An EAACI position paper on the investigation of perioperative immediate hypersensitivity reactions.

Perioperative immediate hypersensitivity reactions are rare. Subsequent allergy investigation is complicated by multiple simultaneous drug exposures, the use of drugs with potent effects and the many differential diagnoses to hypersensitivity in the perioperative setting. The approach to the investigation of these complex reactions is not standardized, and it is becoming increasingly apparent that collaboration between experts in the field of allergy/immunology/dermatology and anaesthesiology is needed to provide the best possible care for these patients. The EAACI task force behind this position paper has therefore combined the expertise of allergists, immunologists and anaesthesiologists. The aims of this position paper were to provide recommendations for the investigation of immediate-type perioperative hypersensitivity reactions and to provide practical information that can assist clinicians in planning and carrying out investigations.

Anaesthetic management of patients with pre-existing allergic conditions: a narrative review.

This narrative review seeks to distinguish the clinical patterns of pre-existing allergic conditions from other confounding non-allergic clinical entities, and to identify the potential related risks and facilitate their perioperative management. Follow-up investigation should be performed after a perioperative immediate hypersensitivity to establish a diagnosis and provide advice for subsequent anaesthetics, the main risk factor for perioperative immunoglobulin E (IgE)-mediated anaphylaxis being a previous uninvestigated perioperative immediate hypersensitivity reaction. The concept of cross-reactivity between drugs used in the perioperative setting and food is often quoted, but usually not supported by evidence. There is no reason to avoid propofol in egg, soy, or peanut allergy. The allergenic determinants have been characterised for fish, shellfish, and povidone iodine, but remain unknown for iodinated contrast agents. Iodinated drugs may be used in seafood allergy. Evidence supporting the risk for protamine allergy in fish allergy and in neutral protamine Hagedorn insulin use is lacking. Conversely, cross-reactivity to gelatin-based colloid may occur in α-gal syndrome. Atopy and allergic asthma along with other non-allergic conditions, such as NSAID-exacerbated respiratory disease, chronic urticaria, mastocytosis, and hereditary or acquired angioedema, are not risk factors for IgE-mediated drug allergy, but there is a perioperative risk associated with the potential for exacerbation of the various conditions.

The use of drug provocation testing in the investigation of suspected immediate perioperative allergic reactions: current status.

Suspected perioperative allergic reactions are often severe. To avoid potentially life-threatening re-exposure to the culprit drug, establishing a firm diagnosis and identifying the culprit is crucial. Drug provocation tests are considered the gold standard in drug allergy investigation but have not been recommended in the investigation of perioperative allergy, mainly because of the pharmacological effects of drugs such as induction agents and neuromuscular blocking agents. Some specialised centres have reported benefits of provocation testing in perioperative allergy investigation, but the literature on the subject is limited. Here we provide a status update on the use of drug provocation testing in perioperative allergy, including its use in specific drug groups. This review is based on a literature search and experiences of the authors comprising anaesthesiologists and allergists with experience in perioperative allergy investigation. In addition, 19 participating centres in the International Suspected Perioperative Allergic Reaction Group were surveyed on the use of provocation testing in perioperative allergy investigation. A response was received from 13 centres in eight European countries, New Zealand, and the USA. Also, 21 centres from the Australian and New Zealand Anaesthetic Allergy Group were surveyed. Two centres performed provocation routinely and seven centres performed no provocations at all. Nearly half of the centres reported performing provocations with induction agents and neuromuscular blocking agents. Drug provocation testing is being used in perioperative allergy investigation in specialised centres, but collaborations between relevant specialties and multicentre studies are necessary to determine indications and establish common testing protocols.

Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations.

