Published papers

Purpose Because the safety of intravenous fentanyl patient-controlled analgesia (iv-PCA) administered during labor remains unclear, we retrospectively examined the labor records from January 2005 to December 2007 in our institution, with a focus on both maternal and neonatal outcomes, as compared to no analgesia. Methods Parturients over 35 weeks of gestational age who received fentanyl iv-PCA (iv-PCA group) or no analgesia (control group) during labor were enrolled. The former group received iv-PCA through a pump programmed to give a loading dose of 0.05 mg fentanyl, followed by bolus injection of 0.02 mg fentanyl, with a lock-out interval of 5 min. This analgesia was initiated at the parturient's request and was discontinued before the second stage of labor, to ensure neonatal safety. During labor, both maternal and fetal heart rates, maternal pulse oximeter oxygen saturation (SpO 2), respiratory rate, and sedation and nausea scores were continuously monitored, and the neonatal outcomes including umbilical arterial pH, Apgar scores, and other parameters were recorded. Results The data of 129 of the 143 parturients who received fentanyl iv-PCA were analyzed, while 697 parturients delivered without any analgesia during the 3-year study period. While iv-PCA prolonged the duration of labor and increased oxytocin use, no obvious maternal or neonatal complications of fentanyl use were recorded. Except for the significantly lower rate of emergency cesarean section in the iv-PCA group, both the maternal and neonatal outcomes were comparable between the groups. Conclusions As compared to no analgesia, fentanyl iv-PCA appears to be safe and clinically acceptable as analgesia during labor, particularly in nulliparous women. © 2011 Japanese Society of Anesthesiologists.

Objective: Since recent study demonstrated beneficial effects of β-adrenergic blocker in sepsis, we tested the hypothesis that infusion of selective β1-blocker, esmolol, improves outcome in sepsis by modulating inflammatory responses and gut barrier function. Design: Prospective randomized animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Interventions: To assess the effects of esmolol infusion on survival time, 19 animals that underwent cecal ligation and perforation were randomized into control (n = 9) or esmolol (n = 10) groups, the latter of which received esmolol infusion (15 mg/kg/h) throughout the study period. In an additional 20 animals, levels of tumor necrosis factor-α (TNF-α) in both plasma and intraperitoneal fluid were measured, and mesenteric lymph nodes (MLNs) and ileum were excised for evaluation of bacterial translocation and mucosal injury at the 18-h study period. Measurements and results: Mean survival time in the esmolol group was significantly longer compared with the control group (69.5 ± 26.8 versus 28.6 ± 11.0 h). Plasma TNF-α was not detectable in either group, while intraperitoneal fluid TNF-α level was elevated in the control group but significantly depressed in the esmolol group (16.8 ± 10.7 versus 5.4 ± 7.1 pg/ml, P < 0.05). Simultaneously, the Escherichia coli positive rate of MLNs was higher (100% versus 44%, P < 0.05) and the gut mucosal injury score was elevated (4.1 ± 0.6 versus 2.8 ± 0.6, P < 0.01) in the control compared with the esmolol group. Conclusions: Beta-1 blocker therapy improves outcome in sepsis possibly through modulation of gut mucosal integrity and local inflammatory response. © 2011 Copyright jointly held by Springer and ESICM.

Purpose: The recruitment maneuver (RM) has been shown to improve oxygenation for post-cardiopulmonary bypass (CPB) patients; however, sustained inflation of the lung gives rise to hypotension. The primary goal of our study was to evaluate the safety and efficacy of our proposed RM, defined on the basis of dynamic lung compliance (Cdyn). Methods: Twenty-eight patients undergoing elective cardiac surgery with CPB were assigned to two treatment groups: an individualized RM group, in which a pressure equal to 15 ml × real body weight/Cdyn + positive end-expiratory pressure (PEEP) cmH2O was applied for 15 s; and a control RM group, in which a pressure of 20 cmH2O was applied for 25 s. Arterial blood pressure, cardiac output, pulmonary artery pressure, and heart rate (HR) were monitored. Tidal volume (VT), and airway pressure were continuously obtained from an expiratory flow meter and pressure monitor. Blood samples were obtained and analyzed with a blood gas analyzer. Results: The changes in HR, mean arterial pressure, mean pulmonary artery pressure, and cardiac index at the end of the RM were not significantly different between the two groups. The mean airway pressure of sustained inflation was 28.3 ± 1.3 cmH2O in the individualized RM group. The individualized RM significantly improved the Cdyn and partial pressure arterial oxygen/inspiratory fraction of oxygen (P/F) ratio compared with values in the control RM group (P = 0.026 and P = 0.012, respectively). Conclusion: The present study indicates that the individualized RM resulted in minimum changes of hemodynamics and brought about improvement in oxygenation and lung compliance. © Japanese Society of Anesthesiologists 2009.

