-mediated reactions are amenable to desensitization techniques if repeat anesthesia is required.

Reactions to radiocontrast media, usually mediated by a nonimmunologic mechanism related to osmolarity, can be reduced in frequency and intensity with use of iso-osmolar contrast. Pretreatment with antihistamines and glucocorticoids has not been demonstrated to provide added preventative benefit when iso-osmolar contrast agents are used [26]. (See "Patient evaluation prior to oral or iodinated intravenous contrast for computed tomography", section on 'Prevention'.)

ETIOLOGIES — The more common identifiable causes of perioperative anaphylaxis are antibiotics, neuromuscular-blocking agents (NMBAs), chlorhexidine, and patent blue and other blue dyes [8]. However, there is a much longer list of agents that are implicated less commonly and include blood products, the NMBA reversal agent sugammadex, hypnotic induction agents, opioids, colloids, and latex. In a significant number of cases, no specific trigger can be identified.

The best longitudinal data about perioperative anaphylaxis are derived from a series of multicenter French surveys, which began in the mid-1990s and have continued to the present [1,27-29]. The causes of perioperative anaphylaxis can be divided into two groups (ie, more common and less common).

More common — Among cases in which a trigger could be identified, the more common causes were [1,5,8,29-34]:

Antibiotics, especially penicillins and cephalosporins (most common cause in several American and some European studies)

NMBAs (most common cause in many European studies)

Chlorhexidine

Blue dyes (also known as vital dyes, including isosulfan blue, patent blue V, methylene blue)

These same medications have been implicated in studies around the world, although the rank order may differ. Specifically, antibiotics appear to be the most common cause of perioperative anaphylaxis in the United States and the United Kingdom (UK), while NMBAs are the leading cause in most European studies [29,35,36].

Antibiotics — Antibiotics, administered before, during, or immediately after anesthesia, are the leading cause of IgE-mediated perioperative anaphylaxis in the United States, the UK, and Spain, accounting for approximately 50 percent of reactions [4,8,36-39]. In other European countries, antibiotics are the second most common cause, and were responsible for 12 to 15 percent of identifiable triggers in the French studies [1,31]. Beta-lactam antibiotics (specifically penicillins and cephalosporins), which cause IgE-mediated anaphylaxis, and vancomycin, which usually causes reactions due to direct histamine release from mast cells, are the most common offenders [30,31,40-43]. Quinolones are infrequently but increasingly incriminated. Hypersensitivity reactions to these agents are reviewed elsewhere. (See "Penicillin allergy: Immediate reactions" and "Cephalosporin hypersensitivity: Clinical manifestations and diagnosis" and "Vancomycin hypersensitivity".)

Neuromuscular-blocking agents — NMBAs (also called muscle relaxants) were the most common identifiable trigger in the French surveys, accounting for 30 to 70 percent of anaphylaxis cases [1,29-31,44]. NMBAs can cause anaphylaxis through both IgE-mediated and nonimmunologic, direct mast cell activation (table 2) [22,45-47]. Commonly implicated agents include rocuronium, succinylcholine (also known as suxamethonium), atracurium, pancuronium, tubocurarine (no longer available in the United States and Canada but used elsewhere), and vecuronium, although this list may largely reflect the frequency with which these agents are used [30,31]. In the 2018 United Kingdom prospective registry, succinylcholine was the most common cause of anaphylaxis among the NMBAs. The reaction rate was equal among the nondepolarizing agents (ie, rocuronium and cisatracurium), with the occurrence reflecting the frequency of use [8]. The data also show that for succinylcholine, a depolarizing NMBA, anaphylaxis more commonly manifests as bronchospasm, whereas atracurium anaphylaxis presents primarily with hypotension, potentially due to its ability to produce non immunologic histamine release. Thus, there may be subtle differences in the incidence of anaphylaxis based on the culprit NMBA.

Allergy to NMBAs is more common in women than men, with three of four reactions occurring in females [1,44]. IgE sensitization is believed due to cross-reactive tertiary or quaternary ammonium groups found in both NMBAs and a variety of topical cosmetics and personal products, as well as certain over-the-counter cough remedies (ie, pholcodine, commonly used in France, Norway, and other European countries) [48-51]. These ammonium groups are highly immunoreactive, multivalent epitopes, which can induce specific IgE antibodies. Sensitization through exposure to nonmedication agents may explain why allergic reactions to NMBAs occasionally occur upon initial exposure.

There may be a specific receptor on mast cells activated by NMBAs as well as other drugs, such as fluoroquinolones and vancomycin [21]. This receptor is designated Mas-related G-protein coupled receptor X2 (MRGPRX2) and has the capability of binding to a variety of ligands, resulting in mast cell activation clinically resembling an immune response. In addition to NMBAs, MRGPRX2 activators include substance P and peptidergic drugs, such as icatibant, used to treat hereditary angioedema by blocking the bradykinin receptor. A specific inhibitor of MRGPRX2 in animal models blocks IgE-independent anaphylaxis.

