Perioperative Hypersensitivity Reactions in Children: An 11.5-year Retrospective Cohort Study from a Japanese Tertiary Center

Abstract

Introduction: Perioperative allergic reactions (PARs) in children are rare but potentially life-threatening events. Epidemiological data remain limited, particularly in Asian populations. This study aimed to describe the clinical characteristics, timing, severity, and outcomes of pediatric PARs at a tertiary referral center in Japan.

Methods: We conducted a retrospective cohort study of pediatric patients (0–18 years) who developed suspected allergic reactions during the perioperative period and were referred to the Allergy Center at the National Center for Child Health and Development, Tokyo, between April 2005 and November 2016. Demographic data, anesthetic modality, timing of symptom onset, clinical severity, and results of allergy investigations were analyzed.

Results: Thirty children were identified: 17 cases associated with local anesthesia (LA) and 13 with general anesthesia (GA). The median age was 7.3 years, and 56.7% were male. Approximately 80% of the patients had no prior exposure to the suspected causative agent. Anaphylaxis occurred in 41.2% of LA-related reactions and 84.6% of GA-related reactions. According to the clinical scoring system, 76.9% of GA cases were classified as almost certain immediate hypersensitivity reactions, and hypotension was documented less frequently under LA (11.8%) than under GA (61.5%). Median time to symptom onset was significantly shorter under GA (5.0 minutes) compared with LA (30.0 minutes). The causative agent was confirmed by allergy testing in 17.6% of LA cases and 69.2% of GA cases. The incidence of in-hospital GA-related anaphylaxis with confirmed causative agents was 1.2 per 10,000 GA procedures.

Conclusions: Although uncommon, PARs in pediatric patients can be severe and may occur without prior allergen exposure. Anaphylaxis may develop rapidly under both LA and GA. Heightened perioperative vigilance—particularly for early signs such as hypotension—is essential regardless of a patient’s allergy history.

Key words: allergy, anesthesia, anaphylaxis, drug hypersensitivity, perioperative hypersensitivity, immediate hypersensitivity reactions

Introduction

Perioperative allergic reactions (PARs) are hypersensitivity events that occur between the induction of anesthesia and the completion of surgery. They are typically triggered by medications or substances administered during the perioperative period and can be life-threatening in severe cases, including anaphylaxis ⁽¹⁾.

The reported frequency of perioperative hypersensitivity in children is low; for example, one study identified an incidence of 0.03% among 2,861 pediatric surgical procedures ⁽¹⁾. Pediatric PARs differ from adult cases in several important respects. The spectrum of causative agents is distinct, with latex reported more frequently in children than in adults, in whom neuromuscular blocking agents (NMBAs) and antibiotics predominate ⁽²⁾. In recent years, the range of recognized perioperative allergens has expanded to include agents such as chlorhexidine and sugammadex, reflecting changes in anesthetic practice ⁽³⁾. In addition, diagnostic evaluation in pediatric patients is often more challenging because of age-related physiological factors and limitations in symptom reporting, necessitating age-specific diagnostic and management strategies.

Despite their clinical importance, epidemiological data on pediatric perioperative hypersensitivity remain limited, particularly in Japan. Most existing evidence is derived from studies conducted outside Japan, and no Japanese reports have described more than 10 pediatric cases or comprehensively evaluated their long-term clinical course. Consequently, the precise incidence and clinical characteristics of pediatric perioperative hypersensitivity in Japan remain unclear. This study aimed to clarify the epidemiology, clinical characteristics, and causative agents of PARs in pediatric patients in Japan and to investigate their subsequent long-term clinical outcomes.

Materials and Methods

Ethical considerations

This study was approved by the Ethics Committee of the National Center for Child Health and Development (NCCHD) (approval number: 1468). Due to the retrospective nature of the study, the requirement for informed consent was waived. Information regarding the study and an opt-out option for the use of medical record data were made publicly available on the NCCHD website.

