Comparison of the diagnostic performance of tryptase and histamine for perioperative anaphylaxis: A multicenter prospective study.

BACKGROUND: Diagnosing perioperative anaphylaxis (POA) is often challenging. Although a guideline recommends measuring tryptase rather than histamine, there is little evidence for this. We aimed to examine the diagnostic performance and appropriate timing of tryptase and histamine measurements for diagnosing anaphylaxis, and the association between Hypersensitivity Clinical Scoring Scheme (HCSS) scores and elevated biomarkers. METHODS: We measured tryptase and histamine levels thrice: 30 min, 2 h, and at least 24 h after an anaphylactic event for patients with suspected anaphylaxis, and at the induction of general anesthesia and 30 min and 2 h after the start of surgery for control patients without a reaction. Absolute values and the magnitude and rate of change from baseline were evaluated. We determined the thresholds of tryptase and histamine levels with the best diagnostic performance and compared their performance. RESULTS: Forty-five patients with perioperative anaphylaxis were included in this study. The control group included 30 patients with uneventful general anesthesia and 12 patients with a suspected but unconfirmed diagnosis of perioperative anaphylaxis. Comparison at the same measurement timings showed that tryptase generally had better diagnostic performance than histamine. Both showed better diagnostic performance when assessed using multiple measurements rather than a single measurement. The best diagnostic performance was seen with the percentage change in the higher tryptase value, whether measured at 30 min or 2 h after anaphylaxis onset, as compared to baseline. However, neither tryptase nor histamine levels correlated with HCSS scores. CONCLUSIONS: Overall, tryptase showed better diagnostic performance than histamine. When multiple tryptase measurements are possible, parameters calculated using two acute phase measurements and the baseline level have better diagnostic performance.

Investigating the optimal diagnostic value of histamine for diagnosing perioperative hypersensitivity: a prospective, observational study.

Although several guidelines recommend measuring blood tryptase and histamine concentrations to diagnose perioperative anaphylaxis (POA), tryptase measurement is more common. The appropriate timing of blood collection and the diagnostic threshold for histamine measurement are still controversial. To address these issues, histamine concentrations in patients with anaphylaxis and those with anaphylaxis-uncertain were compared in our previous study, the Japanese Epidemiologic Study for Perioperative Anaphylaxis (JESPA). However, because we could not rule out the possibility that the anaphylactic-uncertain group included anaphylactic patients, histamine concentrations were measured in patients who underwent general anesthesia with no complications as controls in the present study. Histamine levels were measured at anesthesia induction (baseline), 30 min (first point), and 2 h (second point) after the start of surgery in 30 control patients. Histamine concentrations in controls were lower than in patients with POA in JESPA at the first and second points. At the first point, a threshold of 1.5 ng/ml resulted in sensitivity of 77% and specificity of 100%. A threshold of 1.1 ng/ml at the second point resulted in sensitivity of 67% and specificity of 87%. Measurement of histamine concentrations within two hours after symptom onset might help diagnose POA.

The Japanese Epidemiologic Study for Perioperative Anaphylaxis, a prospective nationwide study: allergen exposure, epidemiology, and diagnosis of anaphylaxis during general anaesthesia.

BACKGROUND: Diagnosis of perioperative anaphylaxis is often challenging. This study describes the utility of a newly developed tool for identifying patients with a high possibility of anaphylaxis, and aimed to investigate the frequency of anaphylaxis with each drug during the perioperative period in Japan. METHODS: This study included patients with anaphylaxis of Grade 2 or higher severity during general anaesthesia at 42 facilities across Japan in 2019 and 2020. We developed and adopted a unique objective evaluation tool yielding a composite score for diagnosing anaphylaxis, which includes the results of skin tests and basophil activation tests, and clinical scores for perioperative anaphylaxis. The number of cases using each drug and the total number of anaphylaxis cases were investigated to calculate the frequency of anaphylaxis. RESULTS: General anaesthesia was performed in 218 936 cases, which included 55 patients with suspected perioperative anaphylaxis. The developed composite score diagnosed 43 of them with a high probability of anaphylaxis. The causative agent was identified in 32 cases. Plasma histamine levels showed high diagnostic accuracy for anaphylaxis. The top causative agents were rocuronium (10 cases in 210 852 patients, 0.005%), sugammadex (7 cases in 150 629 patients, 0.005%), and cefazolin (7 cases in 106 005 patients, 0.007%). CONCLUSIONS: We developed a composite tool to diagnose anaphylaxis, and found that the combination of tryptase levels, skin testing, and basophil activation testing results and clinical score improved the certainty of anaphylaxis diagnosis. The incidence of perioperative anaphylaxis in our study was 1 in about 5000 general anaesthesia cases. CLINICAL TRIAL REGISTRATION: UMIN000035350.

