Total Intravenous Anesthesia Using Remimazolam and Continuous Cardiac Output Monitoring for Dental Anesthesia in a Patient With Takayasu's Arteritis: A Case Report.

Takayasu's arteritis is a persistent chronic progressive inflammation of the large- and medium-caliber arteries. Controlling cardiovascular variability during anesthesia and overcoming difficulties of cardiovascular monitoring due to the impaired vessels are important in patients with Takayasu's arteritis. Remimazolam is a novel short-acting benzodiazepine with mild effects on hemodynamics. We report the case of a patient with Takayasu's arteritis who underwent oral surgery under general anesthesia. This report highlights the use of remimazolam and remifentanil to reduce hemodynamic perturbations using estimated continuous cardiac output monitoring.

Management of a Patient With Tracheal Stenosis After Previous Tracheotomy.

Tracheal stenosis after tracheotomy can cause difficult airway management and respiratory complications. It is difficult to predict tracheal stenosis after tracheotomy based on a patient's symptoms as the symptoms of tracheal stenosis appear only after they become severe. In patients with a history of previous tracheotomy, it is important to consider the risk factors for tracheal stenosis. Detailed preoperative evaluation of patients with a history of previous tracheotomy is essential and should include 3-dimensional assessment of the airway. We report the preoperative assessment and perioperative management of an 83-year-old woman at high risk for tracheal stenosis due to a previous emergency tracheotomy who was scheduled to undergo general anesthesia for a right maxillectomy for squamous cell carcinoma. Preoperative anteroposterior chest radiograph revealed findings indicative of tracheal stenosis. Additional detailed examinations of the stenotic area were conducted with computed tomography imaging and bronchofiberscopy. General anesthesia with nasotracheal intubation was performed, and although there were no adverse intraoperative events, stridor after extubation was observed. Nebulized epinephrine was administered via an ultrasound nebulizer and effectively improved the patient's postoperative transient dyspnea.

A Retrospective Case Series of Anesthetic Patients With Epiglottic Cysts.

Previously undiagnosed or asymptomatic epiglottic cysts may be coincidentally detected during intubation. This retrospective case series identified undiagnosed epiglottic cysts that were discovered during intubation in 4 patients who underwent oral surgery under general anesthesia at our hospital during a 6-year period. Including 2 additional cases, 1 previously diagnosed and 1 detected during preoperative imaging, epiglottic cysts were observed in 6 of 1112 cases (0.54%) total. Among the undiagnosed epiglottic cyst cases, mild dyspnea on effort or snoring was reported in 2 patients, but all others were asymptomatic. Upon discovering previously undiagnosed epiglottic cysts during intubation, it is essential to proceed cautiously, remain alert for potential airway management difficulties, and avoid injuring or rupturing the cysts. In addition, any available preoperative imaging should be reviewed as information pertinent to the airway and any abnormalities may be useful. This report discusses the anesthetic care of 6 patients with epiglottic cysts that were previously known or initially discovered during intubation.

Clinically relevant concentration of propofol and benzodiazepines did not affect in vitro angiogenesis.

PURPOSE: Angiogenesis, one of regenerative medicine, is essential in the process of wound healing. The detailed effects of intravenous anesthetics and sedatives used during perioperative period have not yet been clarified. We investigated the effects of benzodiazepines and propofol on in vitro capillary tube formation. METHODS: The effects of midazolam, diazepam and propofol (1, 10, 50 µM each) on proliferation of human umbilical vein endothelial cells (HUVEC) and normal human diploid fibroblasts (NHDF) were determined. Quantitation of migration was achieved by measuring the fluorescence of migrating HUVEC using angiogenesis system. The effects of midazolam, diazepam and propofol on in vitro angiogenesis were investigated in co-cultured HUVEC and NHDF incubated. The effects of midazolam on activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases were examined by Western blot analysis using phospho-specific antibodies. Parametric data were analyzed with one-way repeated measures analysis of variance followed by the Scheffé test. A value of P < 0.05 was considered statistically significant. RESULTS: Fifty µM of midazolam significantly impaired endothelial cell proliferation, migration, and in vitro capillary tube formation. Propofol, diazepam or lower dose midazolam did not show any enhancing or suppressive effects on in vitro angiogenesis. Fifty µM of midazolam remarkably activated ERK, but not p38 MAPK in HUVEC. CONCLUSION: Propofol and benzodiazepines except high-dose midazolam did not affect in vitro angiogenesis. High-dose midazolam may impair in vitro capillary tube formation due to by suppressing proliferation and migration of endothelial cells via activation of ERK.

