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.

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.

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.

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.

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.

Novel blood sampling method of an artificial endocrine pancreas via the cardiopulmonary bypass circuit.

We tried to perform continuous blood glucose monitoring during cardiovascular surgery involving cardiopulmonary bypass using an artificial endocrine pancreas (STG-22 or -55; Nikkiso, Tokyo, Japan); however, we often encountered problems during these procedures because insufficient blood was obtained for monitoring. Thus, we started performing the blood sampling via the venous side of the cardiopulmonary bypass circuit. As a result, continuous blood glucose monitoring using an artificial endocrine pancreas was proven to be stable and reliable during cardiovascular surgery involving cardiopulmonary bypass.

[Principles, usefulness, and limitations of recent circulatory monitoring].

Less invasive measuring procedures for hemodynamic status and function are increasingly being used. Surgical patients are frequently undifferentiated, need accurate risk assessment and stratification, while their need for diagnosis and therapy is often time-critical. Valid, less invasive hemodynamic monitoring modalities are essential to differentiate high- from low-risk patients, and for goal-directed management. Pulmonary artery catheters, transesophageal echocardiography, pressure pulse waveform analysis, and other less invasive monitoring techniques all are potentially effective for diagnosis and hemodynamic monitoring. This article provides information on the usefulness and limitations of recent circulatory monitoring procedures.

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.

Molecular mechanisms of the inhibitory effects of clonidine on vascular adenosine triphosphate-sensitive potassium channels.

BACKGROUND: We investigated the effects of the imidazoline-derived α2-adrenoceptor agonist clonidine on vascular adenosine triphosphate-sensitive potassium (K(ATP)) channel activity in rat vascular smooth muscle cells and recombinant vascular K(ATP) channels transiently expressed in COS-7 cells. METHODS: Using the patch-clamp method, we investigated the effects of clonidine on the following: (1) native vascular K(ATP) channels; (2) recombinant K(ATP) channels with different combinations of various types of inwardly rectifying potassium channel (Kir6.0 family: Kir6.1, 6.2) and sulfonylurea receptor (SUR1, 2A, 2B) subunits; (3) SUR-deficient channels derived from a truncated isoform of the Kir6.2 subunit (Kir6.2ΔC36 channels); and (4) mutant Kir6.2ΔC36 channels with diminished sensitivity to ATP (Kir6.2ΔC36-K185Q channels). RESULTS: Clonidine (≥3 × 10(-8) M) inhibited native K(ATP) channel activity in cell-attached configurations with a half-maximal inhibitory concentration value of 1.21 × 10(-6) M and in inside-out configurations with a half-maximal inhibitory concentration value of 0.89 × 10(-6) M. With similar potency, clonidine (10(-6) or 10(-3) M) also inhibited the activities of various recombinant SUR/Kir6.0 K(ATP) channels, the Kir6.2ΔC36 channel, and the Kir6.2ΔC36-K185Q channel. CONCLUSIONS: Clinically relevant concentrations of clonidine inhibit K(ATP) channel activity in vascular smooth muscle cells. This inhibition seems to be the result of its effect on the Kir6.0 subunit and not on the SUR subunit.

[Torsade de pointes associated with severe bradycardia after induction of general anesthesia].

An 80-year-old woman with chronic atrial flutter/fibrillation, and chronic renal failure underwent ileocecal resection. The preoperative electrocadiogram showed normal QT interval. Temporary pacemaker catheter was inserted for sinus arrest (5-6 sec) the day before operation. Anesthesia was induced with remifentanil 0.5 micro x kg(-1) min(-1), thiamylal 125 mg, and rocuronium 30 mg after intravenous atropine sulfate 0.5 mg. Because the heart rate was increased with atropine sulfate, the pacemaker was not started. Anesthesia was then maintained with intravenous remifentanil and sevoflurane-air-oxygen. Just after induction of anesthesia, sinus bradycardia occurred, and 9 minutes after tracheal intubation, ECG suddenly showed torsade de pointes (TdP) and the arterial blood pressure decreased leading to asystole. We immediately started cardiopulmonary resuscitation, and TdP stopped spontaneously within 1 minute. We started pacemaker (VVI, 60 beats x min(-1)) and intravenous injection of lidocaine, and TdP did not recur. In this case, TdP seemed to have occurred because of bradycardia-induced abnormal QT prolongation. This should be considered the risk of lethal arrhythmia in patients with severe bradycardia including TdP.

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.

[Anesthetic management for repair of Ebstein's anomaly with WPW syndrome].

Ebstein's anomaly is a rare congenital malformation of the tricuspid valve, often associated with Wolff-Parkinson-White (WPW) syndrome. We report the perioperative management of 3 patients (a 34-year-old man, a 5-month-old boy and a 5-year-old girl) with Ebstein's anomaly associated with WPW syndrome. Anesthetic managements for valvuloplasty of the tricuspid valve and ablation of accessory pathway in 3 patients were successfully accomplished with a combination of fentanyl, sevoflurane, and midazolam. The management of Ebstein's anomaly is based on its severity. The major concerns with anesthesia for children with Ebstein's anomaly include decreased cardiac output, right-to-left atrial level shunting with cyanosis, and the propensity for atrial tachyarrhythmias. We conclude that perioperative management of arrhythmia and evaluation of residual tricuspid regurgitation using transesophageal echocardiography are essential.