Reactions resulting from IgE-mediated allergy generally are less common, although usually more severe, than reactions due to other mechanisms such as direct mast cell activation. Histamine release may be greater with certain NMBAs, such as tubocurarine, mivacurium (where available), atracurium, and rapacuronium, agents that are seldom used or no longer available. Rapacuronium was withdrawn from the United States market because it was implicated in high rates of severe bronchospasm (without other symptoms) [52].

It is possible that the prevalence of sensitization to NMBAs is overestimated. The high rate of reactions attributed to NMBAs in some studies may be based on positive skin testing results without confirmatory challenge, and these drugs can cause nonspecific mast cell release, causing false-positive skin test results. False positive immediate hypersensitivity NMBA skin tests may also be due to cross-reactivity with other products (cosmetics or the cough medicine pholcodine) resulting in a positive skin test without clinical allergy [51]. Skin testing to NMBAs and cross-reactivity among these drugs are discussed separately. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions", section on 'Neuromuscular-blocking agents'.)

Chlorhexidine — Chlorhexidine is a topical antiseptic and surgical scrub that is increasingly implicated in perioperative anaphylaxis [32,53-61], accounting for 9 percent of the cases reported in the 2018 UK prospective registry [8]. Reported culprit products include antiseptic solutions applied to surgical fields (especially mucosal surfaces) and urethral lubricants. Central venous catheter tips impregnated with chlorhexidine have also been implicated [62]. This compound is found in nonmedical products such as toothpastes, antiseptic mouthwashes, bathing solutions, and lozenges. Patients may become sensitized through exposure to such products.

Blue dyes — Isosulfan blue dye and the closely-related patent blue V are used in lymph node mapping, most commonly in patients with breast cancer, genitourinary cancers, and malignant melanoma. These blue dyes have many other commercial names and are also used as food dyes [63]. Allergic reactions ranging from mild (blue-colored urticaria or pruritus) to severe (hypotension) have been reported to both dyes [8,63-72]. In reviewing medical records regarding exposures relative to perioperative anaphylaxis, it is worth noting that blue dyes are often not listed on the anesthesia record because they are typically not administered by the anesthesiologist. Instead, their administration may be described in the operative report, because they are usually administered by the surgeon [73]. Skin testing is discussed separately. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions", section on 'Blue dyes'.)  

Less common — In the French studies mentioned previously, the following groups of agents were implicated in less than 10 to 15 percent of reactions [1]:

Colloids and plasma volume expanders

Hypnotic induction agents

Opioids

Latex

Other agents

Colloids and plasma expanders — Colloids and plasma expanders, such as dextran or hetastarch (hydroxyethyl starch [HES]), accounted for approximately 3 percent of identifiable causes of perioperative anaphylaxis in large series [30,31,74]. These agents are capable of causing both IgE-mediated and non-IgE-mediated immunologic reactions. Reported rates of anaphylaxis were <0.1 percent of administrations for each of several preparations [44,75,76]. Hetastarch is used in major surgeries expected to cause significant fluid shifts (eg, trauma). Dextran is less commonly used as a volume expander, but its antiplatelet effects make it useful as an adjunct to some vascular procedures.

Human albumin has also been implicated in rare perioperative anaphylaxis, although the mechanisms have not been explored [77,78]. In addition, gelatin in the plasma expanders polygeline (eg, Haemaccel) and succinylated gelatins (eg, Gelofusine) has caused IgE-mediated anaphylaxis [8,79-82]. Gelatin-containing plasma expanders are not in use in the United States, although they are used in other countries. Some gelatin-induced anaphylaxis may be related to alpha-gal allergy. (See 'Role of alpha-gal allergy' below.)

Sugammadex — Sugammadex is a highly charged cyclodextrin that rapidly encapsulates and inactivates steroidal NMBAs (ie, rocuronium or vecuronium) [83-88]. It forms a high affinity complex with the NMBA in plasma, thereby reducing the amount of the NMBA available to bind to nicotinic receptors in the neuromuscular junction, which results in rapid reversal of neuromuscular blockade. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Sugammadex'.)

Since its introduction in the European Union in 2008 and subsequently in other countries, sugammadex has been increasingly implicated as a cause of perioperative anaphylaxis [85]. A 2014 systematic review estimated that anaphylactic reactions occur in 1:3500 to 1:20,000 exposures, while a large 2018 series from the United Kingdom reported a lower rate of 1:64,000 exposures [38,89]. A Japanese study estimated the rate of anaphylaxis to be similar to that caused by NMBAs, although this may be partly explained by relatively widespread use of sugammadex in that country [83]. Possible mechanisms for these reactions are discussed separately. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions", section on 'Sugammadex'.)