The Japanese Epidemiologic Study for Perioperative Anaphylaxis, a prospective nationwide study: clinical signs, severity, and therapeutic agents.

BACKGROUND: Diagnosis of perioperative anaphylaxis is difficult because of its non-specific and variable signs and symptoms. Therapeutic agents used to treat anaphylaxis and anaesthesiologist responses also vary depending on the case, which might affect outcomes; however, only a few studies have focused on these factors. METHODS: This prospective study of perioperative anaphylaxis, a part of the Japanese Epidemiologic Study for Perioperative Anaphylaxis, investigated the clinical signs, its severity, therapeutic drugs, epinephrine administration, and anaesthesiologist responses in cases of perioperative anaphylaxis to assess trends and variability. Shock index was used to assess severity of cardiovascular collapse. RESULTS: In 43 patients analysed in this study, cardiovascular signs (88.4%) were the most frequent, followed by skin (81.4%) and respiratory signs (60.5%). The presence of signs increased during the clinical course. The median time from the first signs to diagnosis of anaphylaxis was 10 (5.0-17.8) min. The rates of epinephrine use were 30.2% (unused), 48.8% (i.v.), and 20.9% (i.m.). The median time from diagnosis of anaphylaxis to epinephrine administration was 7 (inter-quartile range: 1.5-8.0) min. Antihistamines and corticosteroids were each used in 69.8% of cases. The worst shock index was higher in patients who received i.v. epinephrine (2.77 [0.90] mean [standard deviation]) than in both no epinephrine use cases (1.35 [0.41]) and i.m. epinephrine cases (1.89 [0.77] (P<0.001]). CONCLUSIONS: The clinical signs and treatments of perioperative anaphylaxis are variable, and the choice regarding epinephrine administration is based on symptom severity. CLINICAL TRIAL REGISTRATION: UMIN000035350.

Prevention of Postoperative Cognitive Dysfunction by Minocycline in Elderly Patients after Total Knee Arthroplasty: A Randomized, Double-blind, Placebo-controlled Clinical Trial.

BACKGROUND: There are no effective pharmacologic interventions for preventing postoperative cognitive dysfunction in daily practice. Since the antibiotic minocycline is known to suppress postoperative neuroinflammation, this study hypothesized and investigated whether minocycline might have a preventive effect on postoperative cognitive dysfunction after noncardiac surgery. METHODS: This study included patients aged more than 60 yr undergoing total knee arthroplasty under general anesthesia. They were randomly assigned to minocycline and placebo groups, to orally receive 100 mg of minocycline or placebo twice daily from the day before surgery until the seventh day after surgery. Cognitive function was evaluated before surgery, and 1 week and 3 months after surgery, using a battery of four cognitive function tests, including Visual Verbal Learning Test, Trail Making Test, Stroop Color and Word Test, and Letter-Digit Coding Task. Additionally, 30 healthy volunteers were subjected to the same tests as the patients to examine the learning effect of repeated tests. The occurrence of postoperative cognitive dysfunction was judged from the results of the neurocognitive test battery, with consideration of the learning effect. The secondary endpoints were the effects of minocycline on postoperative delirium and postoperative pain. RESULTS: A total of 100 patients were randomized to the minocycline group, and 102 were randomized to the placebo group. The average age of patients was 75 yr. Evaluation showed no significant difference in the incidence of postoperative cognitive dysfunction between the minocycline and placebo groups at both 1 week (8 of 90 [8.9%] vs. 4 of 95 [4.2%]; odds ratio, 2.22 [95% CI, 0.64 to 7.65]; P = 0.240) and 3 months (15.3 of 90 [17.0%] vs. 15.3 of 95 [16.1%]; odds ratio, 1.07 [95% CI, 0.49 to 2.32]; P = 0.889) postoperatively. Missing data 3 months after surgery were corrected by the multiple imputation method. There were no differences between the two groups in postoperative delirium and postoperative pain. CONCLUSIONS: Minocycline is likely to have no preventive effect on postoperative cognitive dysfunction.