Purpose: The inflammatory response triggered by transfusion is implicated in the pathophysiology of transfusion-related immunomodulation. The authors hypothesized that two distinctive autotransfusion methods, acute normovolemic hemodilution (ANH) and preoperative donation (PD), have different influences on both inflammatory mediator generation during storage and the inflammatory response after a transfusion. The purpose of this study was to compare the plasma concentrations of neutrophil elastase (NE), interleukin (IL)-6, IL-8, and IL-10 in patients who underwent either of these two autologous transfusion methods. Methods: With institutional review board approval, the plasma concentrations of the above inflammatory mediators were determined in 23 patients with ANH and 8 patients with PD at the following time points: after anesthetic induction, at the end of the operation, and the morning of postoperative day 1. The concentrations of these inflammatory mediators were also measured in the donated blood obtained by either ANH or PD before retransfusion. Results: The mean storage durations were 3.7 h and 6.1 days for ANH and PD, respectively. Higher concentrations of NE and IL-10 were detected in the PD blood than in the ANH blood. Long duration of storage and/or low temperature may have been responsible for the increased NE and IL-10 concentrations in the PD blood. However, the difference between the two groups in the extent of increased plasma concentrations of these inflammatory mediators was not statistically significant. Conclusion: Inflammatory mediators were significantly increased in PD blood during storage compared to the blood obtained by ANH. However, their effects on the inflammatory response elicited in the recipients were not significantly different. © Japanese Society of Anesthesiologists 2009.

BACKGROUND: By using a U-shaped lumen catheter, the authors examined the effects of epidural cooling on spinal cord injury after aortic cross-clamping (ACC), with a focus on changes of spinal cord blood flow and expression of inducible nitric oxide synthase. METHODS: Sixteen pigs were randomized into two groups: Control group (n = 8) or Cooling group (n = 8). In the latter, epidural cooling started at 30 min (baseline) before 45 min of ACC and persisted for the next 30 min of reperfusion period. Spinal cord blood flow and somatosensory-evoked potentials were assessed during peri-ACC period. At 48 h, we evaluated hind limb function by using Tarlov score and expression of inducible nitric oxide synthase on spinal cord using immunohistochemistry. RESULTS: After ACC, spinal cord blood flow dropped to a similar extent in both groups. During the reperfusion period, spinal cord blood flow increased up to 113% (103-124%), median (interquartile range), level transiently and decreased to 32% (22-47%) level versus baseline in the Control group, whereas it increased and remained at 92% (86-97%) level in the Cooling group. Simultaneously, somatosensory-evoked potentials showed that onset of loss time was delayed and recovery time was shortened in the Cooling group. Tarlov scores in the Cooling group were significantly higher and accompanied by normal-appearing motor neurons and significantly greater expression of inducible nitric oxide synthase on spinal cord versus the Control group. CONCLUSIONS: This study shows that epidural cooling during ACC minimized the risk of spinal cord injury, possibly by preventing delayed hypoperfusion and upregulating inducible nitric oxide synthase expression. © 2009, the American Society of Anesthesiologists, Inc.