Suspected perioperative allergic reactions are rare but can be life-threatening. The diagnosis is difficult to make in the perioperative setting, but prompt recognition and correct treatment is necessary to ensure a good outcome. A group of 26 international experts in perioperative allergy (anaesthesiologists, allergists, and immunologists) contributed to a modified Delphi consensus process, which covered areas such as differential diagnosis, management during and after anaphylaxis, allergy investigations, and plans for a subsequent anaesthetic. They were asked to rank the appropriateness of statements related to the immediate management of suspected perioperative allergic reactions. Statements were selected to represent areas where there is a lack of consensus in existing guidelines, such as dosing of epinephrine and fluids, the management of impending cardiac arrest, and reactions refractory to standard treatment. The results of the modified Delphi consensus process have been included in the recommendations on the management of suspected perioperative allergic reactions. This paper provides anaesthetists with an overview of relevant knowledge on the immediate and postoperative management of suspected perioperative allergic reactions based on current literature and expert opinion. In addition, it provides practical advice and recommendations in areas where consensus has been lacking in existing guidelines.

Comparative epidemiology of suspected perioperative hypersensitivity reactions.

Suspected perioperative hypersensitivity reactions are rare but contribute significantly to the morbidity and mortality of surgical procedures. Recent publications have highlighted the differences between countries concerning the respective risk of different drugs, and changes in patterns of causal agents and the emergence of new allergens. This review summarises recent information on the epidemiology of perioperative hypersensitivity reactions, with specific consideration of differences between geographic areas for the most frequently involved offending agents.

Perioperative anaphylaxis: what should be known?

Perioperative anaphylaxis is a unique condition as a result of the additive cardiovascular effects of anesthetics on the cardiovascular disturbances of anaphylaxis. It occurs mainly in adulthood, primarily follows anesthetic induction, and for the most part, is an IgE-mediated pathomechanism. Neuromuscular blocking agents (NMBAs) and antibiotics are the main culprit drugs, while latex is now infrequently involved. The Ring and Messmer scale is a useful tool for demonstrating the clinical severity of perioperative immediate hypersensitivity and guiding its management. Grades III and IV are life-threatening and are referred to as anaphylaxis. Three different clinical patterns of grade III may be observed, where cardiovascular collapse is the cardinal sign. Grade IV presents as cardiac arrest. The initial diagnosis is presumptive, whereas the etiological assessment is linked to the clinical presentation, tryptase levels, and skin test results. Since anaphylaxis presents with significant hypovolemia and vasoplegia, aggressive fluid therapy and epinephrine are the cornerstones of management. Whenever possible, anesthetic discontinuation is also recommended. Scientific evidence in favor of preemptive therapeutic strategies to prevent anaphylaxis in the operative setting is lacking.

Association Between Early Patient Characteristics and IgE-Mediated Allergy in the Perioperative Setting.

BACKGROUND: Early recognition of perioperative anaphylaxis, a life-threatening, usually IgE-mediated, immediate hypersensitivity, is essential, but bedside diagnosis is not always straightforward because clinical presentation may vary. OBJECTIVES: To describe early characteristics of perioperative immediate hypersensitivity, with special attention to cutaneous phenotypes, and identify risk factors for IgE-mediated allergy. METHODS: We retrospectively analyzed data from adults with suspected perioperative immediate hypersensitivity who were investigated in two academic medical centers. Multivariable logistic regression was conducted to evaluate associations among patient, clinical, and paraclinical characteristics and IgE-mediated allergy. RESULTS: Of 145 enrolled patients, 99 (68.3%) and 46 (31.7%) were respectively categorized in the IgE-mediated allergy and non-allergy groups. Cutaneous vasoconstriction phenotype (pallor, piloerection, thelerethism, and sweating with or without cyanosis) occurring within minutes (or even 1 minute) of drug exposure was strongly associated with IgE-mediated allergy (adjusted odds ratio [aOR] = 28.02; 95% CI, 4.41-305.18). IgE-mediated allergy was always life-threatening in this setting. Other early factors associated with allergy were low end-tidal carbon dioxide 25 mm Hg or less (aOR = 5.45; 95% CI, 2.39-26.45), low mean arterial pressure 60 mm Hg or less (aOR = 3.82; 95% CI, 1.28-17.31), and early cutaneous vasodilation (erythema, urticaria, and/or angioedema) (aOR = 2.78; 95% CI, 0.73-20.54). Late cutaneous vasodilation after restoration of hemodynamics corroborated the diagnosis of allergy (aOR = 23.67; 95% CI, 4.94-205.09). The best-fit model including three readily available variables (cutaneous phenotype involving the three modalities [reference lack of cutaneous signs], low mean arterial pressure, and low end-tidal carbon dioxide) had an area under the curve of 0.91. CONCLUSIONS: Cutaneous vasoconstriction phenotype is associated with the strongest risk of life-threatening allergy and thus may be regarded as pathognomonic of perioperative IgE-mediated anaphylaxis.