Intraoperative chlorhexidine-induced anaphylaxis suggesting an immunoglobulin-E-dependent mechanism indicated by basophil activation tests: two case reports.

BACKGROUND: Although chlorhexidine allergy has been shown to be mediated by immunoglobulin (Ig) E, few reports investigated the mechanism of chlorhexidine-induced anaphylaxis using basophil activation tests (BATs). CASE PRESENTATION: A 79-year-old man underwent cholecystectomy under general anesthesia. Anaphylaxis was diagnosed based on the clinical symptoms and high serum tryptase and histamine levels. Skin tests showed positive results only for chlorhexidine. Subsequently, BATs demonstrated that the causative agent was likely chlorhexidine. The inhibitory effect of wortmannin, an inhibitor of phosphoinositide 3-kinase, on basophil activation suggested an IgE-dependent mechanism underlying chlorhexidine-induced anaphylaxis. An 89-year-old man underwent inguinal hernioplasty under general anesthesia. Anaphylaxis was diagnosed based on the clinical symptoms and high serum tryptase and histamine levels. Skin tests and BATs with wortmannin were performed, showing similar results to case 1. CONCLUSIONS: BATs suggested an IgE-dependent mechanism for chlorhexidine-induced anaphylaxis and might be useful for investigating the mechanisms underlying drug-induced anaphylaxis.

Intraoperative anaphylaxis due to aprotinin after local application of fibrin sealant diagnosed by skin tests and basophil activation tests: a case report.

BACKGROUND: There are few cases of anaphylaxis after local application of fibrin sealant diagnosed by skin tests. CASE PRESENTATION: A 49-year-old woman underwent partial lung resection under general anesthesia. Anesthesia was induced uneventfully. Shortly after applying absorbable suture reinforcement felt that contained fibrin sealant, her systolic blood pressure fell to approximately 70 mmHg, along with facial flushing. Anaphylaxis was diagnosed based on the clinical symptoms and high serum tryptase levels. Three months after the event, skin tests were performed with all agents and were positive only for fibrin sealant vial no. 2, whose main component is aprotinin. Subsequently, basophil activation tests using fibrin sealant vial no. 2 and pure aprotinin demonstrated that the causative agent was likely aprotinin. CONCLUSIONS: We diagnosed aprotinin-induced anaphylaxis using skin tests and basophil activation tests. The occurrence of anaphylaxis should be considered when changes in vital signs are observed after the use of fibrin sealant.

Possible immunoglobulin-E-dependent sugammadex-induced anaphylaxis caused by an epitope other than γ-cyclodextrin: a case report.

BACKGROUND: Sugammadex is a synthetic γ-cyclodextrin derivative designed to selectively bind to steroidal neuromuscular blocking agents and reverse their effects. Although many cases of sugammadex-induced anaphylaxis have been reported, few studies have investigated the underlying mechanism. CASE PRESENTATION: A 55-year-old Japanese man underwent a laryngectomy under general anesthesia. One month before laryngectomy, he had undergone laryngoscopy under general anesthesia and received sugammadex administration without causing hypersensitivity. He had no history of allergies. The operation was finished without complications. Shortly after sugammadex administration, his blood pressure dropped to approximately 70 mmHg, and his heart rate increased to 110 beats/minute with systemic erythema. Suspecting anaphylaxis, he was treated with the intravenous injection of phenylephrine, D-chlorpheniramine, and hydrocortisone. After these treatments, his cardiovascular condition stabilized. Eight months after the event, skin prick tests and intradermal tests with all agents used during general anesthesia were performed. Intradermal tests showed positive results only for sugammadex. Subsequently, basophil activation tests with CD203c were performed using sugammadex, γ-cyclodextrin, and positive controls (anti-immunoglobulin-E and formyl-methionyl-leucyl-phenylalanine). In addition to both controls, sugammadex, but not γ-cyclodextrin, induced significant upregulation of CD203c expression. We performed additional basophil activation tests with wortmannin, an inhibitor of phosphoinositide 3-kinase, to investigate the mechanism underlying sugammadex-induced basophil activation. The inhibitory effect of wortmannin on basophil activation due to sugammadex was similar to that of anti-immunoglobulin-E, suggesting an immunoglobulin-E-dependent mechanism. Although the patient showed no hypersensitivity after the first exposure of sugammadex, anaphylaxis appeared after the second administration. Because most cases of sugammadex-induced anaphylaxis reportedly appeared after first administration, this seems to be a rare case. CONCLUSIONS: In the present case, sugammadex-induced anaphylaxis might have occurred through an immunoglobulin-E-dependent mechanism and not involve γ-cyclodextrin as an epitope. Physicians should pay attention to the occurrence of sugammadex-induced anaphylaxis even when the patient has a history of safe administration of sugammadex.