Hypersensitivity reactions to sugammadex typically appear rapidly after intravenous administration (ie, usually within one minute but sometimes up to several minutes later) and can occur with first-time administration. Risk factors have not been identified. Reactions can manifest as clinically significant airway edema and bronchospasm, and if this develops after extubation, reintubation may be required [90-92]. Repeat administration of sugammadex following a suspected reaction is contraindicated.

Hypnotic induction agents — Hypnotic induction agents previously accounted for approximately 2 percent of perioperative anaphylaxis cases, but the prevalence of reactions to these agents is declining [1]. There are two types of induction agents: barbiturates (eg, thiopental, methohexital) and nonbarbiturates (eg, propofol, etomidate, ketamine, benzodiazepines). (See "General anesthesia: Intravenous induction agents".)

Barbiturates – Allergic reactions to IV barbiturates are becoming an uncommon cause of perioperative anaphylaxis. Thiopental and thiamylal are no longer available in the United States but are still used in some other countries. Hypersensitivity reactions to these agents affect females more often than males [31,45]. Most reactions caused by barbiturate induction agents are IgE-mediated, although direct mast cell activation has also been described (table 2) [19,44,93,94]. There is some immunologic cross-reactivity among the barbiturates [93].

Nonbarbiturates – The nonbarbiturate induction agents most commonly used are propofol and benzodiazepines. Both are rare causes of allergic reactions and there is no evidence of cross-reactivity between the two.

Anaphylaxis to propofol can occur but appears to be unrelated to underlying food allergies. Propofol is a nonbarbiturate induction agent that was initially solubilized in Cremophor (polyethoxylated castor oil), a vehicle that was implicated in non-IgE-mediated anaphylaxis [95]. Subsequently, the vehicle for propofol was changed to a soybean oil emulsion with egg phosphatide and glycerol [95-97]. Allergic reactions to these newer preparations are even more rare. Although allergies to egg or soybean are listed in the product information as contraindications to use [98], the vast majority of egg-, peanut- and soy-allergic subjects tolerate propofol [99]. In a study of pediatric patients with egg, peanut, soy, or legume allergy, children with these allergies tolerated propofol at the same rate as nonallergic children [100].

Benzodiazepines are also nonbarbiturate induction agents. Hypotension following intravenous administration is a known adverse effect of these agents, although anaphylaxis is very rare [101]. Benzodiazepines may be capable of activating mast cells in vitro [19]. Skin testing with benzodiazepines has been reported [102], although the significance of a positive wheal-and-flare skin reaction is unknown.

Opioids — Opioids used in anesthesia/analgesia are a common cause of flushing and urticaria following intravenous administration, although opioids rarely cause life-threatening reactions. Typically, opioids cause limited cutaneous symptoms that are non-IgE-mediated. Morphine or meperidine can cause degranulation of dermal mast cells and release of histamine and other mediators, leading to flushing and urticaria, although rarely angioedema, bronchospasm, or hypotension [22].

Specific IgE to morphine or fentanyl has been implicated in case reports, although skin testing with opioids requires specific dilutions and cautious interpretation, because direct mast cell activation, particularly by morphine and codeine, can result in false-positive results [103,104]. Fentanyl and sufentanil are less likely to directly activate mast cells but may cause mast cell degranulation through specific mu receptors. However, testing with fentanyl and sufentanil may cause false-positive results due to direct vasodilation [105]. Skin testing to opioids is reviewed separately. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions", section on 'Opioids'.)

Latex — Natural rubber latex historically has accounted for approximately 20 percent of perioperative anaphylaxis cases and is still a common cause in countries in which latex gloves are used routinely [1,30,31]. However, exposure to latex has been dramatically reduced in most surgical suites in the United States and other countries. The 2018 United Kingdom national registry reported no cases of latex allergy among 266 patients with grade 3 or 4 perioperative anaphylaxis, possibly due to awareness of medical personnel and patients regarding this possibility, as well as increasing use of latex-free materials in hospital settings [8,106].

Anaphylaxis to latex is an IgE-mediated process resulting from the formation of specific IgE against proteins from natural rubber latex. There are a variety of potential sources of latex in surgical and procedural settings (table 3). The most common sources of significant latex exposure in the perioperative setting are flexible items from which latex allergen is easily eluted and that have prolonged contact with skin or mucosal surfaces, such as:

Gloves (sterile and exam)

Drains (Penrose and others)

Catheters (indwelling, straight, and condom)

Hard rubber items, such as straps, tubing, and blood pressure cuffs, elute little or no latex protein and do not contact patient tissues to the same extent as surgical gloves, catheters, and drains. Items that are usually latex-free include bags used in manual ventilation, leg straps for catheter bags, bandages and adhesive pads, tape, electrode pads, endotracheal tubes, infusion sets and ports, and suction catheters.