Study design and setting

The NCCHD is a national tertiary referral center for maternal and pediatric care in Tokyo, Japan. It performs approximately 5,000 anesthetic procedures annually and provides specialized consultations for PARs. We conducted a retrospective cohort study using medical records of pediatric patients referred to the Allergy Center of the NCCHD. Eligible participants were children aged 0-18 years who were referred between April 2005 and November 2016 for evaluation of suspected allergic reactions occurring during the perioperative period, defined as the time from the induction of local anesthesia (LA) or general anesthesia (GA) to the completion of surgery or the immediate postoperative phase. The study period was defined based on the availability of comprehensive allergy consultation records and a period during which evaluation items were consistently documented at our department. We analyzed 11.5 years of data as a methodologically consistent cohort with adequate follow-up. As patients from 2017 onward have been followed separately, this analysis was limited to the period from April 2005 to November 2016. Additionally, for in-hospital patients, cases of suspected drug hypersensitivity occurring during or after anesthesia are referred to our Allergy Center at the discretion of the attending physician in each department. Patients from outside institutions are referred to our center at the discretion of the attending physician when drug hypersensitivity reactions are suspected after anesthesia. Furthermore, for patients referred from within our institution, clinical outcomes were reviewed in the medical records up to February 2026.

Data collection and clinical evaluation

Clinical data were extracted from medical records, including patient demographics (age and sex), relevant medical history (e.g., atopic conditions and prior drug or food allergies), surgical and anesthetic details, characteristics of the hypersensitivity reaction (time of onset, clinical manifestations, and severity), and treatments administered.

Anaphylaxis was defined according to established clinical diagnostic criteria ^{(4), (5)}. Anaphylaxis was considered likely when any one of the following conditions was fulfilled:

1. Acute onset (minutes to hours) involving skin or mucosal symptoms (e.g., urticaria, pruritus, flushing, or angioedema) accompanied by either respiratory compromise (e.g., dyspnea, wheezing, bronchospasm, or stridor) or hypotension and/or related symptoms (e.g., hypotonia or syncope);

2. Two or more symptoms occurring rapidly after exposure to a known allergen for that patient, including skin/mucosal involvement, respiratory compromise, and hypotension or associated symptoms;

3. Hypotension alone occurring within minutes to hours after exposure to a known allergen.

In pediatric patients, hypotension was defined as a systolic blood pressure below age-specific thresholds (<70 mmHg for 1 month-1 year; <70 mmHg + [2 × age in years] for 1-10 years; and <90 mmHg for 11-17 years) or a decrease of more than 30% from baseline. In patients aged 18 years, hypotension was defined as a systolic blood pressure <100 mmHg or a decrease of more than 30% from baseline.

Clinical scoring of immediate hypersensitivity reactions (IHRs)

Patient symptoms were assessed using a standardized clinical scoring system for suspected perioperative IHRs. This system evaluates five domains—cardiovascular, respiratory, dermal/mucosal, combined manifestations, and timing—assigning positive or negative scores to findings that support or argue against an IHR, respectively. The total clinical score was calculated as the sum of scores across all domains; detailed definitions of individual scoring items are provided in the supplementary materials.

Based on the total score, the likelihood of an IHR was categorized as almost certain when the score exceeded 21, very likely for scores between 15 and 21, likely for scores between 11 and 14, possible for scores between 8 and 10, and unlikely for scores below 8.

Diagnostic investigations

Results of diagnostic investigations performed to identify causative agents were recorded. These included serum tryptase measurements (when available), skin prick tests (SPTs), intradermal tests (IDTs), and total serum immunoglobulin E (IgE) assays. Total IgE levels were measured using the ImmunoCAP system (Thermo Scientific Inc., Uppsala, Sweden).

Skin testing was conducted at least 4-6 weeks after the reaction to minimize false-negative results due to the postreaction refractory period ^{(5), (6), (7), (8)}. Nonirritating concentrations for skin testing were based on published recommendations. In selected cases, IDTs were performed even when SPT results were positive or when confirmation of negative SPT results was required. Although latex-containing products are not routinely used at the NCCHD, latex testing was performed for patients referred from other institutions when latex exposure was considered a possible cause.

Statistical analysis

Descriptive statistics were used to summarize patient characteristics, clinical features, suspected causative agents, and diagnostic test results. Categorical variables are presented as frequencies and proportions and continuous variables as medians with ranges. Analyses were performed using Microsoft Excel or equivalent spreadsheet-based software.