Drug-induced anaphylaxis during general anesthesia in 14 tertiary hospitals in Japan: a retrospective, multicenter, observational study.

Since perioperative anaphylaxis occurs suddenly, and it can be life-threatening, anesthesiologists need to have sufficient knowledge of the epidemiology of perioperative anaphylaxis and appropriate coping strategies to deal with it. Recent studies conducted in Western countries reported the characteristics of perioperative anaphylaxis in each country. However, there are few studies of perioperative anaphylaxis in Japan. To bridge the gap between Japan and other countries, the data of 46 anaphylaxis patients at Gunma University Hospital and 13 neighboring hospitals between 2012 and 2018 were collected and analyzed. The recently developed clinical scoring system was combined with a skin test to include only cases with a definite diagnosis. The most common causative agents were sugammadex, followed by rocuronium, cefazolin, and antibiotics other than cefazolin. Furthermore, the characteristics of anaphylaxis for each causative drug were identified. Time from drug administration to appearance of the first symptom was the longest in the cefazolin group. The incidence of canceled operation was the highest in the rocuronium group. Although it is unclear whether the results of this study can apply to Japan as a whole, the information about the agents responsible for perioperative anaphylaxis and the characteristics of anaphylaxis due to each agent would be helpful to anesthesiologists.

Interpreting the results of early skin tests after perioperative anaphylaxis requires special attention: a case report and review of literature.

Skin tests are the gold standard for detecting the culprit drug of anaphylaxis, and should ideally be performed after an interval of 4-6 weeks after the reaction to avoid false-negative results. However, when re-operation cannot be delayed and early allergy tests are necessary, special attention is required during subsequent anesthesia, because early skin tests tend to produce false-negative results. This report presents a case of rocuronium-induced anaphylaxis in which early skin tests showed negative results for all the drugs tested. The second anesthesia was safely performed by avoiding all the drugs used for the first anesthesia. Ultimately, skin tests and basophil activation tests (BATs) performed after re-operation demonstrated rocuronium as the drug responsible for anaphylaxis. We recommend performing BATs in addition to skin tests to improve the accuracy of diagnosis of anaphylaxis. In this report, we also discuss interpretation of the results of early skin tests and subsequent selection of drugs for anesthesia. After postponement of surgery due to anaphylaxis, we are often required to perform allergy tests at an early stage if re-operation cannot be delayed. In such cases, skin test results alone should not be used to guide subsequent anesthesia management to avoid recurrent anaphylaxis.

Anaphylaxis caused by butylscopolamine bromide: a case report.

BACKGROUND: There have been only few reports on butylscopolamine-induced anaphylaxis despite its global usage as an anticholinergic agent for approximately 70 years. We present a case of anaphylaxis caused by butylscopolamine. CASE PRESENTATION: A 63-year-old woman underwent gastrointestinal endoscopic examination. She developed facial cyanosis and hypoxia after intravenous administration of butylscopolamine 10 mg, and her blood pressure was unmeasurable. Her hemodynamic condition recovered after a total of 0.6 mg adrenaline and bolus administration of 100 mg hydrocortisone. One hour after the onset of hypotension, both plasma histamine and serum tryptase were remarkably elevated to 271.7 nmol/L and 174 µg/L, respectively. Skin tests performed 47 days after anaphylaxis showed a positive result only for butylscopolamine among the exposed agents, which was confirmed by basophil activation tests using CD203c and CD63 as markers. CONCLUSION: Butylscopolamine has the potential to cause severe anaphylaxis; hence, identification of the causative agent is important to prevent recurrence of anaphylaxis.