Reactions to latex tend to occur later in surgical procedures (eg, 30 minutes or more after the start of the intervention). Symptoms may develop after visceral surfaces have been handled or manipulated by surgeons wearing latex gloves.

Latex allergy is more likely in subjects with repeated exposure to latex gloves or catheters from prior surgeries or from occupational use, especially children with spina bifida and health care workers [107]. Sensitization to latex can occur as a result of contact with nonmedical sources of latex as well (eg, condoms, balloons, household gloves), and reactions are not limited to patients in high-risk groups. Latex allergy is reviewed in detail separately. (See "Latex allergy: Epidemiology, clinical manifestations, and diagnosis" and "Latex allergy: Management".)

Other agents — A variety of other medications and agents have been implicated in anaphylaxis or reactions resembling anaphylaxis [5,18]. Collectively, these other agents account for less than 5 percent of all episodes of perioperative anaphylaxis [1]. Some of these agents are not administered by the anesthesiologist, but awareness of their potential to cause anaphylaxis is necessary for prompt recognition and treatment [106]. Skin testing protocols for some of these agents are discussed separately (see "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions", section on 'Skin testing to specific agents'):

Radiocontrast agents (see "Diagnosis and treatment of an acute reaction to a radiologic contrast agent")

Blood transfusion (see "Immunologic transfusion reactions")

Metabisulfites and bisulfites used as preservatives in medications [108-112]

Nonsteroidal anti-inflammatory drugs (see "NSAIDs (including aspirin): Allergic and pseudoallergic reactions")

Povidone in the topical antiseptic povidone-iodine [113,114]

Bacitracin used in irrigation solutions [115-119]

The sterilization agents ethylene oxide and ortho-phthalaldehyde (Cidex OPA [brand name]) [120-125]

Streptokinase or urokinase [126,127]

Chymopapain (used in herniated disc surgery) and papain [128-131]

Insulin [132,133] (see "Hypersensitivity reactions to insulins")

Local anesthetics [134,135] (see "Allergic reactions to local anesthetics")

Protamine, used to reverse heparinization [136-138] (see "Hypersensitivity reactions to insulins", section on 'Protamine')

Aprotinin, administered either intravenously or as a component of biologic sealants [1,20,139,140]

Hyaluronidase, used to enhance the diffusion of other drugs and agents [141-145]

Heparin and other anticoagulants: These reactions have been attributed to several mechanisms, including an IgG immune response to platelet factor 4 [146], as well as IgE-mediated reactions to unidentified antigens [147] (see 'Role of alpha-gal allergy' below and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Anaphylaxis')

Gelatin-containing surgical sponges and topical bovine thrombin hemostatic agents [148,149] (see 'Role of alpha-gal allergy' below)

Role of alpha-gal allergy — Some cases of anaphylaxis attributed to animal-derived products, such as gelatin-based colloids [150], bovine or porcine heart valves [151], heparin, and hemostatic agents derived from gelatin (eg, gelfoam powders, sponges, etc), may be caused by allergy to the carbohydrate moiety galactose-alpha-1,3-galactose (also called alpha-gal) [152], although there are other potential allergens in these products. Alpha-gal allergy has been reported in the Southeastern United States, as well as areas of Europe, Asia, and Australia. Alpha-gal is present in the tissues of all mammalian species except catarrhines (ie, primates including humans, chimpanzees, baboons, macaques, orangutans, and other old world monkeys but not new world monkeys). Thus, catarrhines can develop an allergy to tissues and material derived from other mammals. The risk of alpha-gal allergy may be suspected if patients report delayed allergic reactions following ingestion of mammalian meats, most commonly beef, pork, and lamb. Reactions range in severity from transient urticaria to anaphylaxis and are typically delayed by several hours. Understanding of the role of alpha-gal versus other allergens in these reactions is evolving and the prevalence of this allergy is uncertain and varies regionally and seasonally. A positive history would not necessarily preclude the use of animal-derived products, but the surgical team should have increased vigilance so that reactions are detected promptly. Case reports have described successful use of premedications as well [153]. Alpha-gal allergy is discussed in more detail separately. (See "Allergy to meats", section on 'Alpha-gal'.)

