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Anaphylaxis during general anaesthesia: experience from a drug allergy centre in the UK

Anaphylaxis during general anaesthesia is rare but often severe. Identification of the cause of anaphylaxis and recommendation of a range of drugs or agents likely to be safer for future surgery is a collaborative venture between the allergists and the anaesthesiologists, but it often poses a significant challenge.

investigation results, and any conclusions reached must be compatible with the patient's clinical history (anaesthetic chart) and depend on the experience of the allergist to a large extent. In this study, we describe our experience in the investigation of anaphylaxis under GA and compare data from our centre with those from other series.

Methods
All patients who attended the Drug Allergy Unit at University College London Hospital between March 2013 and Dec 2015 with suspected perioperative anaphylaxis during GA were reviewed retrospectively from hospital notes and electronic records. Patients who met one or more of the following conditions were excluded: (1) reactions with local or regional anaesthesia; (2) referrals for predictive tests for future use of anaesthetic agents for patients with a history of multiple drug allergies but without prior history of adverse reactions during anaesthesia; (3) referrals for identification of safe drugs and agents for future use in GA because the patient had an adverse reaction during prior GA, but the reaction was in the distant past and not clearly documented and (4) incomplete assessment or loss to follow-up.

Clinical history
The clinical histories were evaluated systematically based on information provided by the patients, referral letters from the surgeons or anaesthetists and the anaesthetic charts. When further information was required, the referring anaesthetist was contacted. The anaesthetic and drug charts were carefully scrutinised to assess the clinical features and determine the temporal association of events with drug administration. This assessment enabled the preparation of a list of possible culprits (all drugs and agents used during perioperative period with clear temporal association with anaphylaxis).
The severity of the perioperative allergic reactions was graded according to Ring and Messmer system: I Cutaneous signs: generalised erythema, urticaria, angioedema; II Measurable but not life-threatening symptoms: Cutaneous signs, hypotension, tachycardia Respiratory disturbances: cough, difficulty inflating; III Lifethreatening symptoms: collapse, tachycardia or bradycardia, arrhythmias, bronchospasm; IV Cardiac and/or respiratory arrest. 5 Whenever available, serum tryptase levels, obtained at the time of the anaphylaxis were reviewed. An elevated serum tryptase level was defined as higher than 14 lg/l, based on the normal laboratory values (2-14 lg/l).

Skin testing in allergological evaluation
All potential culprits were tested; however, the order of the testing was adapted according to the clinical history of each patient and the timing of the onset of the reaction in relation to the introduction of the drug.

General anaesthetics
The concentrations of general anaesthetics used for skin testing are summarised in Table 1. The procedure for skin testing followed the general principles laid out in the British Society for Allergy and Clinical Immunology (BSACI) drug allergy guideline. 7 SPT was performed on the volar forearm and read after 15-20 min. A weal diameter at least 3 mm larger than that of the negative control was considered positive. The coexistence of flare and itch supported a positive result. 8-10 When SPT was negative or indeterminate, an intradermal test (IDT) was performed. 0.02-0.03 ml of dilutions of commercial preparations was injected into the dermis of the volar forearm to produce an injection papule no larger than 4 mm in diameter. The result was read after 15-20 min. An increase in weal size of more than 3 mm from the initial papule with accompanying flare was considered positive. 10 When skin testing was positive for a specific neuromuscular blocking agent (NMBA), crosssensitisation workup was performed with the remaining NMBAs.

Antibiotics
Whenever GA involved penicillins, investigations for penicillin allergy were performed. Briefly, all penicillin determinants were evaluated: penicilloyl poly-L-lysine (PPL), minor determinant mixture (MDM), benzylpenicillin (BP) and amoxicillin. Clavulanic acid and flucloxacillin were selected if they were indicated as the culprit drugs. The concentrations of agents for skin testing are summarised in Table 2.Serum-specific IgE (sIgE) testing was performed for penicillin V, penicillin G and amoxicilloyl (Phadia, Uppsala, Sweden). If skin testing and sIgE were negative, a supervised oral challenge was performed. A positive result for penicillin was followed by cefuroxime testing to determine future use.
If a cephalosporin was suspected as the cause, the index cephalosporin was evaluated alongside penicillin allergy determinants; if both were negative, challenge with cephalosporin was performed. For non-ß-lactam antibiotics, there are less data on the sensitivity and specificity of the test, and a sequential testing approach was used: SPT (neat), IDT (1 : 100, 1 : 10), and then oral challenge were considered. Because gentamicin has been found to be irritant in skin testing, this test was not performed, and patients were challenged intravenously if necessary.

Latex
All patients were tested with SPT, when SPT was equivocal, sIgE for latex were performed  using commercial standardised products. If latex allergy was strongly suspected and skin test and sIgE were negative, a subsequent 'prick-prick' test with a latex glove was also performed. If the 'prick-prick' test was negative, then glove challenge (exposing the patient to latex by wearing a latex glove) was performed. If the glove challenge was negative, buccal challenge was performed.