Flow cytometric basophil activation tests: Staining of exteriorized basophil granule matrix by fluorescent avidin versus appearance of CD63.

BACKGROUND: Staining of exteriorized basophil granule matrix by fluorescent avidin might be a reliable technique to monitor basophil degranulation. This study compares the avidin-based technique with the upregulation of CD203c and appearance of CD63 in response to various stimuli. METHODS: Fourteen individuals responsive to anti-IgE, nine healthy controls, and five birch pollen-allergic patients, and five nonresponders were studied. Activation experiments included anti-IgE, fMLP, interleukin-(IL)-3, and birch pollen allergen. Basophil activation/degranulation was analyzed by flow cytometry and microscopy using anti-CD63, anti-CD203c, and avidin. RESULTS: Stimulation with anti-IgE, fMLP, and relevant allergen results in upregulation of CD203c, CD63 appearance, and an increase in avidin binding. In response to anti-IgE and allergen, upregulation of CD203c peaks within 10 min, CD63 and avidin binding reach a plateau after 10-20 min. CD63 staining leads to a bimodal distribution, avidin staining causes a unimodal shift with a less clear discrimination between degranulating and nondegranulating cells. In response to fMLP, upregulation of CD203c and CD63 and avidin binding are maximal after 2.5 min. Following incubation with anti-IgE and fMLP, percentages of CD203c+ cells are higher than those of CD63+ and avidin+ cells, pointing to a dissociation between activation and degranulation. Percentages of CD63+ cells are systemically higher than those of avidin+ cells. Incubated with IL-3 only upregulates CD203c, while no CD63 or avidin binding is observed. CONCLUSIONS: Staining of exteriorized proteoglycans by avidin is a reliable technique to quantify basophil degranulation but offers no added value when compared to traditional assays that use CD63 as a readout.

Comparison of incidence of anaphylaxis between sugammadex and neostigmine: a retrospective multicentre observational study.

BACKGROUND: Although cases of anaphylaxis caused by sugammadex have been reported, its incidence remains uncertain. Conversely, no studies have evaluated the incidence of anaphylaxis to neostigmine. METHODS: This was a retrospective multicentre observational study of patients who underwent surgery under general anaesthesia between 2012 and 2016 to compare the incidence of anaphylaxis with sugammadex with that of neostigmine at four tertiary hospitals in Japan. To ensure the quality of diagnosis, only cases with a clinical history suggestive of anaphylaxis, along with positive results from in vitro or in vivo testing, were assessed. RESULTS: From a total of 49 532 patients who received general anaesthesia included in this study, 18 cases of anaphylaxis were reported, of which six were attributable to sugammadex and none to neostigmine. There were no fatalities attributable to anaphylaxis. The incidence of anaphylaxis caused by all drugs or by sugammadex was calculated as 0.036% (95% confidence interval [CI]: 0.022-0.057%) and 0.02% (of the number of sugammadex cases) (95% CI: 0.007-0.044%), respectively. CONCLUSIONS: The results suggest that neostigmine might be safer than sugammadex when assessing only the incidence of anaphylaxis. We believe that there is room for reconsideration of the choice of reversal agent for neuromuscular blocking agents by all anaesthetists. CLINICAL TRIAL REGISTRATION: UMIN000022365; UMIN000033561.

Mepivacaine-induced anaphylactic shock in a pregnant woman undergoing combined spinal and epidural anesthesia for cesarean delivery: a case report.

BACKGROUND: Anaphylactic shock during pregnancy is a rare but life-threatening event for both the mother and the newborn. CASE PRESENTATION: A 42-year-old woman, who was pregnant with twins, was scheduled for cesarean delivery under combined spinal and epidural anesthesia. An epidural catheter was placed uneventfully. After spinal anesthesia, the patient exhibited skin symptoms and severe hypotension. The patient was diagnosed with anaphylaxis, and subsequently, treatment was started. Fetal heart rate monitoring revealed sustained bradycardia, and it was decided to proceed with cesarean delivery. After delivery, the mother's vital signs recovered. Both infants were intubated due to birth asphyxia. Currently, the twins are 4 years old and exhibit no developmental problems. Clinical examination identified mepivacaine as the causative agent of anaphylaxis. CONCLUSIONS: This case report highlights that upon occurrence of anaphylaxis during pregnancy, maternal treatment and fetal assessment should be started immediately. Indication for immediate cesarean delivery should be considered and a definite identification of the causative factor pursued.