Anaphylaxis in the clinical setting of obstetric anesthesia: a literature review.

The prevalence of anaphylaxis occurring during pregnancy is approximately 3 cases per 100,000 deliveries. The management of anaphylaxis occurring during the third trimester of pregnancy may be challenging because of the additive effects of aortocaval compression and cardiovascular disturbances of anaphylaxis. In this review, we identify the clinical signs of anaphylaxis occurring during labor and cesarean delivery, discuss the more common allergens that cause anaphylaxis during this clinical setting, and develop a rational approach to the identification of the offending allergen. We also suggest strategies for the management of anaphylaxis occurring during the third trimester of pregnancy, including the prompt administration of epinephrine and emergency cesarean delivery in cases of severe reactions. Evidence is limited to case reports and extrapolation from nonfatal and fatal cases, interpretation of pathophysiology, and consensus opinion.

Macromolecular capillary leakage is involved in the onset of anaphylactic hypotension.

BACKGROUND: The role of the hypovolemic component secondary to the microcirculatory changes in the onset of inaugural anaphylactic hypotension remains debated. We investigated the microcirculatory permeability in a model of anaphylactic shock using a fluorescence confocal microscopy imaging system. METHODS: Ovalbumin-sensitized anesthetized Brown Norway rats were randomly allocated into two groups (n = 6/group): control and anaphylaxis, respectively induced by intravenous saline or ovalbumin at time 0 (T0). The mesentery was surgically exposed. Macromolecular fluorescein isothiocyanate-dextran was intravenously injected (T0-5min) allowing in vivo visualization of the mesenteric microvascular network by fluorescence microscopy. After a period of stabilization of the contrast agent concentration, a 5-s movie was recorded to obtain baseline signal intensity. Following T0, 5-s movies were recorded every 30 s for 30 min. Capillary leakage of fluorescein isothiocyanate-dextran was assessed in interstitium and compared between groups. Data are expressed as mean ± SD. RESULTS: Following anaphylactic shock onset, an early, progressive, and global signal intensity increase over time was detected in the interstitium. Mean index leakage differed between control and anaphylaxis (respectively 20 ± 11 vs. 170 ± 127%; P < 0.0001), starting at 2 min after shock onset and progressively increasing. Index leakage correlated with the drop in arterial blood pressure until T0 + 10 min (r = -0.75, P = 0.0001). CONCLUSIONS: During anaphylaxis, interstitial capillary leakage occurs within minutes after shock onset. Compared with controls, the mesenteric microcirculation showed at least 8-fold-increased macromolecular capillary leakage. The inflammation-induced microcirculatory changes with subsequent intravascular fluid transfer might be involved in the onset of the inaugural hypotension during anaphylactic shock.

Case Report: perioperative immediate hypersensitivity involves not only allergy but also mastocytosis.

PURPOSE: We report a case of drug-induced immediate hypersensitivity occurring after atracurium injection in a patient with cutaneous mastocytosis. CLINICAL FEATURES: A 69-yr-old woman was scheduled for hysterectomy. She was premedicated with hydroxyzine, and anesthesia was induced with sufentanil, propofol, and atracurium. Within two to three minutes following the injection of atracurium, the patient experienced an episode of generalized erythema and arterial hypotension associated with tachycardia. No bronchospasm was observed. Her cardiovascular signs resolved spontaneously within five minutes, while her cutaneous signs disappeared within 30 min. Anesthesia and surgery remained uneventful. The patient's serum tryptase levels were measured at different time points following the clinical reaction. An in vitro flow cytometry-based basophil activation test was performed with atracurium, and in vivo skin tests to latex and all drugs which were administered just before the clinical reaction were also done. The serum tryptase showed increased concentrations that remained elevated for 24 hr, 48 hr, and even four weeks after the clinical reaction. Atracurium did not induce either CD63 or CD203c upregulation, and the skin tests were negative in response to the medications received (propofol, sufentanil, and atracurium) as well as to latex. CONCLUSIONS: Allergic hypersensitivity to atracurium was ruled out. Increased tryptase concentrations following the clinical reaction, persistent increased levels of basal serum tryptase, and negative skin tests suggested the onset of mast cell degranulation in a patient with mastocytosis. Immediate reaction occurring in patients with mastocytosis should be investigated in order to identify the mechanism of the reaction, either histamine release due to the disease itself or due to a concurrent drug/agent-induced IgE-mediated mechanism.