Cytoskeleton-disrupting agent cytochalasin B reduces oxidative stress caused by high glucose in the human arterial smooth muscle.

The role of cytoskeleton dynamics in the oxidative stress toward human vasculature has been unclear. The current study examined whether the cytoskeleton-disrupting agent cytochalasin B reduces oxidative stress caused by high glucose in the human arterial smooth muscle. All experiments in the human omental arteries without endothelium or the cultured human coronary artery smooth muscle cells were performed in d-glucose (5.5 mmol/L). The exposure toward d-glucose (20 mmol/L) for 60 min reduced the relaxation or hyperpolarization to an ATP sensitive K+ channel (KATP) opener levcromakalim (10-8 to 3 × 10-6 mol/L and 3 × 10-6 mol/L, respectively). Cytochalasin B and a superoxide inhibitor Tiron, restored them similarly. Cytochalasin B reduced the NADPH oxidase activity, leading to a decrease in superoxide levels of the arteries treated with high d-glucose. Also, cytochalasin B impaired the F-actin constitution and the membrane translocation of an NADPH oxidase subunit p47phox in artery smooth muscle cells treated with high d-glucose. A clinical concentration of cytochalasin B prevented human vascular smooth muscle malfunction via the oxidative stress caused by high glucose. Regulation of the cytoskeleton may be essential to keep the normal vascular function in patients with hyperglycemia.

Electrons released from both flavins of NADPH-P450 reductase contribute to the reductive mobilization of iron from ferritin.

Ferritin, an iron storage protein, plays an important role in iron homeostasis. The mechanism of reductive mobilization of iron from ferritin has not been clarified yet despite many studies. The aim of this study was to assess the mechanisms of the mobilization of iron from ferritin by NADPH P-450 reductase. Nucleotide-dependent flavoenzymes generated significant mobilization of iron from ferritin. The possibility of reductive mobilization of iron from ferritin by electrons released from flavin sites or heme site of two flavoenzymes was investigated to elucidate the mediator-independent mechanisms of such reductive mobilization. The mobilization by NADPH-P450 reductase in the presence of ferricyanide increased threefold, while in the presence of cytochrome C increased thirteen-fold. These results indicate that electrons released from both flavins of NADPH-P450 reductase contribute to the reductive mobilization of iron from ferritin. The mechanism of the mobilization of iron from ferritin is discussed. J. Med. Invest. 66 : 230-232, August, 2019.

Accuracy and reliability of continuous blood glucose monitoring during pediatric cardiopulmonary bypass.

The purpose of this study was to assess the accuracy and reliability of a continuous blood glucose monitoring system (artificial endocrine pancreas; STG-55, Nikkiso, Tokyo, Japan) during pediatric cardiopulmonary bypass surgery. Twenty-five pediatric patients scheduled to undergo cardiovascular surgery with cardiopulmonary bypass (age 4 months to 11 years; body weight 5.6-59.7 kg) were enrolled. The glucose sensor line of the artificial endocrine pancreas was connected to the venous side of the cardiopulmonary bypass circuit and used for continuous blood glucose monitoring. We obtained 192 samples for blood gas assessment from the cardiopulmonary bypass circuit, and i-STAT (Abbott, East Windsor, NJ, USA) was used for conventional blood glucose assessment. The accuracies of continuous glucose measurements (STG-55) and conventional intermittent glucose measurements (i-STAT) during cardiopulmonary bypass were compared by means of Clarke error grid analysis. The results were divided into five zones, A, B, C, D, and E, and 78.6% of paired measurements were in zone A, while 21.4% were in zone B. We confirmed that the results of this continuous blood glucose monitoring system for cardiopulmonary bypass during pediatric cardiovascular surgery were highly reliable. An artificial endocrine pancreas may facilitate the safe use of intensive insulin therapy during pediatric cardiovascular surgery.