Required cefazolin concentration to maximize diagnostic accuracy of the basophil activation test for cefazolin-induced anaphylaxis.

PURPOSE: Identifying the causative agent of perioperative anaphylaxis is key to preventing its recurrence. Besides skin testing, the basophil activation test (BAT) is increasingly being accepted as an additional and reliable method. Cefazolin seems to be a major cause of perioperative anaphylaxis. However, few studies have described use of the BAT for cefazolin-induced anaphylaxis. In this study, we aimed to determine the optimum cefazolin concentration required in the BAT for an accurate diagnosis. METHODS: Seven patients who presented with immediate hypersensitivity to cefazolin and 21 control subjects were studied. We conducted skin tests and performed BATs using both CD203c and CD63 as markers of activated basophils. We measured the ratio of activated basophils after stimulation with serial dilutions of cefazolin and investigated the cefazolin concentration that resulted in better sensitivity and specificity. RESULTS: All patients demonstrated positive reactions to cefazolin, while all control subjects showed negative reactions on skin tests. The net percentage of both CD203c- and CD63-labeled activated basophils was greater when higher concentrations of cefazolin than previously reported were used. In control subjects, however, the number of activated basophils by cefazolin stimulation was negligible regardless of its concentration. In the case of CD203c, the sensitivity was 86% with a cefazolin concentration of 3 mg/ml, while in the case of CD63, the sensitivity was 100% with a cefazolin concentration of 10 mg/ml. CONCLUSION: Using a higher concentration of cefazolin than previously reported for the BAT might increase the accuracy of diagnosis of cefazolin-induced anaphylaxis.

Usefulness of Basophil Activation Tests for Diagnosis of Sugammadex-Induced Anaphylaxis.

BACKGROUND: Sugammadex is used to reverse the effects of neuromuscular blocking agents in many cases of general anesthesia. However, there are several reports of anaphylaxis after its use. Skin testing is the gold standard for detecting the causative agent of anaphylaxis. However, due to the lack of validated protocols for skin testing with sugammadex, the diagnostic accuracy might be inadequate. Recently, the basophil activation test (BAT) has been established as a tool to detect the causative agent of anaphylaxis with high sensitivity and specificity. However, few studies have investigated the utility of the BAT for sugammadex-induced anaphylaxis. METHODS: Eight patients who presented with immediate hypersensitivity to sugammadex during general anesthesia were included in this study. We conducted skin tests to confirm the diagnosis of sugammadex-induced anaphylaxis. Twenty-one sugammadex-naive individuals who had a negative skin test for allergy to this drug were enrolled as controls. Basophils were selected on a CD3/CRTH2 gate and labeled with CD63 and CD203c. RESULTS: The ratios of activated basophils in the patients were much higher than those in controls: the median values of areas under the curves in the patients and controls for CD203c were 1,265,985 (95% confidence interval [CI], 77,580-5,040,270) and 116,325 (95% CI, -268,605 to 232,690), respectively (Mann-Whitney U test, P < .01), and the areas under the curves in the patients and controls for CD63 were 788,647 (95% CI, 120,285-3,523,410) and 220,005 (95% CI, -50,346 to 404,680), respectively (Mann-Whitney U test, P < .01). The patients, but not controls, demonstrated clear dose-dependent CD203c upregulation. This was also true for CD63. In the case of CD203c, the sensitivity of the BAT for sugammadex was 88% (95% CI, 47%-100%), and specificity was 100% (95% CI, 84%-100%), while sensitivity and specificity for CD63 were 75% (95% CI, 35%-97%) and 100% (95% CI, 84%-100%), respectively. CONCLUSIONS: The BAT seems to have comparable accuracy to skin tests for the diagnosis of sugammadex-induced anaphylaxis. For this purpose, both CD203c and CD63 can be used to detect activated basophils.