Antiseptics
All patients were tested with antiseptic used during the surgery. Chlorhexidine skin test results were confirmed with sIgE.

Opiates and NSAIDs
Non-IgE-mediated systemic reaction/anaphylaxis was diagnosed for drugs, including opiates and non-steroidal anti-inflammatory drugs (NSAIDs), when there was a clear temporal association with the respective drug, and allergy tests were negative for other drugs and agents that were potentially implicated. However, challenge was considered if there was uncertainty in the clinical history.

Results
In total, 31 patients were referred during the designated period and completed the investigation. The patients included 19 females and 12 males, and the mean age was 48 AE 18 (standard deviation) years, with a range of 18 to 83. The median time from the index reaction to allergy testing was 3 (2-8, interquartile range) months. Most patients (23, 77.4%) were non-atopic in background.
The culprit drug was identified in 21 patients (67.7%). No cause could be identified in six patients (19.4%), despite full investigations. Clinical history suggested non-anaphylactic reactions in four patients (12.9%), but full investigations were performed to eliminate the possibility of allergic causation.
Among the eight patients who had reactions to NMBAs, nine positive skin tests were observed: four patients exhibited positive reactions to rocuronium, three patients exhibited reactions to atracurium, and one patient was found to exhibit reactions to both atracurium and suxamethonium (both of which were administered during anaesthesia). Furthermore, six patients had at least one positive result of cross-sensitisation to other NMBAs (Table 3).
Among the 10 patients who had reaction to antibiotics, three were allergic to penicillin and could tolerate cefuroxime challenge, two were allergic to clavulanic acid and one was allergic to flucloxacillin, (these three patients all tolerated amoxicillin challenge), three patients were allergic to teicoplanin, one was allergic to metronidazole, and one was allergic to rifampicin.
Among the 21 patients for whom the culprit drug was determined, tryptase measurements were available for 12 patients. Of those, nine patients had elevated levels. The remaining three patients had normal levels but suffered grade 3 reaction. Among the six patients for whom no cause was identified, four patients' tryptase were available (three elevated and one normal) ( Table 3).