OBJECTIVE:: To examine whether hyperglycemia would augment gut barrier dysfunction and inflammatory responses in endotoxemic rats, and simultaneously to clarify the roles of tumor necrosis factor (TNF)-α in alterations of gut mucosal permeability associated with hyperglycemia. DESIGN:: Prospective randomized animal study. SETTING:: University research laboratory. SUBJECTS:: Male Wistar rats treated with lipopolysaccharide (LPS) injection. INTERVENTIONS:: After LPS injection (4 mg/kg), rats were randomly allocated into group S (n = 6), group G (n = 7), or group GI (n = 8) with continuous infusion of different fluid solutions: normal saline, 40% glucose or 10% glucose mixed with insulin, respectively. Blood glucose, insulin, and proinflammatory cytokines, accompanied by gut mucosal permeability using an in situ loop preparation of gut with fluorescence isothiocyanate-conjugated dextran, were measured. Bacterial growth or alterations in mesenteric lymph nodes and cecal contents were also assessed. We further determined the roles of TNF-α using an inhibitor of TNF-α converting enzyme in gut barrier dysfunction under the same experimental settings. MEASUREMENTS AND MAIN RESULTS:: Hyperglycemia over 400 mg/dL was achieved and kept in group G during the study period whereas normoglycemia was preserved in group S and GI, the latter of which showed the similar extent of hyperinsulinemia to group G. Plasma concentrations of fluorescence-labeled dextran and TNF-α in group G were significantly higher vs. group S and GI, and the number of bacteria found in mesenteric lymph nodes in group G was greater compared with group S. Intestinal environments including microflora and organic acids were not altered by blood glucose or insulin level. Inhibiting conversion of membrane-bound to soluble type of TNF-α restored gut mucosal permeability augmented by hyperglycemia. CONCLUSIONS:: These findings indicate that hyperglycemia deteriorates LPS-elicited gut barrier dysfunction and bacterial translocation independently of plasma insulin level, and that TNF-α mediates such mucosal dysfunction of gut in endotoxemia. © 2009 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Recent evidence demonstrated that hypercapnic acidosis due to lung protective strategy was not only permissive but also even therapeutic for injured lung. Since the effects of hypercapnic acidosis on extra-pulmonary organs remain to be clarified, we tested the hypothesis that hypercapnic acidosis protects gut mucosal barrier function by modulating inflammation in a rabbit model of endotoxemia. Prospective randomized animal study. University research laboratory. Male New Zealand white rabbits. Thirty-two animals were randomly allocated into two groups: normocapnia (n = 17) and hypercapnia (n = 15). The latter group received FICO2 5% under mechanical ventilation to achieve hypercapnia throughout the study periods, whereas the former with FICO2 0%. Arterial blood gas, intramucosal pH (pHi) and portal blood flow were assessed at baseline, 2-h and 4-h infusion of lipopolysaccharide. At 4 h, ileal myeloperoxidase (MPO) activity and intestinal permeability were measured. The animals in the hypercapnia group showed apparent hypercapnic acidosis and progressive intramucosal acidosis at 4 h, accompanied by significantly lower intestinal permeability versus normocapnia group. Ileal MPO activity was comparable between the study groups. Hypercapnic acidosis attenuates endotoxin-induced gut barrier dysfunction possibly through neutrophil-independent mechanisms. © 2008 Springer-Verlag.

We describe a 42-yr-old woman scheduled for emergency cesarean section who had sudden cardiopulmonary arrest just before induction of general anesthesia. Hypermagnesemia, caused by accidental overdose of magnesium sulfate during transportation to the operating room, was the primary cause of this life-threatening event. Anesthetic management after such events and a brief summary of the literature regarding iatrogenic hypermagnesemia in obsteric patients are provided. (C) 2000 by Elsevier Science Inc.

Study Objective: To examine the effects of additional droperidol or butorphanol to epidural fentanyl infusion on postsurgical analgesia.Design: Prospective, randomized, single blinded clinical study.Setting: University-affiliated medical center.Patients: 60 ASA physical status I and II patients undergoing anorectal surgery by one surgeon.Interventions: Patients were randomly allocated to the following groups according to the medication that was continuously administered into the epidural space: 1) Group C (n = 20) received 0.4 mg fentanyl in 40 ml of 0.125% bupivacaine; 2) Group D (n = 20) received 2.5 mg droperidol and 0.4 mg fentanyl in 40 ml of 0.125% bupivacaine; and 3) Group B (n = 20) received 2 mg butorphanol and 0.4 mg fentanyl in 40 ml of 0.125% bupivacaine over 24 hours postoperatively.Measurements and Main Result: Postsurgical analgesia and the incidence of fentanyl-related complications, such as nausea/vomiting, somnolence, pruritus, and respiratory depression, were assessed for 24 hours postoperatively. At 16 and 24 hours after surgery, 75% of patients in Group D reported no pain versus 35% in Group C (p < 0.05). In addition, the overall visual analogue scale examined at 24 hours was significantly lower in Group D than that in Group C (22 ± 17 mm vs. 44 ± 22 mm, respectively; p < 0.05). Simultaneously, the incidence of postoperative nausea/vomiting was lower in Group D compared with Group C (20% vs. 60%; p < 0.05). On the other hand, butorphanol did not modify the analgesic effects or complications of epidural fentanyl infusion.Conclusion: In this study population, additional droperidol, not butorphanol, improved postsurgical analgesia accompanied by less incidence of nausea/vomiting during epidural fentanyl administration. Copyright (C) 2000 Elsevier Science Inc.