Apical ballooning syndrome following perioperative anaphylaxis is likely related to high doses of epinephrine.

Apical ballooning syndrome, a reversible left ventricle dysfunction, has been reported following anaphylaxis and, during this clinical circumstance, is seemingly linked to the use of either low or high doses of epinephrine. We report a severe succinylcholine-induced IgE-mediated anaphylaxis in a 65-year-old woman, in whom the diagnosis of apical ballooning syndrome following anaphylaxis was established. As a thorough description of the clinical features and resuscitative measures could be obtained, we discuss the reasons for apical ballooning syndrome occurrence and highlight the fact that optimal care management of anaphylaxis should include a progressive titration of epinephrine.

Anesthesia in the patient with multiple drug allergies: are all allergies the same?

PURPOSE OF REVIEW: During the preoperative evaluation, patients frequently indicate 'multiple drug allergies', most of which have not been validated. Potential allergic cross-reactivity between drugs and foods is frequently considered as a risk factor for perioperative hypersensitivity. The aim of this review is to facilitate the recognition of risk factors for perioperative anaphylaxis and help the management of patients with 'multiple drug allergies' during the perioperative period. RECENT FINDINGS: Neuromuscular blocking agents (NMBAs) and antibiotics are the most common drugs triggering perioperative anaphylaxis. Quaternary ammonium ions have been suggested to be the allergenic determinant of NMBAs. Even though the 'pholcodine hypothesis' has been suggested to explain the occurrence of NMBA-induced allergy, this concept remains unclear. Although many practitioners believe that certain food allergies present an issue with the use of propofol, there is no role to contraindicate propofol in egg-allergic, soy-allergic or peanut-allergic patients. IgE-mediated hypersensitivity has been reported with seafood and iodinated drugs, IgE-mediated hypersensitivity has been reported with seafood and iodinated drugs, but there is no cross-reactivity between them. The allergenic determinants have been characterized for fish, shellfish and povidone iodine and remain unknown for contrast agents. SUMMARY: There are many false assumptions regarding drug allergies. The main goal of this article is to review the potential cross-reactivity among specific families of drugs and foods in order to facilitate the anesthetic management of patients with 'multiple drug allergies'.

What investigation after an anaphylactic reaction during anaesthesia?

PURPOSE OF REVIEW: Anaphylactic reactions occurring during anaesthesia may be life threatening. Lethal issues may be involved in up to 3-10% of the cases. The allergological assessment (including biochemical tests and skin tests) is the key to the management of these reactions. The scope of this review is to focus on the allergological assessment required to prove the immune mechanism, to identify the culprit drug or substance and the cross-reactive molecules, especially for neuromuscular blocking agents, allowing preventive measures for future anaesthetic procedures. RECENT FINDINGS: To describe the allergological assessment (including biochemical tests and skin tests performed according to the current guidelines) in order to prove the immune mechanism as the responsibility of the culprit allergen. The most frequent and less frequent drugs involved are described. The different biological tools available are detailed. To ensure an accurate diagnosis, the interpretation of the allergological assessment should be linked to the description of the clinical events as their time onset following the injection/administration of the suspected drug(s)/substance. SUMMARY: To describe the different tools (biochemical tests and skin tests) available in order to prove the diagnosis of an anaphylactic reaction occurring during anaesthesia.

Comparison of Basophil Activation Test and Skin Testing Performances in NMBA Allergy.