Results

Baseline characteristics

Baseline characteristics of the study population are summarized in Table 1. A total of 30 pediatric patients were included, of whom 17 experienced allergic reactions during procedures performed under LA and 13 during those under GA. The median age was 7.3 years, and 56.7% of the patients were male. Nearly half of the patients (46.7%) were referred from within our institution, while the remaining 53.3% were referred from outside hospitals. A history of allergic disease was documented as follows: asthma in 23.3% (7/30) of patients, atopic dermatitis in 20.0% (6/30), food allergy in 26.7% (8/30), and allergic rhinitis in 30.0% (9/30). Most patients had no prior exposure to the suspected causative agent. Specifically, 76.5% of patients in the LA group and 84.6% in the GA group had no previous exposure, corresponding to an overall proportion of 80.5%.

Clinical manifestations and severity

The distribution of clinical manifestations under LA and GA is shown in Figure 1. Erythema was observed in 58.8% (10/17) of LA cases and 100% (13/13) of GA cases. Dyspnea occurred in 35.3% (6/17) and 76.9% (10/13) of LA and GA cases, respectively, while wheezing was observed in 29.4% (5/17) and 69.2% (9/13) of cases. Hypotension was less frequent in LA cases (11.8%, 2/17) than in GA cases (61.5%, 8/13), whereas gastrointestinal symptoms were observed only in LA cases (47.1%, 8/17). Among the GA cases, erythema was the initial manifestation in two cases, was observed concurrently with hemodynamic changes or ventilatory impairment in seven cases, and was observed after these manifestations in four cases.

Figure 1. Patients’ symptoms.
The distribution of clinical manifestations under LA and GA is shown in Figure 1. Erythema was observed in 58.8% (10/17) of LA cases and 100% (13/13) of GA cases. Dyspnea occurred in 35.3% (6/17) and 76.9% (10/13) of LA and GA cases, respectively, while wheezing was observed in 29.4% (5/17) and 69.2% (9/13) of cases. Hypotension was less frequent in LA cases (11.8%, 2/17) than in GA cases (61.5%, 8/13), whereas gastrointestinal symptoms were observed only in LA cases (47.1%, 8/17). Anaphylaxis was diagnosed in 41.2% (7/17) of LA cases and 84.6% (11/13) of GA cases. The median time to symptom onset was 30.0 minutes in LA cases and 5.0 minutes in GA cases (Table 1).
GA: general anesthesia; LA: local anesthesia.

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Anaphylaxis was diagnosed in 41.2% (7/17) of LA cases and 84.6% (11/13) of GA cases. The median time to symptom onset was 30.0 minutes in LA cases and 5.0 minutes in GA cases (Table 1).

Using the clinical scoring system for perioperative IHRs, the likelihood of IHRs differed markedly between the groups. In the LA group, reactions were classified as almost certain in two cases (11.8%), very likely in six cases (35.3%), likely in five cases (29.4%), possible in one case (5.9%), and unlikely in three cases (17.6%). In contrast, most GA cases were classified as almost certain IHRs (10 cases, 76.9%), with the remainder categorized as likely (2 cases, 15.4%) or possible (1 case, 7.7%) (Table 1 and Table 2).

Among the 13 GA cases, surgery was discontinued because of allergic symptoms in 11 cases. In one case, surgery proceeded after recovery from symptoms, whereas in another case, symptoms developed after surgery had been completed.

Results of allergy testing

Table 1 summarizes the results of diagnostic testing. In the LA group, positive results were obtained in 16.7% (2/12) of patients for SPTs and in 25.0% (1/4) for IDTs. In contrast, substantially higher positivity rates were observed in the GA group, with 66.7% (6/9) for SPTs and 100% (6/6) for IDTs. Drug provocation tests (DPTs) were performed in two patients with negative IDT results in each group, and all tests yielded negative results.

Overall, the causative agent was identified through allergy testing (SPTs, IDTs, and/or DPTs) in three patients (17.6%) in the LA group and in nine patients (69.2%) in the GA group, corresponding to 40.0% of the entire cohort. Among patients who developed anaphylaxis, the causative agent was identified in 2 of 7 LA cases (28.6%) and in 9 of 11 GA cases (81.8%), yielding an overall identification rate of 61.1% (Table 1 and Table 3).