Study Objective: To determine whether morphine and its active metabolites such as morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) modulate immune function in patients with advanced cancer who required morphine for pain relief. Design: Prospective observational clinical study. Setting: Pain clinic of a university hospital. Patients: Fifteen patients who visited our clinic for control of advanced cancer pain. Interventions: During the initiation or changes of morphine therapy, venous blood samples were obtained at the enrollment of this study, 1 and 3 weeks after the change of morphine dose or route. Measurements: Lymphocyte subpopulation CD4+ and CD8 +, activity of natural killer cell, phytohemagglutinin (PHA)-induced T-cell proliferation, and plasma immunoglobulin M and G concentrations were measured, as well as plasma concentrations of morphine, M-3-G, and M-6-G. Main Results: At the entry of the study, 6 patients did not receive any type of morphine medication (group 1), whereas 9 patients were treated with morphine for 1 month (group 2). Cancer pain, rated as 4 at the entry period, was reduced to 2 of 10 (visual analogue scale) during the study periods. Although the plasma concentrations of M-3-G and M-6-G in Group 1 were significantly less than those in Group 2, plasma concentrations of immunologic markers were similar between the groups. In Group 1, Spearman linear regression analysis showed negative correlation between morphine-derived metabolites and immunoglobulins or PHA-induced T-cell proliferation, whereas poor correlation was found with all immunologic parameters in Group 2. Stepwise linear regression analyses showed that the metabolites, rather than morphine per se, modulated immune function, reflected by PHA-induced T-cell proliferation and immunoglobulin G concentration in Group 1. Conclusions: The present study suggests that some of humoral and cellular immunity are modulated by morphine-derived metabolites at the early phase of morphine therapy in patients with advanced cancer. © 2005 Elsevier Inc. All rights reserved.

Objective: Since β-blocker therapy is known to be effective in patients with an injured heart, such as infarction, we designed the present study to examine the protective effects of infusion of the β1-selective blocker esmolol on myocardial function in peritonitis-induced septic rats using an isolated working heart preparation. Design: Randomized animal study. Setting: University research laboratory. Subjects: Thirty-one rats treated with cecal ligation and perforation to evoke peritonitis. Interventions: After cecal ligation and perforation, rats were randomly allocated to the control group (normal saline 2 mL/hr, n = 11), low-dose esmolol group (10 mg/kg/hr, n = 10), or high-dose esmolol group (20 mg/kg/hr, n = 10). After obtaining blood samples for measurement of arterial lactate and tumor necrosis factor-α at 24 hrs, we assessed cardiac output, myocardial oxygen consumption, and cardiac efficiency (cardiac output × peak systolic pressure/myocardial oxygen consumption) at various preloads in an isolated perfused heart preparation. Measurements and Main Results: Esmolol infusion did not cause an elevation of arterial lactate levels but reduced tumor necrosis factor-α concentrations vs. the control group (p < .05). Both cardiac output and cardiac efficiency in the esmolol-treated rats were significantly higher throughout the study periods vs. the control group (p < .05). Conclusions: Esmolol infusion in sepsis improved oxygen utilization of myocardium and preserved myocardial function. Copyright © 2005 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

In the present study, we evaluated the effect of epidural analgesia on the alterations of gut barrier function elicited by endotoxin in rabbits. After the placement of an epidural catheter, 28 male rabbits were randomized into either 0.5% lidocaine (group E) or saline (group C) group. The solutions (0.4 mL/kg) were epidurally injected, followed by continuous infusion (0.1 mL · kg-1 · h-1) throughout the study period. Under a continuous infusion of lipopolysaccharide (15 μg · kg-1 · h-1), mean arterial blood pressure, intramucosal pH, and plasma thrombomodulin concentrations were measured. At 4 h, mean arterial blood pressure was lower (P < 0.05), intramucosal pH was higher (P < 0.01), and the progression of hemodilution more profound (P < 0.05) in group E versus group C, whereas plasma thrombomodulin levels were increased to a similar extent between the groups. With less wet-to-dry weight ratio of ileum, histopathological injury scores of gut mucosa were significantly less in group E versus group C(P < 0.01). In a separate series of experiments (n = 10 each group), mucosal permeability in group E was significantly less compared with group C (P < 0.05). Collectively, these studies showed that despite a significant decrease of perfusion pressure and arterial oxygen content, epidural analgesia minimized endotoxin-induced functional and structural injury of gut mucosa possibly through endothelium-independent mechanisms. © 2005 by the International Anesthesia Research Society.