Tissue oxygenation index reflects changes in forearm blood flow after brief ischemia.

Whether the near-infrared spectroscopy (NIRS) technology correctly detects the changes in oxygenation related to ischemia and reperfusion of organs and tissues other than brain remains unclear. The present study examined how different tissue oxygenation parameters derived from NIRS reflect the changes in the forearm blood flow (FBF) according to the brief ischemia and the subsequent reperfusion, and whether values of these parameters move in parallel with the medial and lateral sides of FBF. Thirteen volunteers underwent the prospective observational study. The tissue oxygenation index (TOI), regional saturation of oxygen (rSO2), skin tissue oxygenation (StO2), and FBF values were evaluated in the forearm. Medial rSO2 values at 1 to 3 minutes after the termination of brief ischemia were higher than lateral rSO2 and respective TOI values. FBF and StO2 values quickly increased according to the cessation of brief ischemia, whereas the medial and lateral values did not differ during and after the brief ischemia. TOI and StO2, but not rSO2, reflected changes in FBF of both medial and lateral sides simultaneously in response to the reperfusion after brief ischemia. The muscle tissue oxygenation during reperfusion favors the use of TOI and StO2, but not rSO2, as the surrogate parameter. J. Med. Invest. 64: 228-232, August, 2017.

Successful treatment of mixed (mainly cancer) pain by tramadol preparations.

The patient, a 70-year-old Japanese woman diagnosed with parotid gland cancer, underwent wide excision and reconstruction (facial nerve ablation, nerve transposition). At 1 month after the surgery, she was brought to our hospital's pain medicine department because her postoperative pain and cancer-related pain were poorly controlled. She had already been prescribed a tramadol (37.5 mg)/acetaminophen (325 mg) combination tablet (5 tablets/day). However, in addition to the continuous pain in her face and lower limbs, she was troubled by a trigeminal neuralgia-like prominence ache. Because this pain could not be controlled by an increase to eight combination tablets per day, we switched her medication to a tramadol capsule. At 11 months post-surgery, we then switched her medication to an orally disintegrating tramadol tablet to improve medication adherence of the drug. From 14 months post-surgery, the patient also used a sustained-release tramadol preparation, and she was then able to sleep well. Her current regimen is an orally disintegrating sustained-release tablet combination (total 300 mg tramadol) per day, and she achieved sufficient pain relief. Because tramadol is not classified as a medical narcotic drug, it widely available and was shown here to be extremely useful for the treatment of our patient's mixed (mainly cancer) pain. J. Med. Invest. 64: 311-312, August, 2017.

Strict blood glucose control by an artificial endocrine pancreas during hepatectomy may prevent postoperative acute kidney injury.

The aim of the present study was to evaluate the usefulness of a closed-loop system (STG-55; Nikkiso, Tokyo, Japan), a type of artificial endocrine pancreas for the continuous monitoring and control of intraoperative blood glucose, for preventing postoperative acute kidney injury (AKI) in patients undergoing hepatectomy. Thirty-eight patients were enrolled in this study. Glucose concentrations were controlled with either a manual injection of insulin based on a commonly used sliding scale (manual insulin group, n = 19) or the programmed infusion of insulin determined by the control algorithm of the artificial endocrine pancreas (programmed insulin group, n = 19). After the induction of anesthesia, a 20-G intravenous catheter was inserted into the peripheral forearm vein of patients in the programmed insulin group and connected to an artificial endocrine pancreas (STG-55). The target range for glucose concentrations was set to 100-150 mg/dL. The mean serum creatinine concentrations of preoperative, postoperative 24 and 48 h were 0.72, 0.78, and 0.79 mg/dL in the programmed insulin group, and 0.81, 0.95, and 1.03 mg/dL in the manual insulin group, respectively. Elevations in serum creatinine concentrations postoperative 48 h were significantly suppressed in the programmed insulin group. The STG-55 closed-loop system was effective for maintaining strict blood glucose control during hepatectomy with minimal variability in blood glucose concentrations and for suppressing elevations in serum creatinine concentrations. Strict blood glucose control by an artificial endocrine pancreas during hepatectomy may prevent postoperative AKI.