In the LA group, the causative drug was identified in three of 17 cases based on SPT and IDT results. In the remaining 14 cases, identification was not possible for several reasons: in five cases, anaphylaxis had occurred, and further testing was considered unsafe; in four cases, IHR was suspected based on clinical course and drug exposure, but testing was not performed due to safety concerns; in three cases, alternative diagnoses such as vasovagal syncope, hyperventilation syndrome, or drug toxicity were suspected; and in two cases, the IHR score was low, and patients declined further evaluation.

In the GA group, the causative agent was identified in nine of 13 cases. Among the four cases without definitive identification, anaphylaxis had occurred in two cases in which NMBAs or reversal agents were suspected, but testing was not performed because of safety concerns. In the remaining two cases, testing was omitted because of low clinical likelihood of IHR or patient preference.

Causative agents

The first section of Table 2 presents the distribution of causative agents confirmed by SPTs, IDTs, or DPTs. In the LA group, latex was the most frequently identified trigger, accounting for 66.7% (2/3) of confirmed cases, followed by antibiotics (33.3%, 1/3). In the GA group, NMBAs—most commonly rocuronium—were the leading causative agents (44.4%, 4/9), followed by antibiotics, predominantly cephalosporins (33.3%, 3/9), latex (11.1%, 1/9), and other agents, including plasma substitute (11.1%, 1/9).

The second section of Table 2 presents the distribution of highly suspected causative agents, including those that could not be definitively confirmed because of the risk of inducing anaphylaxis. Under LA, anesthetics such as lidocaine with adrenaline bitartrate were most frequently suspected (58.3%, 7/13), followed by antibiotics and latex (each 16.7%, 2/13) and contrast media (8.3%, 1/13). Under GA, NMBAs were again the most commonly suspected triggers (31.3%, 5/16), followed by antibiotics (25.0%, 4/16), general anesthetics such as propofol and contrast media (12.5%, 2/16), and neuromuscular blockade reversal agents and latex (each 6.3%, 1/16).

When analysis was limited to patients with anaphylaxis, the most frequently suspected causative agents under LA were anesthetics and latex (each 40.0%, 2/5), followed by antibiotics (20.0%, 1/5), while the causative agent remained unidentified in 20.0%.

Under GA, NMBAs accounted for 33.3% (5/15), antibiotics for 26.7% (4/15), and contrast media for 13.3% (2/15); anesthetics, neuromuscular blockade reversal agents, latex, and other agents were each implicated in 6.7% (1/15). (When there is a risk of anaphylaxis, allergy testing cannot be performed; therefore, these data include cases where multiple causative substances are suspected.) No blood transfusions were administered in this cohort.

Table 3 summarizes the anesthetic purpose, clinical score category, suspected agents, causative agents, and outcomes for each patient. Each patient underwent removal of the suspected agent and/or substitution with alternative medications. Among the patients referred within our institution, no recurrences have been observed as of February 2026.

During the 11.5-year study period, a total of 57,331 GA procedures were performed. Seven cases of anaphylaxis with confirmed causative agents were identified, an estimated incidence of 1.2 per 10,000 GA procedures.

Discussion

To our knowledge, this is the first Japanese case series describing the clinical characteristics, incidence, and subsequent clinical course of pediatric perioperative hypersensitivity reactions, including perioperative anaphylaxis (PA). Reported frequencies vary across studies and countries, with national surveillance programs estimating severe PA at approximately 1 per 10,000 anesthetic procedures ^{(9), (10), (11), (12)}. In Japan, pediatric-specific data remain limited, although a predominantly adult cohort reported suspected and probable PA rates of 2.5 and 2.1 per 10,000 procedures, respectively, with causative agents identified in 58% of cases ⁽¹³⁾. During the study period, the incidence of GA-related anaphylaxis with confirmed causative agents was 1.2 per 10,000 procedures, and the overall causative-agent identification rate was 40%, consistent with previous reports ⁽¹³⁾.

Most anaphylaxis cases in our cohort occurred under GA, accounting for 85% of reactions, although a substantial proportion of LA cases also met diagnostic criteria for anaphylaxis. Severe reactions were therefore more common during GA, but LA also carried significant risk. Previous pediatric studies similarly reported hypotension as a frequent initial manifestation of PA ⁽¹⁴⁾. In our study, hypotension was also more common in GA-associated reactions.