Neutrophils play an important role in ischemia-reperfusion injury. The neutrophil elastase not only causes tissue damage, but also mediates neutrophil priming. In the present study, we use a rabbit model of hepatoenteric ischemia-reperfusion to test the hypothesis that neutrophil elastase inhibition ameliorates an ischemia-reperfusion injury by attenuating neutrophil priming and suppressing enzymatic activity. Twenty-four Japanese white rabbits underwent 30 min of supraceliac aortic cross-clamping and 180 min of reperfusion under isoflurane anesthesia. The rabbits randomly received the neutrophil elastase inhibitor, sivelestat (n = 10), or saline (n = 14). Neutrophil priming was then assayed with luminol-dependent neutrophil chemiluminescence. Hepatic, intestinal, renal, and pulmonary damages were assessed with serum transaminase, lactate dehydrogenase concentrations, urinary N-acetyl glucosaminidase activity, and protein concentration in post mortem bronchoalveolar lavage fluid. We discovered that neutrophil elastase inhibition suppressed plasma neutrophil elastase, and that lipid peroxide concentrations increased after reperfusion. It improved ischemia-reperfusion injuries in the liver, intestine, kidney, and lung. Furthermore, inhibition of neutrophil elastase with sivelestat significantly attenuated post-reperfusion neutrophil priming. The results of this study demonstrate that neutrophil elastase inhibition could effectively attenuate an ischemia-reperfusion injury caused by supraceliac aortic cross-clamping, most likely from the attenuation of neutrophil priming.

Massive hepatic infarction associated with pregnancy is extremely rare, but is potentially fatal. A 35-year-old primigravida with mild preeclampsia developed acute right upper quadrant pain and marked elevation of liver enzymes at 26 weeks' gestation. After emergent cesarean section, her condition was complicated by oliguric renal failure and pulmonary edema with further deterioration of hepatic function (aspartate transaminase 4339 IU/L; alanine transaminase 3489 IU/L; lactate dehydrogenase 10780 IU/L). The contrast-enhanced computed tomography revealed non-enhancing low attenuation throughout the right lobe of liver, compatible with infarction. Continuous hemodiafiltration was initiated as renal support on postpartum day one. However, excessive fluid accumulation persisted, and she developed severe edema formation in both lung and systemic body surface. To ameliorate microvascular endothelial injury, corticosteroid therapy was begun on postpartum day five. Following treatment initiation, her renal and hepatic function showed steady improvement, accompanied by drastic resolution of edema formation. She was discharged five weeks postpartum with no additional treatment, and is without sequelae six months later. Massive hepatic infarction should be considered in preeclamptic patients who present acute abdominal pain and severe hepatic dysfunction, and continuous hemodiafiltration with corticosteroid therapy may improve the maternal outcome.

KL-6 is a pulmonary epithelial mucin more prominently expressed on the surface membrane of alveolar type II cells when these cells are proliferating, stimulated, and/or injured. We hypothesized that high levels of KL-6 in epithelial lining fluid and plasma would reflect the severity of lung injury in patients with acute lung injury (ALI). Epithelial lining fluid was obtained at onset (day 0) and day 1 of acute respiratory distress syndrome (ARDS)/ALI by bronchoscopic microsampling procedure in 35 patients. On day 0, KL-6 and albumin concentrations in epithelial lining fluid were significantly higher than in normal controls (P < 0.001), and the concentrations of KL-6 in epithelial lining fluid (P < 0.002) and in plasma (P < 0.0001) were higher in nonsurvivors than in survivors of ALI/ARDS. These observations were corroborated by the immunohistochemical localization of KL-6 protein expression in the lungs of nonsurvivors with ALI and KL-6 secretion from cultured human alveolar type II cells stimulated by proinflammatory cytokines. Because injury to distal lung epithelial cells, including alveolar type II cells, is important in the pathogenesis of ALI, the elevation of KL-6 concentrations in plasma and epithelial lining fluid could be valuable indicators for poor prognosis in clinical ALI.