BACKGROUND: Neuromuscular blocking agents (NMBAs) are the main agents involved during perioperative immediate hypersensitivity. The etiological diagnosis (IgE-mediated allergy vs nonallergy) is linked to the clinical presentation together with tryptase and histamine levels and skin test results. The role of basophil activation test (BAT) needs to be better defined in this setting. OBJECTIVES: To assess the role of BAT compared with the results of skin testing in 31 patients experiencing immediate NMBA hypersensitivity and compare skin test results and BAT performances in the identification of alternative NMBAs. METHODS: Histamine and tryptase levels were quantified. Anesthetic drugs, including NMBAs, were skin-tested. Basophil CD63 and CD203c expressions were measured in response to serial dilutions of the different NMBAs. RESULTS: Allergy and Nonallergy groups involved 19 and 12 patients, respectively. Circulating histamine and tryptase levels were significantly increased in allergic patients. In the Allergy group, while skin test results were positive in 100% (19 of 19) of the cases, BAT positivity to the culprit NMBA reached 78.9% (15 of 19) when combining CD63 and CD203c. NMBAs cross-reactivity was identified through skin testing and BAT in 36.8% (7 of 19) and 26.3% (5 of 19) of the cases, respectively. The concordance (culprit and cross-reactive NMBAs) between skin tests and BATs was between 73.6% (14 of 19) and 100% (19 of 19) for each NMBA. Negative skin-tested NMBAs were uneventfully used in 7 NMBA-allergic patients. In the Nonallergy group, skin test results were negative in 100% of the cases while BAT result was positive once (CD63 upregulation). CONCLUSION: In our technical conditions, BAT does not replace skin testing in the assessment of NMBA allergy.

Immediate Hypersensitivity to Contrast Agents: The French 5-year CIRTACI Study.

BACKGROUND: Iodinated and gadolinium-based contrast media (ICM; GBCM) induce immediate hypersensitivity (IH) reactions. Differentiating allergic from non-allergic IH is crucial; allergy contraindicates the culprit agent for life. We studied frequency of allergic IH among ICM or GBCM reactors. METHODS: Patients were recruited in 31 hospitals between 2005 and 2009. Clinical symptoms, plasma histamine and tryptase concentrations and skin tests were recorded. Allergic IH was diagnosed by intradermal tests (IDT) with the culprit CM diluted 1:10, "potentially allergic" IH by positive IDT with pure CM, and non-allergic IH by negative IDT. FINDINGS: Among 245 skin-tested patients (ICM = 209; GBCM = 36), allergic IH to ICM was identified in 41 (19.6%) and to GBCM in 10 (27.8%). Skin cross-reactivity was observed in 11 patients with ICM (26.8%) and 5 with GBCM (50%). Allergy frequency increased with clinical severity and histamine and tryptase concentrations (p < 0.0001). Cardiovascular signs were strongly associated with allergy. Non-allergic IH was observed in 152 patients (62%) (ICM:134; GBCM:18). Severity grade was lower (p < 0.0001) and reaction delay longer (11.6 vs 5.6 min; p < 0.001). Potentially allergic IH was diagnosed in 42 patients (17.1%) (ICM:34; GBCM:8). The delay, severity grade, and mediator release were intermediate between the two other groups. INTERPRETATION: Allergic IH accounted for < 10% of cutaneous reactions, and > 50% of life-threatening ones. GBCM and ICM triggered comparable IH reactions in frequency and severity. Cross-reactivity was frequent, especially for GBCM. We propose considering skin testing with pure contrast agent, as it is more sensitive than the usual 1:10 dilution criteria.

Allergic reaction to contrast medium following gastric band adjustment.

Bariatric surgery is increasingly performed for effective weight loss. A morbidly obese 27-year-old woman underwent laparoscopoic adjustable gastric banding. After a postoperative adjustment of the stomal diameter of the band with ioxaglate, she presented an immediate hypersensitivity reaction. With the patient's consent, cutaneous tests to contrast agents used during the procedure and to latex were performed. Allergy to ioxaglate was confirmed by skin-test positivity. This case suggests the need for allergological investigation of drugs/substances administered during the perioperative period, in case of hypersensitivity reaction.