Suspected Accidental Infiltration of Rocuronium During General Anesthesia Induction: A Case Report.

There are few reports on rocuronium infiltration under general anesthesia. We report a case of suspected accidental rocuronium infiltration during anesthesia induction. A 25-year-old woman with autism spectrum disorder, intellectual disability, and epilepsy was scheduled for the extraction of 4 impacted third molars under general anesthesia. After induction with sevoflurane, an intravenous (IV) line was established in the left cephalic vein. Rocuronium was administered; however, subcutaneous swelling at the IV site was observed immediately. Spontaneous ventilations were maintained until additional rocuronium was administered via a new IV line. After heat pack application, the swelling disappeared 60 minutes after infiltration, and no tissue damage was observed. A strategy was developed to continue neuromuscular monitoring until recovery occurred. Acceleromyography was used, and the train-of-4 ratios at 99, 130, and 140 minutes after infiltration were 0.79, 0.91, and 1.0, respectively. Sugammadex was administered to prevent neuromuscular blockade recurrence. The patient was extubated once adequate return of muscle function and consciousness were observed. No neuromuscular block prolongation or recurrence were observed postoperatively. When rocuronium infiltration is suspected, it is important to eliminate swelling at the infiltration site and determine a management strategy based on neuromuscular monitoring.

General anesthesia with a transcutaneous pacemaker for a Noonan syndrome patient with advanced atrioventricular block discovered in the remote period after open-heart surgery: a case report.

We provided general anesthesia management to a patient with advanced atrioventricular block, which was discovered in the remote period after open-heart surgery. A 21-year-old man with Noonan syndrome was scheduled to undergo excision of a median intramandibular tumor. At 2 months of age, the patient underwent endocardial repair for congenital heart disease. During our preoperative examination, an atrioventricular block was detected, which had not been previously noted. Emergency drugs were administered, and a transcutaneous pacemaker was placed. During anesthesia induction, mask ventilation was easy, and intubation was performed smoothly using a video laryngoscope. The transcutaneous pacemaker was activated in demand mode at a pacing rate of 50 cycles/min approximately throughout the anesthesia time, and the hemodynamic status remained stable. The effect of intraoperatively administered atropine was brief, lasting only a few seconds. Although body movements due to thoracoabdominal muscle spasm were observed during pacemaker activation, they did not interfere with surgery. In postoperative patients with congenital heart disease, an atrioventricular block may be identified in the remote period, and preoperative evaluation should be based on this possibility. In addition, during anesthesia management, it is important to prepare multiple measures to maintain hemodynamic status.

Risk factors for postoperative nausea and vomiting in patients of orthognathic surgery according to the initial onset time: a cross-sectional study.

Background: A high incidence (40-73%) of postoperative nausea and vomiting (PONV) has been reported following orthognathic surgery, and various risk factors have been associated with it. Identifying PONV risk factors based on initial onset time will help establish preventive measures. This study aimed to identify factors that are significantly related to PONV based on the initial onset time after orthognathic surgery. Methods: This study included 590 patients who underwent orthognathic surgery. Multivariate logistic regression analysis was performed to identify the risk factors that are significantly related to PONV. The objective variables were classified into three categories: no PONV, early PONV (initial onset time: 0-2 h after anesthesia), and late PONV (initial onset time: 2-24 h after anesthesia). The explanatory variables included relevant risk factors for PONV, as considered in previous studies. Results: Total intravenous anesthesia with propofol was a significant depressant factor for early PONV (adjusted odds ratio [aOR] = 0.340, 95% confidence interval [CI] = 0.209-0.555) and late PONV (aOR = 0.535, 95% CI = 0.352-0.814). The administration of a combination of intraoperative antiemetics (vs. no administration) significantly reduced the risk of early PONV (aOR = 0.464, 95% CI = 0.230-0.961). Female sex and young age were significant risk factors for late PONV (aOR = 1.492, 95% CI = 1.170-1.925 and unit aOR = 1.033, 95% CI = 1.010-1.057, respectively). Conclusion: We identified factors that are significantly related to PONV based on the initial onset time after orthognathic surgery. Total intravenous anesthesia with propofol significantly reduced the risk of PONV not only in the early period (0-2 h after anesthesia) but also in the late period (2-24 h after anesthesia).