C-terminal region of GADD34 regulates eIF2α dephosphorylation and cell proliferation in CHO-K1 cells.

GADD34 is a member of a growth arrest and DNA damage (GADD)-inducible gene family. Here, we established a novel Chinese hamster ovary (CHO)-K1-derived cell line, CHO-K1-G34M, which carries a nonsense mutation (termed the Q525X mutation) in the GADD34 gene. The Q525X mutant protein lacks the C-terminal 66 amino acids required for GADD34 to bind to and activate protein phosphatase 1 (PP1). We investigated the effects of GADD34 with or without the Q525X mutation on the phosphorylation status of PP1 target proteins, including the α subunit of eukaryotic initiation factor 2 (eIF2α) and glycogen synthase kinase 3ß (GSK3ß). CHO-K1-G34M cells had higher levels of eIF2α phosphorylation compared to the control CHO-K1-normal cells both in the presence and absence of endoplasmic reticulum stress. Overexpression of the wild-type GADD34 protein in CHO-K1-normal cells largely reduced eIF2α phosphorylation, while overexpression of the Q525X mutant did not produce similar reductions. Meanwhile, neither wild type nor Q525X mutation of GADD34 affected the GSK3ß phosphorylation status. GADD34 also did not affect the canonical Wnt signaling pathway downstream of GSK3ß. Cell proliferation rates were higher, while expression levels of the cyclin-dependent kinase inhibitor p21 were lower in CHO-K1-G34M cells compared to the CHO-K1-normal cells. The GADD34 Q525X mutant had a reduced ability to inhibit cell proliferation and enhance p21 expression of the CHO-K1-normal cells compared to the wild-type GADD34 protein. These results suggest that the GADD34 protein C-terminal plays important roles in regulating not only eIF2α dephosphorylation but also cell proliferation in CHO-K1 cells.

Impact of newly developed, next-generation artificial endocrine pancreas.

BACKGROUND: Recent studies have shown that strict perioperative blood glucose management may reduce mortality and morbidity in critically ill adult patients. The purpose of this study was to assess the accuracy and efficacy of the intraoperative application of a newly developed, next-generation artificial endocrine pancreas (STG-55, Nikkiso Co., Ltd., Tokyo, Japan). METHODS: Twenty patients scheduled to undergo surgery were enrolled in this study. The STG-55 is designed to be more user-friendly than its conventional counterpart (STG-22) while maintaining the latter's fundamental functions, such as a closed-loop system using algorithms for insulin and glucose infusion. After anesthetic induction, a 20G intravenous catheter was inserted into a peripheral forearm vein and connected to a continuous blood glucose monitor. The resultant 105 scores for paired blood glucose values were compared by Bland-Altman analysis. RESULTS: Stable blood glucose values were maintained automatically, and there were no complications related to use of the STG-55. A close correlation (r=0.96) was observed between continuous glucose measurements using the STG-55 and conventional intermittent glucose measurements. The difficulty of manipulation using this system was decreased by improved preparation procedures. CONCLUSION: The glycemic control system using the STG-55 could provide an alternative way to achieve effective and safe perioperative glycemic control.

Propofol-induced relaxation of rat aorta is altered by aging.