RISK FACTORS — Risk factors for perioperative anaphylaxis include female sex (for certain medications), mast cell disorders, multiple past surgeries or procedures (especially for latex, neuromuscular-blocking agents [NMBAs], and ethylene oxide), and history of anaphylaxis, allergic drug reactions, or other allergic conditions (such as asthma, eczema, or hay fever). In addition, a 2018 registry identified obesity, a higher level on the American Society of Anesthesiologists Physical Status Classification system (table 4), and beta-blocker and/or angiotensin-converting enzyme inhibitor therapy as risk factors for death or cardiac arrest among 286 cases of more severe perioperative anaphylaxis [8]. However, even in patients at increased risk, perioperative anaphylaxis is an uncommon event.

Patients with asthma or chronic obstructive pulmonary disease are at greater risk for fatal anaphylaxis from a variety of causes and may be at higher risk for perioperative anaphylaxis, although data are mixed [1,7,154,155].

Females are at higher risk than males for reactions to NMBAs and hypnotic induction agents, although reactions are equal for males and females before adolescence.

Previous medication reactions nonspecifically increase the possibility of future adverse medication reactions, and multiple previous drug reactions pose a proportionately greater risk.

Patients with multiple past surgeries or other procedures may be at increased risk for latex allergy and reactions to NMBAs. (See "Latex allergy: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

Certain types of surgeries, including transplants and hematologic, cardiac, or vascular procedures, were associated with higher risk in one series [7].

Patients with mast cell disorders, including hereditary alpha tryptasemia, idiopathic mast cell activation syndrome, monoclonal mast cell activation disorder, and systemic mastocytosis, are at increased risk for clinically significant mast cell-mediator release from a variety of stimuli, including the administration of medications that cause nonspecific mast cell activation and physiologic events during surgery (eg, handling of the bowel, extremes of temperature) [156]. Thus, these patients require specific precautionary management prior to procedures or surgery. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis", section on 'Preparation for medical, surgical, and radiologic procedures'.)

CLINICAL MANIFESTATIONS AND DIAGNOSIS

Characteristic signs and symptoms — Anaphylaxis in any setting is diagnosed clinically, based on the presence of characteristic signs and symptoms that begin suddenly and progress rapidly in most cases (table 5). There is no definitive test to prove or disprove anaphylaxis. The diagnosis of perioperative anaphylaxis is also made clinically.

There are important differences in the presentation of anaphylaxis in an intubated and sedated patient compared with an ambulatory patient (table 6) [157,158]:

Perioperative anaphylaxis is more likely to present as sudden changes in cardiovascular or respiratory parameters [8,66]. This is because early or mild symptoms, such as itching or shortness of breath, may go unnoticed if the patient cannot communicate, and skin symptoms may not be visible if the skin is draped or covered. Cardiovascular collapse, which can present with signs ranging from hypotension to cardiac arrest, is the first detected manifestation in up to 50 percent of cases [8,11].

Hypotension is common during anesthetic induction (especially with propofol). Recognizing hypotension that is part of anaphylaxis can also be complicated by the effects of positive pressure ventilation, surgical manipulation, and sympathectomy associated with spinal/epidural anesthesia. Additional causes of hypotension are discussed below. (See 'Other causes of hypotension/shock' below.)

Bronchospasm may present as a sudden increase in the ventilatory pressure required to inflate the lungs, an upsloping pattern in the end-tidal carbon dioxide waveform or a decrease in arterial oxygen saturation.

Rapidly developing laryngeal edema may present as difficulty with intubation or as postextubation stridor.

Tachycardia is a classic cardiovascular sign of anaphylaxis, although bradycardia occasionally develops later in the reaction if the patient becomes hypoxemic or develops heart block [159].

As a result of these factors, anaphylaxis may be recognized only when dramatic respiratory and hemodynamic changes develop.

Timing — Anaphylaxis due to an IgE-mediated reaction usually develops within a few minutes to approximately 20 minutes following intravenous administration of the causal agent. Symptoms may manifest later if the trigger was administered orally, intramuscularly, or through contact with skin or tissues (eg, latex, chlorhexidine). Timing of the reaction with respect to the onset of anesthesia may provide additional clues to the underlying cause:

Allergic reactions occurring during the first 30 minutes of anesthesia are more likely due to antibiotics, neuromuscular-blocking agents, or hypnotic induction agents, because these agents are given at the start of or prior to the procedure.

Anaphylaxis presenting after the first 30 minutes of anesthetic induction are more likely due to agents that are used during or at the conclusion of a surgical procedure, such as latex, blood products, colloid volume expanders, blue dyes, or protamine.

Anaphylaxis to sugammadex occurs postoperatively when the agent is administered to reverse muscle paralysis.