Anesthetic management of a pediatric patient with Dravet syndrome: A case report.

INTRODUCTION: Dravet syndrome (DS) is a rare and severe myoclonic epilepsy, with onset commonly occurring in infancy. Seizures are triggered by various causes, including fever, bathing, and light stimulus. DS is refractory to drug treatment. Moreover, status epilepticus (SE) can cause serious encephalopathy and epilepsy-related deaths. There are very few reports of general anesthesia in DS patients. Herein, we report our experience with the anesthetic management of a pediatric patient with DS. PATIENT CONCERNS AND DIAGNOSES: A 5-year-old boy (height, 112 cm; weight, 19 kg) was diagnosed with DS through SCN1A genetic testing, which revealed a de novo novel missense mutation. His medical history included drug-resistant epilepsy, developmental delay, and hypotonia. His seizures tended to be triggered daily by a rise in body temperature (BT), bathing, and light stimulus. He could not receive adequate dental treatment due to DS, although he had previously undergone dental treatment under restraint at the pediatric dentistry department of our hospital. INTERVENTIONS AND OUTCOMES: The patient was scheduled for intensive dental treatment under general anesthesia due to noncooperation, and DS-related limitations. By considering the risk posed by elevated BT, seizure-inducing drugs were avoided, and general anesthesia was completed as planned, uneventfully. Although fluctuation of BT occurred during the procedure, it was finally controlled at the end of anesthesia at about the same level as at anesthesia induction. However, small seizures and a single generalized convulsion were observed accompanied by fever on postoperative day 1. The patient was discharged from the hospital without major problems on postoperative day 3, because of detailed planning and close preoperative cooperation with the attending pediatrician. CONCLUSION: It is essential to pay attention to managing BT and to avoid drugs that induce seizures during anesthesia for patients with DS. Cautious preoperative planning for anesthesia based on evaluation of the patient and rapid postoperative response in collaboration with the attending pediatrician is necessary in case an epileptic seizure occurs.

Predictors of hypotension during anesthesia induction in patients with hypertension on medication: a retrospective observational study.

BACKGROUND: Hypotension during anesthesia induction is a common event, and occurs more frequently in patients with hypertension than in healthy individuals. Intraoperative hypotension in non-cardiac surgery is reportedly associated with various postoperative complications. However, the predictors of hypotension during anesthesia induction in patients with hypertension have not yet been ascertained. Therefore, we aimed to determine the predictors of hypotension during anesthesia induction in patients with hypertension on medication focusing on the half-life of the medication used. METHODS: In this retrospective observational study, we enrolled patients with hypertension on medication who underwent general anesthesia for oral and maxillofacial surgery between January 1, 2013, and December 31, 2019. Multivariable logistic regression analysis was conducted to test for associations between clinical factors and hypotension during anesthesia induction in patients with hypertension on medication. RESULTS: A total of 395 patients were included in this study. The risk factors for hypotension during anesthesia induction in patients with hypertension on medication were pre-induction mean arterial blood pressure (adjusted unit odds ratio, 0.96 [95% confidence interval, 0.94 to 0.98]), female sex (adjusted odds ratio [aOR], 1.63 [1.03 to 2.57]), regular use of angiotensin receptor blockers (ARBs)/angiotensin-converting enzyme inhibitors (ACE-Is) with a long half-life (vs. no regular use of ARBs/ACE-Is aOR, 4.02 [1.77 to 9.12]; vs. regular use of ARBs/ACE-Is with a short-to-middle half-life aOR, 3.17 [1.46 to 6.85]), and regular use of beta blockers (aOR, 2.45 [1.19 to 5.04]). Regular use of calcium channel blockers (aOR, 0.44 [0.25 to 0.77]) was a suppressive factor for hypotension during anesthesia induction in patients with hypertension. CONCLUSIONS: In patients with hypertension on medication, regular use of ARBs/ACE-Is with a long half-life, regular use of beta blockers, low pre-induction mean arterial blood pressure, and female sex were risk factors for hypotension during anesthesia induction. Notably, regular use of ARBs/ACE-Is with a long half-life was a high-risk factor for hypotension during anesthesia induction in patients with hypertension on medication even after a 24-h preoperative withdrawal period.