BACKGROUND: Propofol causes vasodilation via endothelium-dependent and -independent mechanisms. Because endothelial function is impaired with aging, the effects of propofol on endothelium-dependent vasodilation might be altered by aging. The aim of this study was thus to determine the effects of aging on vascular responses to propofol. METHODS: Young (4-6 weeks old) or adult (16-25 weeks old) rats were anesthetized with sevoflurane. The thoracic aorta was dissected and cut into pieces 3-4 mm in length. In some rings, the endothelium was deliberately removed. The ring segment of the aorta was mounted for isometric force recording at a resting tension of 0.5-1.0 g in a 2 ml organ bath, containing Krebs-Ringer bicarbonate buffer. Arteries were precontracted with phenylephrine, and the function of endothelium was confirmed with acetylcholine. Then, we studied the concentration-dependent effects of propofol in endothelium-intact (control group) and -denuded aortic rings (denuded group), as well as those treated with N(ω)-nitro-L-arginine methylester (L-NAME group). RESULTS: Relaxation due to propofol was observed in the control groups of both young and adult rats in a concentration-dependent manner, but the magnitude of relaxation was significantly greater in young rats. In addition, in young rats, relaxation due to propofol was significantly and equally reduced in both L-NAME and denuded groups at all propofol concentrations that we studied (10(-6)-10(-3) M). In adult rats, relaxation due to propofol was quite similar between control and L-NAME groups at all propofol concentrations, whereas it was significantly reduced in the denuded group. CONCLUSION: These results suggest that endothelium-derived nitric oxide plays an important role in propofol-induced vasodilation in young rats, but not in adult rats.

Usefulness of artificial endocrine pancreas during resection of insulinoma.

A 71-year-old woman had an episode of syncope due to hypoglycemia of 27 mg/dl. She was diagnosed with insulinoma and scheduled for laparoscopic enucleation along with the use of an artificial endocrine pancreas (STG-22, Nikkiso Co., Ltd., Tokyo, Japan). Anesthesia was maintained with sevoflurane and remifentanil. Her blood glucose level was controlled using the artificial endocrine pancreas, which enabled continuous blood glucose monitoring and computer-operated glucose and insulin infusion to maintain the blood glucose level at a steady state. The target concentration of blood glucose was set at 80-120 mg/dl during surgery. Until removal of the tumor, the blood glucose level was kept at around 80-100 mg/dl. After removal of the tumor, the blood glucose level gradually increased, but it was kept in the normal range by the artificial endocrine pancreas. The artificial endocrine pancreas was useful to monitor and maintain blood glucose levels during and after the removal of insulinoma, without any hyper- or hypoglycemia.

Cuffed oropharyngeal airway for difficult airway management.

Difficulties with airway management are often caused by anatomic abnormalities due to previous oral surgery. We performed general anesthesia for a patient who had undergone several operations such as hemisection of the mandible and reconstructive surgery with a deltopectoralis flap, resulting in severe maxillofacial deformation. This made it impossible to ventilate with a face mask and to intubate in the normal way. An attempt at oral awake intubation using fiberoptic bronchoscopy was unsuccessful because of severe anatomical abnormality of the neck. We therefore decided to perform retrograde intubation and selected the cuffed oropharyngeal airway (COPA) for airway management. We inserted the COPA, not through the patient's mouth but through the abnormal oropharyngeal space. Retrograde nasal intubation was accomplished with controlled ventilation through the COPA, which proved to be very useful for this difficult airway management during tracheal intubation even though the method was unusual.

Geranylgeranylacetone and volatile anesthetic-induced cardiac protection synergism is dependent on caveolae and caveolin-3.