Reactions may also occur after sudden shifts in blood or other fluids, such as removal of a tourniquet, unclamping of blood vessels, or after uterine manipulation followed by administration of oxytocin [30,160,161]. If the trigger was administered or applied by the surgeon (eg, antibiotics in irrigation solutions, topical hemostatic agents, injections of a blue dye for lymph node identification), the anesthesiologist may not immediately make the connection between the exposure and the reaction, so a careful review of the events preceding the reaction with the entire team is critical. (See "Overview of topical hemostatic agents and tissue adhesives".)

Severity — Perioperative anaphylaxis tends to be severe and has a higher mortality rate than anaphylaxis occurring in other settings. In a retrospective review of 266 survivors of perioperative anaphylaxis, psychological, cognitive, or physical sequelae were reported in one-third of cases [38]. Estimates of mortality due to perioperative anaphylaxis range from 1.4 to 6 percent, with another 2 percent of patients surviving with anoxic cerebral injury [17,38,155,162]. In contrast, fatal anaphylaxis from all causes is estimated to be 0.7 to 2 percent of cases.

The heightened severity of perioperative anaphylaxis may be attributable to the intravenous route of drug administration and/or the factors that impair early recognition of reactions. Another possibility is that individuals receiving anesthesia may be more vulnerable to physiologic perturbations, especially following spinal/epidural anesthesia, which may cause a sympathectomy. The concomitant stresses of surgery or illness may also contribute.

IgE-mediated anaphylaxis is generally more severe than non-IgE-mediated anaphylaxis [1], although both types can be fatal. A review of fatal anaphylaxis from all causes is presented separately. (See "Fatal anaphylaxis".)

MANAGEMENT

Initial management — The treatment of anaphylaxis during anesthesia is based on prompt hemodynamic resuscitation that includes epinephrine, fluids, and other strategies (table 7). The perioperative/intensive care unit setting is one of the few places that intravenous bolus epinephrine is used regularly in initial management, outside of advanced cardiac life support algorithms. For acute shock and cardiopulmonary dysfunction, it is essential to use intravenous treatment agents, carefully titrated to specific effects. In most other settings, clinicians should use intramuscular epinephrine for anaphylaxis.

A detailed discussion of anaphylaxis management in other settings is found separately. (See "Anaphylaxis: Emergency treatment".)

Subsequent allergy evaluation should take place after the patient has recovered fully. This evaluation is reviewed separately. (See 'Referral for allergy evaluation' below and "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions".)

Laboratory tests at the time of the reaction — Blood collected at the time of the reaction (or shortly after) may reveal elevations in tryptase, a mediator released nearly exclusively by mast cells and basophils. The release of tryptase can help distinguish anaphylaxis from other perioperative events, such as cardiogenic shock [163,164]. However, not all episodes of anaphylaxis result in elevations in tryptase, so a normal tryptase does not exclude anaphylaxis. Tryptase was elevated in 68 percent of IgE-mediated reactions and 4 percent of non-IgE-mediated reactions in the largest French study [1]. Elevations in serum tryptase are most often detected in cases of anaphylaxis that involve hypotension.

Serum tryptase has a half-life of approximately two hours. Blood for serum tryptase should be collected as soon as possible after the onset of symptoms [165]. Thirty minutes to three hours after the onset of symptoms is optimal, although increases may be detectable longer following massive mast cell activation. Blood for serum tryptase should be collected in a red-top tube, and a minimum of 1 mL is recommended.

A serum tryptase >11.4 ng/mL is considered elevated. However, an increase in tryptase can occur with mast cell activation and not exceed the normal range if the baseline level for that individual is low. An increase in serum total tryptase of 20 percent + 2 ng/mL is accepted as evidence of mast cell activation. The equation 1.2 x baseline tryptase + 2 ng/mL is used to calculate the level indicative of mast cell activation [166,167]. For example, if a patient's baseline tryptase is 2 ng/mL, then a level of 7 ng/mL drawn shortly after a perioperative reaction is consistent with anaphylaxis. In most cases, the patient's baseline serum tryptase is not known, but it can be obtained by repeating the serum tryptase several days after the reaction, as tryptase is rapidly cleared from the circulation. The interpretation of laboratory tests in patients with anaphylaxis is discussed in more detail elsewhere. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)

Serum that was collected at the time of the reaction for other reasons can sometimes be retrieved at a later time and assayed. Tryptase is stable in frozen serum for up to one year. Levels of tryptase can increase dramatically after death due to nonspecific mediator release during cell death. For postmortem samples, blood should be collected from the femoral artery or vein and not the heart. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis", section on 'Fatal anaphylaxis'.)