Cross-sectional Study of PONV Risk Factors for Oral Surgery After Intubated General Anesthesia With Total Intravenous Anesthesia.

OBJECTIVE: The incidence of postoperative nausea and vomiting (PONV) after general anesthesia with total intravenous anesthesia (TIVA) was reported to be significantly lower than with volatile inhalational agents (13.3% vs 25%). However, no investigation of PONV risk factors associated with TIVA has ever been reported. This cross-sectional retrospective study aimed to investigate whether known risk factors influenced PONV in intubated general anesthetics utilizing TIVA for dental or oral and maxillofacial surgery. METHODS: Subjects were 761 patients who underwent dental or oral and maxillofacial surgery under TIVA with propofol, fentanyl, and remifentanil. Univariate and multivariable logistic regression analyses were performed using PONV (within 24 hours) as the dependent variable and previously reported risk factors as independent variables. RESULTS: Age (odds ratio [OR]: 1.020 per year decrease; 95% confidence interval [CI]: 1.0002-1.0418; P = .047) and female sex (OR: 2.73; 95% CI: 1.60-4.84; P < .001) were positively associated with PONV. Sagittal split ramus osteotomy (SSRO) (OR: 2.28; 95% CI: 1.21-4.33; P = .011) and bimaxillary osteotomy (OR: 5.69; 95% CI: 2.09-15.99; P < .001) were more likely to be associated with PONV than operations that were neither bimaxillary osteotomy nor SSRO. Late PONV (2-24 hours) had an ∼2.7 times higher incidence than early PONV (0-2 hours). CONCLUSION: These findings suggest further PONV countermeasures, aside from TIVA with propofol and prophylactic antiemetics for orthognathic surgeries especially bimaxillary osteotomy, are needed.

Prolonged Washout Period for Avoiding Azilsartan-Induced Refractory Hypotension During General Anesthesia for a Patient With Renal Impairment.

Angiotensin receptor blockers (ARBs) are widely used to treat hypertension, but severe refractory hypotension during general anesthesia is a well-known complication associated with the continuation of ARBs during the perioperative period. It has therefore been recommended that ARBs be withheld for 24 hours before induction of general anesthesia. However, impaired renal function affects the pharmacokinetics of each ARB differently. The half-life of azilsartan is prolonged in accordance with the degree of renal impairment. Herein, we describe a patient with chronic kidney disease grade 3B who experienced severe refractory hypotension after induction of general anesthesia requiring administration of dopamine following inadequate responses to ephedrine and phenylephrine despite a 24-hour azilsartan washout period. When the same patient underwent general anesthesia for a subsequent surgery, azilsartan was withheld for 48 hours before induction, resulting in mild intraoperative hypotension that responded adequately to phenylephrine. Severe refractory hypotension during general anesthesia cannot always be avoided by holding azilsartan for 24 hours in patients with significant renal impairment. Therefore, a longer washout period may be preferable for patients regularly taking azilsartan who also have concurrent substantial renal impairment.

Anesthetic Management of a Rett Syndrome Patient at High Risk for Respiratory Complications.

Rett syndrome (RTT) is a rare genetic disorder that can present challenges in airway management during general anesthesia. This is a case report involving a 23-year-old woman with RTT who received an intubated general anesthetic 3 times for dental treatment. The patient also had severe scoliosis, was bedridden, and had dysphagia. These contributing factors likely led to the development of postoperative respiratory complications including pneumonia after the first case. As a result, several changes were incorporated into the 2 subsequent anesthetic plans in efforts to reduce the risk of such complications. Despite these measures, the patient was suspected of having bronchitis postoperatively after the second anesthetic, although the third occurred uneventfully. Anesthetic management alterations included use of desflurane for anesthetic maintenance and postoperatively delaying oral intake and instituting active postural changes.