Recognition of PARs during GA is challenging because patients cannot report symptoms, cutaneous findings may be obscured by surgical drapes, and anesthetic agents may confound hemodynamic changes. Mechanical ventilation may also mask early airway compromise ⁽¹⁵⁾. These factors may delay diagnosis, highlighting the importance of prompt recognition of unexplained hypotension and other early warning signs.

Compared with previous adult reports, our study suggested differences in perioperative hypersensitivity reactions between children and adults. Cutaneous symptoms were observed in all GA cases in our cohort, whereas adult studies have reported predominant cardiovascular manifestations with less recognizable cutaneous symptoms ⁽¹⁰⁾. Several mechanisms may contribute to these differences. First, children generally have fewer cardiovascular comorbidities and less endothelial dysfunction than adults. Because peripheral circulation is relatively preserved, cutaneous vasodilation and erythema may become clinically apparent before progression to severe cardiovascular collapse, whereas adults with hypertension, atherosclerosis, or endothelial dysfunction may present predominantly with cardiovascular instability ^{(15), (16)}. Second, developmental differences in immune and autonomic responses may also influence the clinical phenotype. A previous report suggests that mast cell mediator release, vascular responsiveness to histamine, and compensatory autonomic responses vary with age ⁽¹⁷⁾. Third, adults are more likely to receive antihypertensive medications and have underlying cardiovascular disease, potentially affecting intraoperative hemodynamics and clinical presentation.

Next, regarding the incidence of anaphylaxis, a previous Japanese adult study reported incidences of 0.059% for intraoperative anaphylaxis and 0.039% for sugammadex-associated anaphylaxis, whereas the incidences in our study were lower at 0.012% and 0.0017% (1/57,331), respectively ^{(13), (18)}. These findings may reflect several factors. First, pediatric patients may have fewer perioperative drug exposures and sensitization opportunities than adults. Repeated exposure to antibiotics, antiseptics, latex, and perioperative drugs has been associated with sensitization and perioperative hypersensitivity reactions in adults ^{(9), (11), (18)}. Second, chronic comorbidities and polypharmacy are less common in children than in adults. Adult patients are more frequently exposed to cardiovascular medications and repeated antimicrobial therapy, which may influence immune sensitization and increase the risk of severe reactions ⁽¹⁰⁾. Third, perioperative management may differ between pediatric and adult anesthesia practice. Differences in prophylactic antibiotic selection, neuromuscular blockade strategies, reversal agent use, and anesthetic protocols may influence allergen exposure patterns and recognition of perioperative hypersensitivity reactions ⁽¹⁹⁾.

Consistent with previous pediatric and adult studies, NMBAs and antibiotics were the most frequently identified causative agents in our cohort ^{(13), (20), (21)}. However, regarding the distribution of causative agents, the introduction of a neuromuscular blockade reversal agent in Japan in 2010 may have influenced the pattern of perioperative hypersensitivity reactions during the study period, which represents a limitation of this study. Other reported triggers, including dyes, latex, chlorhexidine, neuromuscular blockade reversal agents, inhalational anesthetics, plasma expanders, and excipients such as polyethylene glycol and polysorbates, have been increasingly recognized in the literature ⁽²²⁾. Notably, latex remained an important trigger in our cohort, highlighting the need to consider latex exposure even in institutions where latex-containing products are not routinely used.

The identification rate of causative agents was substantially lower in the LA group than in the GA group. In GA-associated reactions, causative agents were often identified by SPTs and IDTs, whereas negative or inconclusive results were more common in LA cases. Importantly, several patients in the LA group experienced anaphylaxis despite negative test results. Because DPT with suspected local anesthetics was considered unsafe, definitive identification of the causative agent was frequently not possible, and management generally relied on avoidance of the suspected drug and use of alternative agents.

Differentiating allergic reactions to local anesthetics from nonallergic adverse events remains a major diagnostic challenge. Previous studies have shown that most adverse reactions following local anesthetic administration are attributable to nonallergic mechanisms, including vasovagal syncope, hyperventilation syndrome, drug toxicity, incorrect administration, or the pharmacological effects of coadministered adrenaline ^{(23), (24), (25), (26)}. These reactions are typically not accompanied by cutaneous manifestations. Accordingly, the presence of skin symptoms in combination with cardiovascular and/or respiratory compromise increases the likelihood of an allergic etiology. DPTs remain controversial in this context because of ethical and safety concerns and should only be considered in carefully selected cases in settings equipped for emergency management.