Assays of other mast cell and basophil products, such as serum and urinary histamine, histamine metabolites, and prostaglandins, are of limited clinical value. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)

Decisions regarding proceeding with surgery — The decision to proceed with surgery following anaphylaxis should be individualized depending on the severity of the reaction, cardiopulmonary stability, and the urgency of the procedural intervention. Ultimately, the clinicians involved must use clinical judgement to determine the most sensible course of action. In one retrospective analysis, proceeding with surgery was safe after grade 1 or 2 anaphylactic reactions (limited to cutaneous signs and/or vital sign changes that are not life-threatening). After grade 3 reactions (profound hypotension or severe bronchospasm), the risk of adverse events attributable to the reaction was higher but did not differ in cases where surgery was continued or abandoned [168]. Surgical procedures were frequently abandoned after grade 4 reactions (associated with cardiac arrest and/or inability to ventilate) in this study, although there was no evidence of further harm as a result of proceeding with emergency or partially completed major surgery. In the 2018 United Kingdom prospective registry, the surgical procedure was not started or abandoned in more than one-half of the cases with a grade 3 or higher anaphylactic reaction, including 10 percent where surgery was urgent [38].

REFERRAL FOR ALLERGY EVALUATION

Whom to refer — Patients with suspected perioperative anaphylaxis should prompt consideration for referral. In contrast, transient, limited flushing or localized erythema (eg, following vancomycin infusion) is unlikely to represent a significant hypersensitivity reaction and does not need evaluation [5].

Timing of referral — Patients should be referred to an allergy specialist as soon as possible after the reaction. It is common practice to defer skin testing for four to six weeks after a significant reaction, but each case requires data collection and planning before skin testing can be performed, so prompt referral is helpful. Although an allergy evaluation performed in the weeks after a reaction is most likely to identify a culprit drug, skin testing performed even years after a reaction can be informative. Thus, for patients reporting perioperative anaphylaxis years earlier, an evaluation may still be able to provide some useful information, although the sensitivity will be lower. The impact of timing on skin testing results is discussed in greater detail separately. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions", section on 'Timing of skin testing'.)

Documentation for referral — To maximize the likelihood of identifying the culprit allergen, the referring anesthesiologist and/or surgeon should provide the following information to the allergist:

A detailed description of the event, including all signs and symptoms.

Copies of anesthesia records and surgical reports.

The timing of anaphylaxis onset relative to the administration of drugs, blood products, blue dyes, or other agents or to the performance of procedures (ie, what was happening during the surgery just before the reaction was detected).

The results of serum tryptase levels drawn near the time of the reaction, if available.

Whether surgical instruments were used in the procedure (because disinfectant chemicals can be allergens).

Any type of sterilizing agent (eg, ethylene oxide) used for instruments and disinfectants (especially chlorhexidine), local anesthetic sprays/gels, dyes, or cements used during the surgery.  

A description of the composition of any arterial, venous, and urinary catheters and stents used.

Whether and when any gelatin-containing volume expanders or hemostatic agents were used.

Alternative anesthetic agents available for use in the facility.

Skin testing is the major tool utilized by allergists/immunologists to identify the likely culprit drug and/or to recommend alternative agents. Although the positive predictive value or likelihood ratio of positive skin tests for most agents or drugs, other than penicillin, is not well-defined, this approach has proven successful in a majority of cases. One study of 70 patients showed that assessment with skin testing in a specialty clinic resulted in 67 patients undergoing repeat anesthesia without adverse events [169]. The few cases of repeat anaphylaxis were attributed to either limitations in the historical information provided to the allergy consultant or to the presence of undetected mast cell disorders. This highlights the importance of providing a detailed description of the events and timing of drug administration to the consulting allergist. Ideally, the anesthesiologist should also be prepared to provide small aliquots of anesthetic drugs to facilitate testing, as these agents are not readily available to other clinicians. However, the logistics of providing these regulated materials is often a challenge.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of an allergic or anaphylactic reaction during or following general anesthesia includes a broad list of reactions and physiologic events [5,41,170-172]. Tryptase levels should be normal in all of these other disorders:

Other causes of respiratory or airway symptoms

Acute asthmatic reaction in a patient known to have asthma/COPD (see "Anesthesia for adult patients with asthma", section on 'Intraoperative bronchospasm')

Undiagnosed asthma/COPD

Aspiration

Inadequate depth of anesthesia

Endotracheal tube malposition

Malignant hyperthermia (succinylcholine) (see "Malignant hyperthermia: Diagnosis and management of acute crisis", section on 'Diagnosis')

Myotonias and masseter spasm (succinylcholine) (see "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Trismus')

Postextubation stridor (see "Respiratory problems in the post-anesthesia care unit (PACU)", section on 'Upper airway obstruction')

Pulmonary edema

Pulmonary embolus (see "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism")

Tension pneumothorax

Transfusion-related acute lung injury (TRALI) (see "Transfusion-related acute lung injury (TRALI)", section on 'Clinical presentation')

(See "Assessment of respiratory distress in the mechanically ventilated patient".)