Methemoglobinemia caused by a low dose of prilocaine during general anesthesia.

Methemoglobinemia is a blood disorder in which an abnormal amount of methemoglobin is produced, and prilocaine is one of the drugs that can cause this disorder. The maximum recommended dose of prilocaine is 8 mg/kg. We report a case of methemoglobinemia caused by the administration of 4.2 mg/kg of prilocaine without other methemoglobinemia-inducing drugs during general anesthesia. A 17-year-old girl with hyperthyroidism and anemia was scheduled to undergo maxillary sinus floor elevation and tooth extraction. The patient's peripheral oxygen saturation (SpO2) decreased from 100% at arrival to 95% after receiving prilocaine with felypressin following induction of general anesthesia. However, the fraction of inspired oxygen was 0.6. Blood gas analysis showed that the methemoglobin level was 3.8% (normal level, 1%-2%), fractional oxygen saturation was 93.9%, partial pressure of oxygen was 327 mmHg, and arterial oxygen saturation was 97.6%. After administration of 1 mg/kg of methylene blue, her SpO2 improved gradually to 99%, and the methemoglobin value decreased to 1.2%. When using prilocaine as a local anesthetic, it is important to be aware that methemoglobinemia may occur even at doses much lower than the maximum recommended dose.

A Case of Methemoglobinemia Thought to Have Been Caused by the Combined Use of Propitocaine and Nitroglycerin During General Anesthesia.

This is a case report of methemoglobinemia presumably caused by the combined use of prilocaine (propitocaine) and nitroglycerin under general anesthesia. Methemoglobinemia is reportedly caused by the administration of prilocaine at a dose of ≥8 mg/kg. Moreover, ≥3 µg/kg/min of nitroglycerin can also trigger methemoglobinemia. In this patient, methemoglobinemia occurred despite neither drug having been administered at the aforementioned doses. Even if individual doses of drugs predisposed to causing methemoglobinemia are low, combined use may increase the risk of methemoglobinemia.

Refractory Hypotension During General Anesthesia Despite Withholding Telmisartan.

Angiotensin receptor blockers (ARBs) are commonly used to treat hypertension. However, similar to angiotensin-converting enzyme inhibitors, ARBs can also cause refractory hypotension during general anesthesia. Therefore, it has been recommended that ARBs be withheld for 24 hours prior to the induction of anesthesia. This is a case report of refractory hypotension requiring the administration of potent vasopressors after the induction of general anesthesia despite withholding telmisartan for 24 hours. In the same patient undergoing a subsequent general anesthetic, telmisartan was withheld for 5 days before induction, leading to mild intraoperative hypotension that responded adequately to phenylephrine. The primary cause of refractory hypotension during the first general anesthetic was suspected to be an insufficient telmisartan washout period. Telmisartan's half-life of 24 hours is notably the longest of all ARBs in current use. This case report demonstrates that refractory hypotension during general anesthesia cannot always be avoided by withholding telmisartan for 24 hours before the induction of anesthesia. Therefore, a washout period greater than 24 hours is preferable for patients taking telmisartan.

Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment.

BACKGROUND: Tumor endothelial cells (TECs) perform tumor angiogenesis, which is essential for tumor growth and metastasis. Tumor cells produce large amounts of lactic acid from glycolysis; however, the mechanism underlying the survival of TECs to enable tumor angiogenesis under high lactic acid conditions in tumors remains poorly understood. METHODOLOGY: The metabolomes of TECs and normal endothelial cells (NECs) were analyzed by capillary electrophoresis time-of-flight mass spectrometry. The expressions of pH regulators in TECs and NECs were determined by quantitative reverse transcription-PCR. Cell proliferation was measured by the MTS assay. Western blotting and ELISA were used to validate monocarboxylate transporter 1 and carbonic anhydrase 2 (CAII) protein expression within the cells, respectively. Human tumor xenograft models were used to access the effect of CA inhibition on tumor angiogenesis. Immunohistochemical staining was used to observe CAII expression, quantify tumor microvasculature, microvessel pericyte coverage, and hypoxia. RESULTS: The present study shows that, unlike NECs, TECs proliferate in lactic acidic. TECs showed an upregulated CAII expression both in vitro and in vivo. CAII knockdown decreased TEC survival under lactic acidosis and nutrient-replete conditions. Vascular endothelial growth factor A and vascular endothelial growth factor receptor signaling induced CAII expression in NECs. CAII inhibition with acetazolamide minimally reduced tumor angiogenesis in vivo. However, matured blood vessel number increased after acetazolamide treatment, similar to bevacizumab treatment. Additionally, acetazolamide-treated mice showed decreased lung metastasis. CONCLUSION: These findings suggest that due to their effect on blood vessel maturity, pH regulators like CAII are promising targets of antiangiogenic therapy. Video Abstract.

