There is fairly limited data about epidemiology and clinical practice of POA in China. From 2009 to 2020, our research team used both skin tests and BAT for assessment of perioperative allergen, and identified culprit agents in 55 cases out of 109 patients diagnosed with POA. The results demonstrated that these diagnostic tests were useful methods to find allergens responsible for POA. To our best knowledge, there are only a few anesthesia allergy research teams with ability to perform both in vivo and in vitro diagnostic tests, and this is the first retrospective study describing data on perioperative allergen detection in mainland of China.
Recent studies showed that POA appeared more frequent than initially assumed (Au et al. 2020). As the included patients were from different hospitals, this study was not able to provide the incidence of POA in China. However, some significant demographic features were still provided. For example, this study suggested a greater proportion of females (70.3%) for POA, which is consistent with the finding some previous works (Harboe et al. 2005; Huang et al. 2019). For example, a Singaporean study indicated that the female-to-male percentage for POA was 56.3: 43.8 (Harboe et al. 2005). Similarly, a 3:1 female-to-male ratio was also reported in a Norwegian study (Huang et al. 2019). A higher incidence POA in females may be due to cross-reactivity to cosmetics, which females are more commonly exposed to than males (Harboe et al. 2005). Cosmetics contain the quaternary ammonium group, which is an important structural component of available NMBAs. In addition, 63.3% of patients with a confirmed POA had a history of allergy, which is much higher than the data reported in the above Singaporean study (Harboe et al. 2005). It has been confirmed that a history of drug, food and other substances is a significant risk of POA (Ebo et al. 2019). Thus, allergy evaluation followed by anti-allergy premedication may play an important role in prevention of POA.
As POA is a consequence of multiple potential pathomechanisms and has heterogeneous clinical presentations (Harper et al. 2018), clinical manifestations and intraoperative diagnostic tests such as serum tryptase are needed to determine the occurrence of POA. However, serum tryptase test is rarely applied in China, and only clinical manifestations serve as the clue for diagnosis of POA in most cases, which poses a great challenge for anesthetists. Consistent with previous report (Patil et al. 2020), this study showed that the commonest clinical manifestations of patients with POA were cardiovascular symptoms, accounting for 57.8%, followed by respiratory and cutaneous symptoms. The immediate-phase response's proinflammatory mediators such as histamine, neutrophil and eosinophil chemotaxis factors, and proteolytic enzymes, are responsible for many clinical symptoms (Justiz et al. 2020). It is generally believed that the mediators promote histological changes. For example, histamine and lipid mediators can cause vascular leakage, and subsequent hypovolemia leading to reduced venous return and circulatory failure (Harper et al. 2018; Haybarger et al. 2016).
As avoidance of reexposure to culprits of POA is a key to ensure the safety of patients receiving subsequent anesthesia, identification of causative agents is of great significance for both patients and anesthetists. Since many drugs are administered intravenously in a few minutes during anesthesia induction, it is difficult to find the culprits just by reviewing drug history. Diagnostic tests, such as skin tests, BAT, and specific IgE, are the most crucial methods of allergen detection. It is recommended that skin tests including SPT and IDT should be applied to all cases with a clinical history supporting diagnosis of POA (Laguna et al. 2018). Despite a positive result of diagnostic tests has a high predictive value for patient with a history of POA, the results of SPT are usually negative (Takazawa et al. 2019), just as shown in this study. Both BAT and sIgE are in vitro diagnostic procedures, which have been suggested as useful supplements to skin tests, as they have the advantage with no risk of recurrence of immediate hypersensitivity reactions (Mertes et al. 2011). It is reported that BAT has a high diagnostic accuracy in identifying culprit agents of POA, with sensitivities of 50-90% and specificities >90% (Ebo et al. 2018). Our data showed that the results of skin tests and BAT significantly differed in various drugs, especially for the NMBAs and sedatives. Indeed, previous work revealed that sensitization of skin tests and BAT completely matched only in 15% of patients (Li et al. 2019a). It is worth noting that the positive rates of IDT and BAT in our study were 46.8% and 16.5%, respectively, which are significantly lower than previously published data. Kim’s study showed the BAT yielded positive results in 57.9% of the cases, which was similar to the results of SPT and IDT (42.1% and 57.9%, respectively) (Kim et al. 2016). The main reasons for low diagnostic sensitivity of these tests are that they are mainly used for IgE mediated allergy, and a considerable number of cases in this study might be non-IgE mediated allergy. Another possible explanation for these different results might be not all materials were tested in our diagnostic work up. To improve the efficacy of identifying culprits (Mertes et al. 2011), an integration of both BAT and skin tests was adopted for evaluation of POA in this study.
Our results showed that NMBAs were the main causative agents of POA, which is consistent with the findings of previous studies from other countries (Di Leo et al. 2018; Eberlein et al. 2017; Petitpain et al. 2018). Hypersensitive reaction to NMBAs may be either IgE or not-IgE mediated. The IgE-mediated hypersensitive response is mainly attributable to the quaternary ammonium structures that represent the main antigenic epitope of NMBAs (Di Leo et al. 2018). Environmental chemicals, such as cosmetics with quaternary ammonium structures, are responsible for anaphylactoid reaction(Rouzaire et al. 2013). In the general population, even if peoples do not have any clinical symptom, 9.3% of them have a positive skin test for specific IgE quaternary ammonium ions as in NMBAs (Hepner et al. 2003). Among the four NMBAs tested in our clinic, cisatracurium represented the first cause of POA, followed by rocuronium, atracurium, and succinylcholine. Recent work indicates isolated instances of modestly increased histamine levels after cisatracurium administration, which may cause POA (Berroa et al. 2015). Cisatracurium can also trigger mast cell degranulation and the release of pro-inflammatory mediators through MRGPRX2 (Che et al. 2018). In addition, cisatracurium can get into the circulating blood and cause systemic allergic reactions (Au et al. 2020). Besides, epitopes that are ubiquitous in NMBAs (such as substituted ammonium groups) lead to high cross-reactivity between these drugs (most consistently between pancuronium, rocuronium and vecuronium) (Di Leo et al. 2018). So, the previous exposure to non-anesthetic drugs may cause covert sensitization to NMBAs, resulting in reactions among patients without prior anesthesia.
It should be realized that the fundamental goal of allergen detection is avoidance of reexposure to culprits, and to ensure safety of subsequent anesthesia and surgery without allergic risk. Our study demonstrated that repeat anesthesia was safely performed in all patients receiving subsequent surgery, with none experiencing recurrent POA. This suggests that skin tests combined with BAT are useful for finding causative agents and suitable alternative drugs. However, further studies are still needed to prove our findings, due to insufficient sample size and data quality.
Overall, our study emphasizes the importance of referral procedure, accompanied by anesthetic information and allergy tests in identifying potential culprits. Although there is much diagnostic uncertainty, analysis of data on the outcome of repeat anesthesia and its congruence with results published by others validates our approach to the investigation of POA. For patients attending our clinic, it enables us to quantify future risk of POA after an assessment in our clinic and provides a benchmark for other anesthesiologists.