Other causes of hypotension/shock

Arrhythmias

Cardiac tamponade (see "Cardiac tamponade", section on 'Acute cardiac tamponade')

Cardiogenic shock

Pulmonary embolus

Amniotic fluid embolus

Hemorrhage

Hyperkalemia

Overdose of vasoactive drugs

Partial sympathectomy from spinal/epidural anesthesia

Sepsis

Vasovagal reaction

Venous air embolism (see "Air embolism", section on 'Clinical features')

Bone cement implantation syndrome (see "Complications of total hip arthroplasty", section on 'Bone cement implantation syndrome')

Other causes of angioedema

Hereditary or acquired C1 esterase inhibitor deficiency (see "Hereditary angioedema: Acute treatment of angioedema attacks")

Treatment with angiotensin-converting enzyme inhibitors (see "An overview of angioedema: Pathogenesis and causes", section on 'Causes')

Soft tissue swelling due to difficult intubation

Other causes of urticaria — Cold urticaria can occasionally be mistaken for perioperative anaphylaxis or a drug reaction. Cold urticaria can usually be excluded by the negative results of an ice cube challenge, except for familial cold urticaria associated with cryopyrin dysfunction [173]. (See "Cold urticaria".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity" and "Society guideline links: Anaphylaxis".)

SUMMARY AND RECOMMENDATIONS

Anaphylaxis definition and mechanisms – Anaphylaxis is a potentially lethal reaction usually resulting from the sudden, clinically significant release of mast cell- and/or basophil-derived mediators into the circulation. Both immunoglobulin E (IgE) and non-IgE-mediated immune mechanisms have been implicated, and some agents may cause reactions by more than one mechanism (table 1 and table 2). (See 'Mechanisms of anaphylaxis' above.)

Causes of perioperative anaphylaxis – The more common identifiable causes of perioperative anaphylaxis are antibiotics, neuromuscular-blocking agents, chlorhexidine, and blue dyes used in lymph node mapping. However, there is a much longer list of agents that are implicated less commonly. (See 'Etiologies' above.)

Risk factors – Risk factors for perioperative anaphylaxis include female sex (for certain medications), other allergic conditions (eg, asthma, eczema, or hay fever), multiple past surgeries or procedures (especially for latex), and mast cell disorders. High-risk procedures include transplants and hematologic, cardiac, or vascular procedures. (See 'Risk factors' above.)

Clinical presentation and diagnosis – Perioperative anaphylaxis may exhibit cutaneous, respiratory, and cardiovascular signs and symptoms, as well as variable involvement of other organ systems, although these signs may be more difficult to recognize in sedated or anesthetized patients (table 6). The diagnosis is clinical. One-half of cases are initially detected as sudden cardiovascular collapse. Bronchospasm may present as an increase in the ventilatory pressure required to inflate the lungs or as a decrease in arterial oxygen saturation. (See 'Clinical manifestations and diagnosis' above.)

Comparison with anaphylaxis from other causes – Perioperative anaphylaxis tends to be severe and has a higher mortality rate than anaphylaxis occurring in other settings. This is at least partly attributable to factors that impair early recognition of anaphylaxis, such as the inability of the patient to report initial symptoms and coverage of the skin with surgical drapes. The intravenous administration of triggering drugs and concomitant stresses of surgery or illness may also contribute. (See 'Severity' above.)

Epinephrine is critical for treatment – The treatment of anaphylaxis during anesthesia is based on cardiopulmonary resuscitation that includes prompt administration of epinephrine and fluid resuscitation (table 7). Intravenous epinephrine is commonly used in the operating room while the patient is monitored, and intravenous access is readily available. (See 'Initial management' above.)

Obtain a serum tryptase within three hours of the reaction – An increase from baseline or elevated serum total tryptase, ideally obtained within three hours of a suspected reaction, is highly suggestive of anaphylaxis, although normal levels do not exclude the diagnosis. Total tryptase should be compared to a baseline value, collected prior to surgery or after recovery, to assess the possibility of an increase during the suspected anaphylaxis episode. An increase of 1.2 x baseline tryptase + 2 ng/mL during the suspected anaphylaxis is consistent with a mast cell-mediated event. Thus, a normal acute tryptase value may still suggest mast cell-mediator release if the baseline level is low. (See 'Laboratory tests at the time of the reaction' above and 'Differential diagnosis' above.)

Referral to an allergist – Patients who experience perioperative anaphylaxis should be referred to an allergy specialist. Clinical history and record review are used to determine all of the agents to which the patient was exposed leading up to the reaction. The allergist performs skin testing if feasible and appropriate to identify the likely culprit drug and/or to recommend alternative agents. This approach allows most patients to undergo future anesthesia safely. (See 'Referral for allergy evaluation' above.)

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