Development of Immortalized Human Tumor Endothelial Cells from Renal Cancer.

Tumor angiogenesis research and antiangiogenic drug development make use of cultured endothelial cells (ECs) including the human microvascular ECs among others. However, it has been reported that tumor ECs (TECs) are different from normal ECs (NECs). To functionally validate antiangiogenic drugs, cultured TECs are indispensable tools, but are not commercially available. Primary human TECs are available only in small quantities from surgical specimens and have a short life span in vitro due to their cellular senescence. We established immortalized human TECs (h-imTECs) and their normal counterparts (h-imNECs) by infection with lentivirus producing simian virus 40 large T antigen and human telomerase reverse transcriptase to overcome the replication barriers. These ECs exhibited an extended life span and retained their characteristic endothelial morphology, expression of endothelial marker, and ability of tube formation. Furthermore, h-imTECs showed their specific characteristics as TECs, such as increased proliferation and upregulation of TEC markers. Treatment with bevacizumab, an antiangiogenic drug, dramatically decreased h-imTEC survival, whereas the same treatment failed to alter immortalized NEC survival. Hence, these h-imTECs could be a valuable tool for drug screening to develop novel therapeutic agents specific to TECs or functional biological assays in tumor angiogenesis research.

Combined Theoretical and Experimental Studies of Nickel-Catalyzed Cross-Coupling of Methoxyarenes with Arylboronic Esters via C-O Bond Cleavage.

Nickel(0)-catalyzed cross-coupling of methoxyarenes through C-O bond activation has been the subject of considerable research because of their favorable features compared with those of the cross-coupling of aryl halides, such as atom economy and efficiency. In 2008, we have reported nickel/PCy3-catalyzed cross-coupling of methoxyarenes with arylboronic esters in which the addition of a stoichiometric base such as CsF is essential for the reaction to proceed. Recently, we have also found that the scope of the substrate in the Suzuki-Miyaura-type cross-coupling of methoxyarenes can be greatly expanded by using 1,3-dicyclohexylimidazol-2-ylidene (ICy) as the ligand. Interestingly, a stoichiometric amount of external base is not required for the nickel/ICy-catalyzed cross-coupling. For the mechanism and origin of the effect of the external base to be elucidated, density functional theory calculations are conducted. In the nickel/PCy3-catalyzed reactions, the activation energy for the oxidative addition of the C(aryl)-OMe bond is too high to occur under the catalytic conditions. However, the oxidative addition process becomes energetically feasible when CsF and an arylboronic ester interact with a Ni(PCy3)2/methoxyarene fragment to form a quaternary complex. In the nickel/ICy-catalyzed reactions, the oxidative addition of the C(aryl)-OMe bond can proceed more easily without the aid of CsF because the nickel-ligand bonds are stronger and therefore stabilize the transition state. The subsequent transmetalation from an Ar-Ni-OMe intermediate is determined to proceed through a pathway with lower energies than those required for ß-hydrogen elimination. The overall driving force of the reaction is the reductive elimination to form the carbon-carbon bond.

ROS enhance angiogenic properties via regulation of NRF2 in tumor endothelial cells.

