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.

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.

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.

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.

Three suspected cases of sugammadex-induced anaphylactic shock.

BACKGROUND: Sugammadex has a unique mechanism of action and is widely used because of its safety and efficacy. A few recent reports have described allergic reactions to clinical doses of sugammadex. We hereby describe another series of cases of possible anaphylaxis to sugammadex. CASE PRESENTATION: We present three suspected cases of sugammadex-induced anaphylactic shock, including a 13-year-old boy who underwent laparoscopic appendectomy, a 75-year-old woman who underwent left knee arthroplasty, and a 34-year-old man who underwent left pansinectomy for sinobronchitis. All three patients received general anesthesia with rocuronium and their tracheas were intubated. Shortly after injection of sugammadex for reversal of rocuronium, all of them experienced a decrease in blood pressure along with mucocutaneous erythema. In the most severe case, reintubation after extubation was required due to difficulty in manual ventilation. All patients recovered with anti-allergic therapy. On later investigation, all three patients had a positive skin reaction to sugammadex. CONCLUSION: Our results suggest that physicians using sugammadex should be aware of the possibility of sugammadex-induced anaphylaxis.

[Case of unexpected intraoperative hyperkalemia].

We experienced a case of unexpected ECG abnormality with hyperkalemia. A 65-year-old man was suffering from maxillary sinus cyst and Caldwell-Luc procedure was scheduled. He had diabetes mellitus and hypertension for 15 years, and was taking oral hypoglycemic agent and hypotensive drug (angiotensin converting enzyme and angiotensin receptor blockers : ARB). Abnormal findings were HbA1c 7.7% and glycosuria over 1,000 mg x dl(-1). ECG and other laboratory tests were within normal limits. The patient was monitored with 3 leads ECG during the operation. At one hour and 33 minutes after the start of operation, we detected sudden ECG changes consisting of wide QRS wave and peaked T wave. We consider hyperkalemia and checked blood potassium concentration three times. The results were 5.8, 6.3, 6.2 mmol x l(-1), respectively. We treated the patient with calcium gluconate injection, saline infusion, furosemide injection and glucose-insulin therapy. The ECG was normalized one hour and 23 minutes after the abnormal ECG finding and the potassium concentration decreased to 4.8 mmol x min(-1). After the operation, the potassium concentration and creatinine clearance were within normal limits. Hyperkalemia in this case might have been induced by diabetes mellitus, administration of ACEI and ARB, and hypovolemia.

[Spinal subdural hematoma following spinal anesthesia in a patient without coagulation abnormalities].

We experienced an extremely rare complication of spinal anesthesia, a spinal subdural hematoma, in a 56-year-old man. Delayed paraplegia became apparent after the discharge from hospital, and at approximately 30 hours after the dural puncture. Surgical decompression of nerve fibers and removal of the hematoma were performed at 37 hours after the puncture. Neurological symptoms stared to recover immediately after the surgery, and at 3 months after the surgery, the patient mostly recovered his muscle powers and sensory functions. In the preoperative assessments, the patient did not have coagulation abnormality; however, several punctures were necessary for the proper needle placement during the spinal anesthesia procedure. Awareness of this rare complication, and the importance of rapid diagnosis by CT or MRI imaging followed by immediate surgical decompression should be emphasized to prevent permanent neurological deficits. Also, patients undergoing spinal anesthesia should be told to report back to hospital if they experience any neurological abnormalities.

Relationship between cardiac output and onset of succinylcholine chloride action in electroconvulsive therapy patients.

BACKGROUND: Succinylcholine chloride (Sch) is ideal for electroconvulsive therapy (ECT). However, the appropriate interval between Sch administration and electrical stimulation has not been reported. Cardiac output at the time of drug administration seems to be the major contributing factor for variability in onset time. The present study therefore investigated relationships between cardiac output before Sch administration and the onset of Sch action. METHODS: Cardiac output and cardiac index (CI) were continuously monitored in 24 patients using a noninvasive impedance cardiac output monitor. Anesthesia was induced using intravenous propofol at 1 mg kg(-1). After loss of consciousness, dorsiflexion of the hallux was monitored as single-twitch stimulations using a peripheral nerve stimulator equipped with an acceleration sensor. A 1 mg kg(-1) dose of Sch was administered, and patients were assisted by mask ventilation with 100% oxygen. A bilateral ECT was performed after single-twitch response reached zero. We measured the intervals between Sch administration and the appearance of the first fasciculation (int-F), and between Sch administration and the loss of the single twitch response (int-S0) as time of Sch onset. To determine the effective duration of Sch action, we measured the intervals between the first fasciculation and the single-twitch response above zero (int-A) and between loss of the single-twitch response and recovery above zero (int-R). RESULTS: The alteration in CI during ECT was biphasic. The CI before Sch administration (pre-CI) varied from 2.01 to 5.94 L min(-1) m(-2) (4.23 +/- 1.20 L min(-1) m(-2)). The int-F was 40 +/- 5 seconds (range, 31-49 seconds) and int-S0 was 90 +/- 17 seconds (range, 58-124 seconds). The correlations were significantly inverse between int-F and pre-CI (n = 10, R2 = 0.504, P = 0.0189), and between int-S0 and pre-CI (n = 17, R2 = 0.339, P = 0.0127). The int-A was 236 +/- 95 seconds (range, 119-391 seconds) and int-R was 184 +/- 106 seconds (range, 60-369 seconds). We also found correlations between int-A and pre-CI (n = 10, R2 = 0.413, P = 0.0438) and between int-R and pre-CI (n = 17, R2 = 0.405, P = 0.0466). CONCLUSIONS: The onset of muscle relaxation varies among patients receiving ECT and is related to CI before Sch administration. In patients for whom fasciculation is difficult to determine, the effects of a muscle relaxant should be objectively confirmed before electrical stimulation of the brain.

