Tokujiro Uchida

Elevated Levels of the Receptor for Advanced Glycation End Products, a Marker of Alveolar Epithelial Type I Cell Injury, Predict Impaired Alveolar Fluid Clearance in Isolated Perfused Human Lungs

BACKGROUND Although alveolar epithelial injury is a major determinant of outcome in patients with acute lung injury, there is no reliable biological marker of alveolar epithelial injury. The primary objective was to determine whether elevated levels of the receptor for advanced glycation end products (RAGE), a marker of alveolar epithelial injury, reflect impaired alveolar fluid clearance (AFC) in an ex vivo perfused human lung preparation. A second objective was to determine whether levels of a marker of endothelial injury, von Willebrand factor antigen (vWF:Ag), are associated with impaired AFC. METHODS Human lungs (N = 30) declined for transplantation by the California Transplant Donor Network were perfused at a constant pulmonary artery pressure of 12 mm Hg. Following rewarming to 36 degrees C, the lungs were inflated with a continuous positive airway pressure of 10 cm H(2)O. RAGE and vWF:Ag levels and AFC rates were then measured. RESULTS The rate of AFC was inversely correlated with RAGE levels in the alveolar fluid (p < 0.005). Similarly, the concentration of RAGE in the alveolar fluid was significantly higher in lungs with submaximal AFC, defined in a prespecified analysis as <or= 14%/h, when compared with lungs with preserved AFC (median 0.82 vs 0.43 microg/mL; p < 0.05). In contrast, vWF:Ag levels did not correlate with the rate of AFC. CONCLUSIONS RAGE may be a useful biological marker of alveolar epithelial injury and impaired AFC in donor lungs prior to transplant and perhaps in patients with acute lung injury.

The McCoy levering laryngoscope in patients with limited neck extension.

PurposeThe McCoy levenng laryngoscope is a modified Macintosh laryngoscope, which has a hinged tip controlled by a lever on the handle. The purpose of this study was to investigate whether the tip elevation of this laryngoscope results in better laryngeal visualization than using the Macintosh laryngoscope when the patient’s neck is fixed in the neutral position.MethodsFifty female patients (ASA physical status I–II) undergoing elective surgery during general anaesthesia were investigated. The patient’s neck was manually fixed in the neutral position by an assistant, and laryngeal visualization was attempted first with a size #3 Macintosh laryngoscope (Macintosh trial), and then with a size #3 McCoy levering laryngoscope with blade tip elevation (McCoy trial), and tracheal intubation was attempted. Trials of laryngeal visualization were evaluated with the Cormadc score.ResultsIn the Macintosh trial, 36 of 50 (72%) patients were evaluated grade 3, and two grade 4. In most of the patients graded 2 and 3 in the Macintosh trial (70% of the grade 2 and 83% of the grade 3 cases), the laryngeal view was improved by using the McCoy levering laryngoscope. The Cormack grade in the McCoy trial was less than that in the Macintosh tnal (P < 0.01). No complications were observed during the study.ConclusionThe McCoy levenng laryngoscope improved laryngeal visualization in patients whose neck cannot be extended.AbstractObjectifLe laryngoscope à levier de McCoy est un laryngoscope Macintosh modifié dont l’extrémité articulée est contrôlée par un levier située dans le manche. Cette étude visait à vérifier si l’élévation de l’extrémité de ce laryngoscope permettait de mieux visualiser le larynx que le laryngoscope de Macintosh quand la position de la tête était maintenue en position neutre.MéthodesCinquante patientes (ASA I et II) soumises à une chirurgie gynécologique programmée non urgente sous anesthésie générale ont été étudiées. Un assistant maintenait la tête en position neutre et après avoir fait une première tentative de visualisation du larynx avec un laryngoscope Macintosh N∘ 3 (essai Macintosh) et l’avoir répétée avec un laryngoscope à levier McCoy N∘ 3 (essai McCoy), on essayait d’intuber la trachée. Les essais de visualisation laryngée étaient évalués sur l’échelle de Cormack.RésultatsDurant l’essai Macintosh, 36 patientes sur 70 (72%) étaient considérées grade 3 et deux, grade 4. Chez la plupart des patientes grade 2 et 3 pendant l’essai Macintosh (70% des grades 2 et 83% des grades 3), la visualisation de la trachée était améliorée par le laryngoscope McCoy. Les grades de Cormack pendant l’essai McCoy étaient inféneurs à ceux de l’essai Macintosh (P < 0.01). Aucune complication n’a été observée.ConclusionLe laryngoscope de McCoy améliore la visualisation de la trachée lorsque le cou n’est pas en extension.