Notably, approximately 80% of patients in our cohort had no prior exposure to the suspected causative agent, indicating that first-time administration does not preclude the development of perioperative hypersensitivity. This finding is consistent with previous reports demonstrating that anaphylaxis may occur in patients without a history of GA or known drug allergy ^{(20), (27)}. Although our sample size precluded formal risk factor analysis, a high proportion of patients who developed reactions under GA had a history of asthma. Previous studies have identified asthma and other allergic conditions as potential risk factors for anesthetic-induced anaphylaxis, suggesting that increased vigilance may be warranted in pediatric patients with allergic comorbidities ^{(28), (29)}.

The influence of race and ethnicity on pediatric perioperative hypersensitivity reactions remains largely unexplored. Although large-scale data are limited, studies of general anaphylaxis suggest that British South Asian children may be at higher risk of severe reactions ⁽²⁹⁾. In addition, drug allergy patterns differ by race and ethnicity. For example, carbamazepine-induced Stevens–Johnson syndrome/toxic epidermal necrolysis is more common in Southeast Asian populations carrying HLA-B*15:02, whereas penicillin allergy labeling is more frequent in White populations ^{(30), (31), (32)}. There have been reports on pediatric perioperative allergies from European countries ^{(33), (34)}; however, reports from Asian countries are limited. These observations highlight the need for future multiethnic cohort studies to clarify whether the risk of perioperative hypersensitivity reactions differs across ethnic groups.

This study has several limitations. Its retrospective design may have affected the completeness of clinical documentation and diagnostic evaluation. As a single-center study, the generalizability of the findings is limited, and multicenter studies are needed to validate these results. This study is based on data from patients who were referred to our Allergy Center at the discretion of the attending physician. Although the referral rate is presumed to be high in severe cases, mild cases may not always be referred. Therefore, the true incidence of perioperative hypersensitivity reactions may have been underestimated, which represents a limitation of this study. In addition, skin testing is operator dependent, and advanced diagnostic tools such as basophil activation tests and routine perioperative tryptase measurements were not consistently available. Finally, positive skin test results do not necessarily indicate IgE-mediated mechanisms, as IgE-independent pathways—such as activation of the Mas-related G protein–coupled receptor X2 (MRGPRX2)—may also contribute to perioperative reactions.

Conclusion

Although perioperative hypersensitivity reactions are uncommon in children, our findings highlight three key clinical implications:

1. PARs in pediatric patients can be severe and may occur without prior allergen exposure.

2. Anaphylaxis may develop rapidly under both LA and GA.

3. Heightened perioperative vigilance—particularly for early signs such as hypotension and ventilatory impairment—is essential regardless of a patient’s allergy history.

4. With appropriate management, such as removal of the suspected agents or selection of alternative medications, recurrence is not observed long term.

This retrospective cohort study provides the first detailed characterization of pediatric perioperative hypersensitivity reactions in Japan and may serve as a reference for clinical assessment and management. On the basis of these findings, we plan to establish a nationwide multicenter registry to improve the recognition, diagnosis, and prevention of perioperative hypersensitivity in pediatric patients.

Article Information

Acknowledgments

We thank the children and their families for participating in our study. Grammarly supported English editing.

Author Contributions

Yumiko Miyaji and Kiwako Yamamoto-Hanada contributed to the conception and design of the study. Yumiko Miyaji performed the data analysis and prepared the study results. All authors contributed to the interpretation of the data. YM and Kiwako Yamamoto-Hanada drafted the manuscript. Tatsuki Fukuie participated in the critical review, drafting, and final approval of the manuscript. All authors critically revised the manuscript for important intellectual content, approved the final version for publication, and agree to be accountable for all aspects of the work.

Conflicts of Interest

None

Funding

This study was funded by the National Center for Child Health and Development, Japan. This article’s findings and conclusions are solely the authors’ responsibility.

Ethical Considerations

This study was approved by the Ethics Committee of the National Center for Child Health and Development (approval number: 1468). Because of the retrospective study design, the requirement for informed consent was waived. Information about the study, including the option to opt out of the use of medical record data, was publicly disclosed on the National Center for Child Health and Development website.

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