Reactive oxygen species (ROS) are unstable molecules that activate oxidative stress. Because of the insufficient blood flow in tumors, the tumor microenvironment is often exposed to hypoxic condition and nutrient deprivation, which induces ROS accumulation. We isolated tumor endothelial cells (TECs) and found that they have various abnormalities, although the underlying mechanisms are not fully understood. Here we showed that ROS were accumulated in tumor blood vessels and ROS enhanced TEC migration with upregulation of several angiogenesis related gene expressions. It was also demonstrated that these genes were upregulated by regulation of Nuclear factor erythroid 2-related factor 2 (NRF2). Among these genes, we focused on Biglycan, a small leucine-rich proteoglycan. Inhibition of Toll-like receptors 2 and 4, known BIGLYCAN (BGN) receptors, cancelled the TEC motility stimulated by ROS. ROS inhibited NRF2 expression in TECs but not in NECs, and NRF2 inhibited phosphorylation of SMAD2/3, which activates transcription of BGN. These results indicated that ROS-induced BGN caused the pro-angiogenic phenotype in TECs via NRF2 dysregulation.

Tumor endothelial cells express high pentraxin 3 levels.

It has been described that tumor progression has many similarities to inflammation and wound healing in terms of the signaling processes involved. Among biological responses, angiogenesis, which is necessary for tumor progression and metastasis, is a common hallmark; therefore, tumor blood vessels have been considered as important therapeutic targets in anticancer therapy. We focused on pentraxin 3 (PTX3), which is a marker of cancer-related inflammation, but we found no reports on its expression and function in tumor blood vessels. Here we showed that PTX3 is expressed in mouse and human tumor blood vessels based on immunohistochemical analysis. We found that PTX3 is upregulated in primary mouse and human tumor endothelial cells compared to normal endothelial cells. We also showed that PTX3 plays an important role in the proliferation of the tumor endothelial cells. These results suggest that PTX3 is an important target for antiangiogenic therapy.

Redox chemistry of nickel(II) complexes supported by a series of noninnocent ß-diketiminate ligands.

Nickel complexes of a series of ß-diketiminate ligands ((R)L(-), deprotonated form of 2-substituted N-[3-(phenylamino)allylidene]aniline derivatives (R)LH, R = Me, H, Br, CN, and NO2) have been synthesized and structurally characterized. One-electron oxidation of the neutral complexes [Ni(II)((R)L(-))2] by AgSbF6 or [Ru(III)(bpy)3](PF6)3 (bpy = 2,2'-bipyridine) gave the corresponding metastable cationic complexes, which exhibit an EPR spectrum due to a doublet species (S = 1/2) and a characteristic absorption band in near IR region ascribable to a ligand-to-ligand intervalence charge-transfer (LLIVCT) transition. DFT calculations have indicated that the divalent oxidation state of nickel ion (Ni(II)) is retained, whereas one of the ß-diketiminate ligands is oxidized to give formally a mixed-valence complex, [Ni(II)((R)L(-))((R)L(•))](+). Thus, the doublet spin state of the oxidized cationic complex can be explained by taking account of the antiferromagnetic interaction between the high-spin nickel(II) ion (S = 1) and the organic radical (S = 1/2) of supporting ligand. A single-crystal structure of one of the cationic complexes (R = H) has been successfully determined to show that both ligands in the cationic complex are structurally equivalent. On the basis of theoretical analysis of the LLIVCT band and DFT calculations as well as the crystal structure, the mixed-valence complexes have been assigned to Robin-Day class III species, where the radical spin is equally delocalized between the two ligands to give the cationic complex, which is best described as [Ni(II)((R)L(0.5•-))2](+). One-electron reduction of the neutral complexes with decamethylcobaltocene gave the anionic complexes when the ligand has the electron-withdrawing substituent (R = CN, NO2, Br). The generated anionic complexes exhibited EPR spectra due to a doublet species (S = 1/2) but showed no LLIVCT band in the near-IR region. Thus, the reduced complexes are best described as the d(9) nickel(I) complexes supported by two anionic ß-diketiminate ligands, [Ni(I)((R)L(-))2](-). This conclusion was also supported by DFT calculations. Substituent effects on the electronic structures of the three oxidation states (neutral, cationic, and anionic) of the complexes are systematically evaluated on the basis of DFT calculations.