Proteolytic release of the receptor for advanced glycation end products from in vitro and in situ alveolar epithelial cells

Although the receptor for advanced glycation end products (RAGE) has been used as a biological marker of alveolar epithelial cell injury in clinical studies, the mechanism for release of soluble RAGE from lung epithelial cells has not been well studied. Therefore, these studies were designed to determine the mechanism for release of soluble RAGE after lipopolysaccharide (LPS) challenge. For these purposes, alveolar epithelial cells from rat lungs were cultured on Transwell inserts, and LPS was added to the apical side (500 μg/ml) for 16 h on day 7. On day 7, RAGE was expressed predominantly in surfactant protein D-negative cells, and LPS challenge induced release of RAGE into the medium. This response was partially blocked by matrix metalloproteinase (MMP) inhibitors. Transcripts of MMP-3 and MMP-13 were upregulated by LPS, whereas RAGE transcripts did not change. Proteolysis by MMP-3 and MMP-13 resulted in soluble RAGE expression in the bronchoalveolar lavage fluid in the in situ rat lung, and this reaction was inhibited by MMP inhibitors. In human studies, both MMP-3 and -13 antigen levels were significantly correlated with the level of RAGE in pulmonary edema fluid samples. These results support the conclusion that release of RAGE is primarily mediated by proteolytic damage in alveolar epithelial cells in the lung, caused by proteases in acute inflammatory conditions in the distal air spaces.

Delayed emergence from anesthesia resulting from cerebellar hemorrhage during cervical spine surgery

Cerebellar hemorrhage is an unpredictable complication of spinal surgery. We encountered a case of cerebellar hemorrhage presenting with delayed emergence from anesthesia and hemiplegia after resection of an intradural extramedullar tumor from the cervical spine. Postoperative brain computed tomography revealed hematoma in the cerebellar vermis and right cerebellar hemisphere. The patient made a gradual recovery with conservative treatment. Although the mechanism of cerebellar hemorrhage remains speculative, loss of cerebrospinal fluid may play an important role. Cerebellar hemorrhage must therefore be considered in patients with unexplained neurological deterioration or disturbance on emergence from anesthesia after spinal surgery.

Ketamine causes mitochondrial dysfunction in human induced pluripotent stem cell-derived neurons.

Purpose Ketamine toxicity has been demonstrated in nonhuman mammalian neurons. To study the toxic effect of ketamine on human neurons, an experimental model of cultured neurons from human induced pluripotent stem cells (iPSCs) was examined, and the mechanism of its toxicity was investigated. Methods Human iPSC-derived dopaminergic neurons were treated with 0, 20, 100 or 500 μM ketamine for 6 and 24 h. Ketamine toxicity was evaluated by quantification of caspase 3/7 activity, reactive oxygen species (ROS) production, mitochondrial membrane potential, ATP concentration, neurotransmitter reuptake activity and NADH/NAD+ ratio. Mitochondrial morphological change was analyzed by transmission electron microscopy and confocal microscopy. Results Twenty-four-hour exposure of iPSC-derived neurons to 500 μM ketamine resulted in a 40% increase in caspase 3/7 activity (P < 0.01), 14% increase in ROS production (P < 0.01), and 81% reduction in mitochondrial membrane potential (P < 0.01), compared with untreated cells. Lower concentration of ketamine (100 μM) decreased the ATP level (22%, P < 0.01) and increased the NADH/NAD+ ratio (46%, P < 0.05) without caspase activation. Transmission electron microscopy showed enhanced mitochondrial fission and autophagocytosis at the 100 μM ketamine concentration, which suggests that mitochondrial dysfunction preceded ROS generation and caspase activation. Conclusions We established an in vitro model for assessing the neurotoxicity of ketamine in iPSC-derived neurons. The present data indicate that the initial mitochondrial dysfunction and autophagy may be related to its inhibitory effect on the mitochondrial electron transport system, which underlies ketamine-induced neural toxicity. Higher ketamine concentration can induce ROS generation and apoptosis in human neurons.

Effects of atrial natriuretic peptide on inter-organ crosstalk among the kidney, lung, and heart in a rat model of renal ischemia-reperfusion injury