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.

Low-dose sevoflurane inhalation enhances late cardioprotection from the anti-ulcer drug geranylgeranylacetone.

BACKGROUND: We investigated in rabbits whether sevoflurane enhances late cardioprotection induced by geranylgeranylacetone (GGA), a gastric antiulcer drug. METHODS: S(+)-ketamine and xylazine-anesthetized rabbits were assigned to one of seven experimental groups: a control (vehicle only) group, a GGA group, a sevoflurane group, a GGA+sevoflurane group, a sodium 5-hydroxydecanoate (5HD) group, a GGA + 5HD group, and a heat stress group. All rabbits were subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion. Rabbits were pretreated with IV vehicle, GGA (10 mg/kg), or heat stress (42 degrees C for 15 min) 24 h before coronary occlusion. Sevoflurane (0.5 minimum alveolar concentration) or 5HD (5 mg/kg) were administered before myocardial ischemia. Myocardial infarct size and the area at risk for ischemia were measured, and heat shock protein (Hsp) 70 levels in each experimental group were determined. RESULTS: Compared with vehicle only, GGA significantly reduced the size of myocardial infarction in relation to the area at risk (39 +/- 10% vs 59 +/- 9%, P < 0.02). Sevoflurane enhanced the GGA-induced cardioprotection (23 +/- 17%, P < 0.05 vs GGA). The cardioprotective effect of GGA was abolished by administration of 5HD (56 +/- 15%, P < 0.01). GGA enhanced Hsp 70 expression compared with that in the control group (0.69 +/- 0.15 vs 0.36 +/- 0.05, P < 0.02). Administration of GGA with sevoflurane resulted in the same level of Hsp 70 expression as GGA (0.69 +/- 0.16, P > 0.98). CONCLUSIONS: GGA appears to reduce myocardial infarct size in association with increased Hsp 70 expression. Sevoflurane enhances the GGA-induced cardioprotective effect.

Two unusual complications associated with cardiopulmonary bypass for pediatric cardiac surgery detected by transesophageal echocardiography after decannulation.

We describe two rare cases of complications associated with cannulation for cardiopulmonary bypass during pediatric cardiac surgery detected by transesophageal echocardiography (TEE). The first patient (a 20-month-old boy, 11 kg) was scheduled for complete repair of an atrial septal defect and partial anomalous pulmonary venous connection. After decannulation of the superior vena cava, a mosaic jet was observed by means of TEE. The second patient (an 11-month-old boy, 6.4 kg), with a double outlet right ventricle, was scheduled for a hemi-Fontan procedure. After decannulation of the ascending aorta, high blood flow velocity of 4 m x s(-1) was detected by TEE. Intraoperative TEE was useful for early detection of complications associated with cardiopulmonary bypass cannulation during pediatric cardiac surgery.

[Intraoperative application of transesophageal echocardiography].

Transesophageal echocardiography (TEE) has become a routine monitor in the operating room for cardiac surgery because it provides instantaneous and continuous assessment of cardiac function and anatomy. TEE aids intraoperative management and improves outcome in patients undergoing cardiac valve repairs, complex congenital heart corrections, and high-risk patients undergoing coronary artery bypass graft surgery. Especially in mitral valve repair surgery, it is mandatory to evaluate the results of the surgical procedure after cardiopulmonary bypass during surgery. Multiple investigations have also documented the improved sensitivity of TEE for the detection of myocardial ischemia compared with ECG or pulmonary capillary wedge pressure measurements. Intraoperative TEE is, however, not without risks, so emerging evidence demonstrating the utility of TEE as a diagnostic monitor or to alter the management of patients is required, especially in non-cardiac surgery. TEE is less frequently used in non-cardiac surgery; however, the emergent use of intraoperative or perioperative TEE to determine the cause of an acute, persistent, and life-threatening hemodynamic abnormality is well indicated. A task force of the American Society of Anesthesiologists and the Society of Cardiovascular Anesthesiologists developed guidelines for the appropriate use of TEE, which were evidence-based and focused on the effectiveness of perioperative TEE in improving clinical outcomes. Compliance with the guidelines for basic intraoperative TEE resulted in a marked improvement in intraoperative TEE practice. Technical progress of echocardiographic equipment and the TEE probe will increase the application of intraoperative and perioperative TEE in the future.

Non-cardiac surgery applications of extracorporeal circulation.

Although the efficacy of extracorporeal circulation (ECC) is well established for open-heart surgery, application of ECC in other surgical areas has not been given much attention. Advances in the related surgical technique and anesthetic management combined with refinements in the ECC procedure itself have encouraged several institutions to use ECC for complex non-cardiac surgeries. ECC is beginning to be used for circulatory support or tissue oxygenation during surgery on the lung, brain, liver, and kidney as well as in emergency situations. With ECC, difficult and complex surgeries can be performed more safely, and the success rate of certain surgeries has been positively affected. It is important that the surgeon, anesthesiologist, and perfusionist are trained in non-cardiac surgery applications of ECC. Thus, we review here non-cardiac uses that have emerged and summarize the related procedures.

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.