[Evaluation of a medical education program by medical students].

BACKGROUND: Clinical clerkship is widely performed in Japanese medical schools. To achieve a better understating of anesthetic medical program in clinical clerkship, simulation training including a high-fidelity simulator for medical students has become popular gradually in Japan. METHODS: A questionnaire survey was conducted by asking the students how they evaluate our departmental program. The questionnaires consist of 4 questions about the simulation using CD-R, intubation training, maintenance of anesthesia practice, and simulation using a high-fidelity simulator. RESULTS: Understanding and interest in intubation practice were equally high. Many students had a great interest in a high-fidelity simulator. CONCLUSIONS: Although our clinical clerkship program was highly evaluated by medical students, preparing texts before the program for the students seemed to be necessary to achieve better understanding.

[A pitfall of AirWay Scope--an experience of distinctive airway edema after palatal laceration caused by irWay Scope].

Pentax AirWay Scope (AWS) is a new videolaryngoscope which allows indirect visualization of the vocal cords and provides a better laryngeal view compared with the conventional Macintosh laryngoscope. We report a female patient who developed distinctive upper airway edema after palatal laceration at the time of insertion of the AWS. She was scheduled for tympanoplasty. After anesthesia induction, there was technical difficulties in tracheal intubation with Macintosh laryngoscope (her Cormack grade was rated as 3), and we used the AWS, but could not obtain an appropriate view on the monitor. When the device was removed, we detected bleeding derived from the right palatal laceration. Following the aspiration of the blood, we could barely achieve tracheal intubation with a flexible fiberscope without hypoxemic episode. The upper airway including the arytenoid and vocal cords were distinctively edematous after the operation. Then, the tracheal tube was left for three days after the operation, to secure the airway until the reduction of airway edema. On the postoperative day 4, following the fibroscopic confirmation that the airway edema was reduced, the patient was extubated successfully. AWS should be used more carefully, especially at the time of insertion along the palate.

Novel photoactive aggregates of rhodamine 6G: dequenched and quasi-stable aggregates induced by a dewetting process.

Self-organized rhodamine 6G particles prepared by wetting/dewetting process of an ethanol solution on a hydrophilic glass surface exhibits fluorescence without quenching, showing a sharp linewidth of 2 nm with a large redshift, which indicates an existence of dye aggregates, similar to J-aggregates, inside the particle. Polarized evanescent field excitation showed that the dye molecule's transition moment along the pi-conjugation was oriented unidirectionally within particles and parallel to the substrate surface. This deduced dye orientation showed correlation between adjacent, but separated, particles and pointed roughly 45 degrees off the dewetting direction. In contrast, the particles of another pi-conjugated NK1420 dye, J-aggregates of which grows easily from an oversaturated solution, showed dye orientation along the dewetting direction preferably, still indicating the effect of self-organization, however based on a different mechanism. An annealing procedure revealed that both aggregates are in quasi-stable states, which is consistent with the rapidness of the dewetting process that may lead to crystallization in nonequilibrium.

[Useful MRI findings for diagnosis of postspinal headache: a case report].

A 49-year-old man developed severe headache after spinal anesthesia. We found diffuse meningeal enhancement on gadolinium enhanced MRI and diffuse meningeal thickening on plain MRI. These MRI findings and postural headache suggest intracranial hypotension. Injection of autologous blood 10 ml into his epidural space was effective to ameliorate the headache. MRI findings were useful for the diagnosis of postspinal headache.

[Intra-operative pulmonary air embolism caused by left subclavian vein injury, during cervical tumor resection: a case report].

A 73-year-old male developed intra-operative pulmonary air embolism during cervical tumor resection under general anesthesia. Just after unexpected bleeding (about 700 ml) from the left subclavian vein, PetCO2 decreased suddenly from 32 mmHg to 22 mmHg, SpO2 decreased from 99% to 87% and systolic blood pressure decreased from 110 mmHg to 80 mmHg. Nitrous oxide was discontinued immediately, and blood transfusion and continuous infusion of dopamine (5 micrograms.kg-1.min-1) were started. In spite of the recovery of PetCO2 and blood pressure, hypoxemia (PaO2 54 mmHg at 100% oxygen) continued. The operation was discontinued and the patient was transferred to the intensive care unit. Postoperative chest radiograph showed findings of pulmonary edema. We suspected that the air embolism would have been induced by spontaneous respiration associated with the injury of the subclavian vein. Pulmonary edema may have been induced by pulmonary embolism and volume overload for the acute hemorrhage. The intra-operative pulmonary air embolism can be accelerated by use of nitrous oxide and spontaneous respiration.