BackgroundRenal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury and a frequent occurrence in critically ill patients. Renal IRI releases proinflammatory cytokines within the kidney that induce crosstalk between the kidney and other organ systems. Atrial natriuretic peptide (ANP) has anti-inflammatory as well as natriuretic effects and serves important functions as a regulator of blood pressure, fluid homeostasis, and inflammation. The objective of the present study was to elucidate whether ANP post-treatment attenuates kidney-lung-heart crosstalk in a rat model of renal IRI.MethodsIn experiment I, a rat model of unilateral renal IRI with mechanical ventilation was prepared by clamping the left renal pedicle for 30 min. Five minutes after clamping, saline or ANP (0.2 μg/kg/min) was infused. The hemodynamics, arterial blood gases, and plasma concentrations of lactate and potassium were measured at baseline and at 1, 2, and 3 h after declamping. The mRNA expression and localization of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the kidney, lung, and heart were examined. In experiment II, a rat model of bilateral renal IRI without mechanical ventilation was prepared by clamping bilateral renal pedicles for 30 min. Thirty minutes after clamping, lactated Ringers (LR) solution or ANP (0.2 μg/kg/min) was infused. Plasma concentrations of TNF-α, IL-6, and IL-1β were determined at baseline and at 3 h after declamping.ResultsIn unilateral IRI rats with mechanical ventilation, ANP inhibited the following changes induced by IRI: metabolic acidosis; pulmonary edema; increases in lactate, creatinine, and potassium; and increases in the mRNA expression of TNF-α, IL-1β, and IL-6 in the kidney and lung and IL-1β and IL-6 in the heart. It also attenuated the histological localization of TNF-α, IL-6, and nuclear factor (NF)-κB in the kidney and lung. In bilateral IRI rats without mechanical ventilation, ANP attenuated the IRI-induced increases of the plasma concentrations of potassium, IL-1β, and IL-6.ConclusionsRenal IRI induced injury in remote organs including the lung and the contralateral kidney. ANP post-treatment ameliorated injuries in these organs by direct tissue protective effect and anti-inflammatory effects, which potentially inhibited inter-organ crosstalk.

Treatment of pulmonary hypertension and hypoxia due to oleic acid induced Lung injury with intratracheal prostaglandin E1 during Partial liquid ventilation

Background Partial liquid ventilation using perfluorocarbon liquids may be of therapeutic benefit in patients with acute respiratory failure. This study investigated the effects of prostaglandin E1 (PGE1) delivered intratracheally during partial liquid ventilation on lung function and pulmonary circulation in rabbits with acute respiratory distress syndrome. Methods Lung injury was induced by intravenous oleic acid in adult Japanese white rabbits, 1 h after which they were divided into four groups of 10 animals. Group 1 received mechanical ventilation alone, group 2 received aerosolized PGE1 (5 [micro sign]g followed by 0.1 [micro sign]g [middle dot] kg-1 [middle dot] min-1) under mechanical ventilation combined with 5 cm H2 O positive end-expiratory pressure, and groups 3 and 4 received partial liquid ventilation with 15 ml/kg perflubron. Group 4 received a 5-[micro sign]g bolus followed by 0.1 [micro sign]g [middle dot] kg-1 [middle dot] min-1 PGE1 instilled intratracheally (not by aerosol) in combination with partial liquid ventilation. Measurements were performed at 30-min intervals for 120 min after lung injury. Results After lung injury, hypoxemia, hypercapnia, acidosis, and pulmonary hypertension developed in all animals and were sustained in groups 1 and 2 throughout the experiment. The partial pressure of oxygen in arterial blood of animals in group 3 improved with initiation of treatment, with statistical significance achieved at the 30 and 60 min time points as compared with controls. Group 4 animals had immediate and sustained increases in the partial pressure of oxygen in arterial blood that were significant compared with all other groups during the experiment. Statistically significant reductions in mean pulmonary artery pressure were seen only in group 4 animals compared with all other groups. Conclusions These results suggest that PGE1 delivered intratracheally during partial liquid ventilation may be a useful therapeutic strategy for patients with the acute respiratory distress syndrome.