Discussion
Allergological assessment of every patient who suffers anaphylaxis under GA is essential, 11 and allergy centres that provide drug allergy evaluations play a crucial role in the prevention of future perioperative anaphylaxis.
In our series, the culprit drug was identified in 67.7% of patients, whereas the cause could not be identified in 19.4% of patients, even after repeated diagnostic workups for some individuals. A total of 12.9% were considered to have suffered non-allergic events. This finding illustrates the difficulty of allergy diagnosis in anaphylaxis during GA. The proportion of patients in our study for whom no causative agent could be determined was comparable to those in other reports. [12][13][14] Among the 21 patients who suffered anaphylaxis during anaesthesia and the cause was subsequently identified, antibiotics were the most common causative agent (52.3%), followed by , hypnotics (7%), antibiotics (6%), plasma substitutes (3%) and opioids (2%). 5 In our study, antibiotics were the most common cause of anaphylaxis, whereas none of the adverse reactions were attributable to latex or hypnotics. These differences might be due to the small size of our study, which was limited to one centre and thus may not be representative. Within the NMBA family, rocuronium was the most common culprit drug, followed by atracurium and suxamethonium. Although, no conclusions can be drawn as to the incidence of anaphylaxis with rocuronium from our small sample, previous studies published in France, 2 Norway 15 and Australia 16 indicated a higher rate of anaphylaxis with rocuronium than other NMBAs. A 7-year, retrospective, observation cohort study conducted in New Zealand demonstrated that, although the rate of anaphylaxis to either rocuronium or atracurium is extremely rare, it appears to be approximately 10-fold higher to rocuronium than to atracurium. 17 The clinical histories indicated that only two of our patients had prior surgery and thus may have been sensitised to NMBAs via prior exposure. Fisher et al. also reported that in the case of NMBA-induced allergy, only approximately 15% of affected subjects have ever been exposed to NBMAs previously. 18 Why do NMBAs deviate from accepted mechanisms underlying IgEmediated allergic reactions? The explanation might be that the origin of allergic sensitisation is an environmental agent or another drug containing an ammonium ion which has been confirmed to be the main allergenic structure of NMBAs. 19 Recently, Florvaag et al. suggested that sensitisation with pholcodine could increase the titre of specific IgEs to quaternary ammonium ions and thereby increase the risk of allergic reaction to NMBAs. 20 The extent of allergenic cross-sensitisation between NMBAs has been estimated to be approximately 65% by skin testing and 80% by IgE tests. 21 A total of 75.0% of our patients allergic to NMBAs had cross-sensitisation with other NMBAs upon further testing, consistent with published data. 22 Six patients showed cross-sensitisation with vecuronium (2 at 1 : 100 and 4 at 1 : 10 concentration). It has been recommened that vecuronium should be tested at a lower concentration of 1 : 100 and hence we may have overestimated vecuronium cross-sensitisation. 23 In our study, two patients were allergic to clavulanic acid, both tolerated amoxicillin on subsequent challenge. Although initially considered as nonimmunogenic, 24 recent studies indicate that immediate selective reactions to clavulanic acid account for approximately 22-30% of immediate allergic reactions to co-amoxiclav. 25,26 Three of our patients were diagnosed with Teicoplanin allergy. Teicoplanin is a glycopeptide antibiotic that is now a first-line prophylactic therapy for orthopaedic, cardiac, breast, gastrointestinal, vascular and plastic procedures and is frequently used as a second-line therapy in penicillin-allergic patients. Anaphylaxis to teicoplanin was previously considered extremely rare, but in recent years, with the increase in prescribing, allergic reactions appear to be more common than previously thought. Patient No 16 developed anaphylaxis 30 min after uneventful induction and immediately after IV teicoplanin and gentamicin infusion. In view of negative challenge to gentamicin and negative skin testing to other possible culprits, although skin tests to teicoplanin were negative, a likely diagnosis of teicoplanin allergy was made. Attempts to challenge the patient were not performed due to his comorbidities. Savic et al. 27 suggested that the paradox of negative teicoplanin skin testing despite dramatic clinical presentations indicates that mast cell and possibly basophil activation might be caused by direct cell stimulation not involving IgE, or the concentration of the dilution used for testing might be sub-optimal. Of the remaining two patients who were diagnosed with teicoplanin allergy, one (No 17) suffered anaphylaxis during intradermal testing and the other skin tested positive ( Table 3). The mechanism underlying teicoplanin allergy is not clear and further work is needed to establish an appropriate testing regimen for potential teicoplanin allergy.
We observed no sensitisation to latex, despite systematic testing of all of our patients. This finding was in accordance with recent data from four centres in the United Kingdom that implicated only one latex allergy (0.6%). 12 This appears to be a general trend, as although previous French series indicated that latex was the second (17%) most frequent cause of perioperative anaphylaxis, 2 more recent French series showed that latex is now only the fourth cause and the decrease in latex related anaphylaxis is likely due to primary and secondary prevention measures. 28 Serum tryptase is an indicator of mast cell degranulation and tends to be elevated in both IgE-mediated and non-IgE-mediated anaphylaxis. Guidelines suggest serial measurements of serum tryptase including baseline value 1,24 . However, practical experience suggests that this recommendation is not always followed. In our study, only 54.8% of the referred patients underwent tryptase testing.
There is no consensus regarding the threshold level of tryptase for the diagnosis of anaphylaxis. In this study, the normal range was set at 2-14 lg/l. Serum tryptase > 25 lg/l is highly suggestive of an IgE-mediated mechanism. 5 Recently, Laroche  respectively. 29 Krishna proposed that an acute serum tryptase level elevated from baseline (percentage change> 141%, absolute quantification change > 15.7 lg/l) is highly predictive of IgE-mediated anaphylaxis, 12 whereas Sprung et al. recommended that the clinically significant elevation be at least 2 + 1.2 9 baseline level. 30 In our study, most of the patients in the culprit drug detected-group who underwent tryptase measurement exhibited elevated levels > 25 lg/l, with the exception of three patients (No7, 8 and 18) who had normal levels but suffered from grade 3 reactions (patient 18 tested positive by Sprung criteria 30 ). Normal tryptase levels do not exclude the possibility of anaphylaxis, which can remain normal in 36% of patients who had clinically defined anaphylaxis. 31 A possible explanation is anaphylaxis attributed to local release of tryptase (e.g. in laryngeal oedema), which may not be sufficient to increase the total serum tryptase concentration; alternatively, there may be a greater participation of basophils than mast cells in the mechanism of anaphylaxis in some situations. 32 Although there are limitations in the use of this biomarker, interpreting the result in the context of the clinical picture, and the baseline level of tryptase, provides useful information.
In the no-cause-identified group, three patients had elevated tryptase both by our and Sprung criteria 30 and one had normal tryptase. According to Gurrieri et al., 14 they could be classified as non-IgE and possible non-IgE mediated anaphylaxis, but it is also possible that our investigations or the clinical history missed hidden IgE-mediated culprit. Tryptase was not available for two patients and hence we were not able to comment on the mechanism of their reaction.
In conclusion, this study has demonstrated that in the United Kingdom, antibiotics and NMBAs are commonly implicated as causative agents of perioperative anaphylaxis. Despite the constant expansion of knowledge, the diagnosis of anaphylaxis during GA remains challenging for both anaesthetists and allergists.