PURPOSE: Pharmacological preconditioning, including that with geranylgeranylacetone (GGA) and volatile anesthetics, has been shown to confer cardiac protection from ischemia/reperfusion injury although the mechanisms for this protection are poorly understood. Caveolins, integral membrane proteins that act as scaffolding proteins in caveolar membranes, localize molecules involved in cardiac protection. We have tested the hypothesis that caveolin-3 (Cav-3), the predominant isoform in cardiac myocytes, is essential for the synergistic effect observed between GGA and volatile anesthetics. METHODS: Mice were randomly assigned to receive GGA, isoflurane [0.5 and 1.0 minimum alveolar concentration (MAC)], or GGA + isoflurane (0.5 MAC). An in vivo mouse model of ischemia/reperfusion injury was tested in wild-type and Cav-3 knockout mice, and the infarct size was determined. Biochemical assays were also performed in excised hearts. RESULTS: Geranylgeranylacetone and therapeutic isoflurane (1.0 MAC) independently reduced infarct size (31.6 ± 6.1 and 28.0 ± 5.0% of the area at risk, respectively; n = 10) as compared to the controls (45.8 ± 9.4%; n = 10). The combination GGA + sub-therapeutic isoflurane (0.5 MAC) further decreased the infarct size to 19.3 ± 5.1% (n = 10). Preconditioning [GGA, isoflurane (1.0 MAC), and GGA + isoflurane] increased the amount of Cav-3 protein in the discontinuous sucrose-gradient buoyant fractions. Additionally, cardiac protection was not observed in Cav-3 knockout mice following the administration of GGA, isoflurane, and GGA + isoflurane. CONCLUSIONS: Combined administration of GGA + isoflurane had a synergistic effect, enhancing the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by Cav-3 expression.

Anesthetic cardioprotection in relation to mitochondria: basic science.

Anesthetic pre- and postconditioning pharmacologically reduces ischemia/reperfusion injury. Mitochondria play a central role in these myocardial protective salvage effects. In the preconditioning, low levels of reactive oxygen species, which are produced by anesthetics in the mitochondria, act as a trigger to prevent cardiomyocytes death and modify intracellular signaling mechanisms. In the postconditioning, decreased mitochondrial matrix pH, which was caused by anesthetics, triggers the onset of a rapid protective effect. The mitochondrial membranes have several ion channels that act as major determining factors of cellular life and death under pathophysiological conditions. In these channels, the mitochondrial adenosine triphosphate-sensitive K(+) channels, the mitochondrial Ca(2+)-activated K(+) channels and mitochondrial permeability transition pores play critical roles in cardioprotection against ischemia/reperfusion injury. Mitochondrial permeability transition pores are end effectors, which contribute to myocardial preconditioning and postconditioning. Activation of intracellular signaling and acidification of mitochondrial matrix pH prevent the mitochondrial permeability transition pore opening, and therefore, preserve the mitochondrial function to supply adenosine triphosphate, resulting in myocardial protection due to the maintenance of intracellular homeostasis.

Usefulness of continuous blood glucose monitoring and control for patients undergoing liver transplantation.

BACKGROUND: The purpose of this study was to evaluate the usefulness of the closed-loop system (STG-22; Nikkiso, Tokyo, Japan), a type of artificial endocrine pancreas for the continuous monitoring and control of intraoperative blood glucose in patients undergoing liver transplantation. METHODS: Sixteen patients undergoing living-donor liver transplantation were enrolled in this study. Glucose levels were controlled with either a manual injection of insulin based on a commonly used sliding scale (manual insulin group, n=8) or a programmed infusion of insulin determined by the control algorithm of the artificial endocrine pancreas (programmed insulin group, n=8). The target glucose level range was set at 80-150 mg/dl. RESULTS: The mean and SD of blood glucose concentration during surgery (Glu-Ave and Glu-SD, respectively) for the programmed insulin group were lower than for the manual insulin group. The coefficient of variability (Glu-CV=Glu-SD×100 /Glu-Ave) for the programmed insulin group was also lower than for the manual insulin group (20.1±4.9% vs. 26.9±6.1%; mean±SD). No hypoglycemia was detected in either group. CONCLUSION: The STG-22 closed-loop system is effective for maintaining strict blood glucose control during liver transplantation with minimal variability in blood glucose concentration.