Clinical assessment of a continuous intra- arterial blood gas monitoring system

We evaluated the clinical performance of a continuous intraarterial blood gas monitoring (CIABG) system which includes a fluorometric intravascular sensor. Seventeen patients undergoing elective surgery were monitored perioperatively with the CIABG system (PB3300; Puritan Bennett, Carlsbad, CA). Conventional laboratory blood gas analyses (BGA) were performed simultaneously whenever indicated, and the values were compared with those obtained from the CIABG system. Monitoring time ranged from 24 to 72 hr. The biases (average error between PB3300 and BGA) of pH, PCO2 and PO2 were 0.003 pH unit,- 2.8 mmHg, and 0.9 mmHg in the operating room (OR), and 0.005 pH unit, 3.9 mmHg, and 8.5 mmHg in the intensive care unit (ICU), respectively. The precision (standard deviation of the bias) of pH, PCO2 and PO2 were 0.030 pH unit, 2.1 mmHg, and 29.9 mmHg in the OR and 0.035 pH unit, 3.8 mmHg, and 14.7 mmHg in the ICU, respectively. Although the PB3300 system was clinically useful as a trend monitor, the system’s precision and reliability were unacceptable for estimation of true blood gas values.RésuméNous évaluons en clinique la performance d’un système de monitorage continu des gaz artériels (CIABG) qui contient un senseur fluorométrique intravasculaire. Dixsept patients subissant une chirurgie programmée sont monitorisés pendant la période périopératoire avec le système CIABG (PB 3300; Puritan Bennett, Carbbad, Californie). Des mesures conventionnelles de laboratoire (BGA) sont réalisées simultanément lorsqu’indiquées et les résultats sont comparés avec ceux obtenus par le système CIABG. La durée du monitorage se situe entre 24 et 72 heures. Le biais (l’erreur moyenne entre PB 3300 et BGA) du pH, de la PCO2 et de la PO2 est de 0,003 unité de pH, - 2,8 mmHg et 0.9 mmHg en salle d’opération (SO); de 0,005 unité de pH, 3,9 mmHg et 8,5 mmHg à l’unité de soins intensifs (USI). La précision (écarttype du biais de la moyenne) du pH, de la PCO2 0,030 unité de PH, 2,1 mmHg et 29,9 mmHg en SO et de 0,035 par unité de PH, 3,8 mmHg et 14,7 mmHg à l’USI. Bien que le système PH 3300 soit cliniquement utile comme moniteur de tendance, sa précision et sa fiabilité sont inacceptables pour l’estimation des valeurs absolues des gaz sanguins.

Soluble Isoform of the Receptor for Advanced Glycation End Products as a Biomarker for Postoperative Respiratory Failure after Cardiac Surgery

Purpose Postoperative respiratory failure is a major problem which can prolong the stay in the intensive care unit in patients undergoing cardiac surgery. We measured the serum levels of the soluble isoform of the receptor for advanced glycation end products (sRAGE), and we studied its association with postoperative respiratory failure. Methods Eighty-seven patients undergoing elective cardiac surgery were enrolled in this multicenter observational study in three university hospitals. Serum biomarker levels were measured perioperatively, and clinical data were collected for 7 days postoperatively. The duration of mechanical ventilation was studied for 28 days. Results Serum levels of sRAGE elevated immediately after surgery (median, 1751 pg/mL; interquartile range (IQR) 1080–3034 pg/mL) compared with the level after anesthetic induction (median, 884 pg/mL; IQR, 568–1462 pg/mL). Postoperative sRAGE levels in patients undergoing off-pump coronary artery bypass grafting (median, 1193 pg/mL; IQR 737–1869 pg/mL) were significantly lower than in patients undergoing aortic surgery (median, 1883 pg/mL; IQR, 1406–4456 pg/mL; p = 0.0024) and valve surgery (median, 2302 pg/mL; IQR, 1447–3585 pg/mL; p = 0.0005), and postoperative sRAGE correlated moderately with duration of cardiopulmonary bypass (rs = 0.44, p<0.0001). Receiver operating characteristic curve analysis demonstrated that postoperative sRAGE had a predictive performance with area under the curve of 0.81 (95% confidence interval 0.71–0.88) for postoperative respiratory failure, defined as prolonged mechanical ventilation >3 days. The optimum cutoff value for prediction of respiratory failure was 3656 pg/mL, with sensitivity and specificity of 62% and 91%, respectively. Conclusions Serum sRAGE levels elevated immediately after cardiac surgery, and the range of elevation was associated with the morbidity of postoperative respiratory failure. Early postoperative sRAGE levels appear to be linked to cardiopulmonary bypass, and may have predictive performance for postoperative respiratory failure; however, large-scale validation studies are needed.

Inhaled nitric oxide improved the outcome of severe right ventricular failure caused by lipopolysaccharide administration

ObjectiveTo evaluate the efficacy of nitric oxide (NO) inhalation against endotoxin-induced lung injury.DesignRandomized prospective short-term study.SettingUniversity school of Medicine Laboratory.InterventionsAnimal experiment (using 16 Japanese white rabbits). The animals inhaled NO at a concentration of 10 ppm.Measurements and resultsThe rabbits were randomly divided into the NO inhaling group (n=7) and the control group (n=9). Both groups received continuous infusion of 1200 mcg lipopolysaccharide (LPS) and the NO group inhaled 10 ppm NO during the LPS administration. In the control group, severe right ventricular (RV) failure was observed at 30–90 min of LPS infusion, and 4 of 9 animals died within 90 min of LPS infusion. In the NO group, none of the animals died and the early phase hemodynamic deterioration was milder than in the control group. But pulmonary gas exchange was not significantly different between the two groups throughout the study. At the end of the study there were no significant differences in any parameters of the surviving animals between the two groups.ConclusionAlthough an improvement of pulmonary gas exchange was not demonstrated, NO inhalation (10 ppm) improved the outcome of severe RV failure caused by LPS infusion.