Yung-Fong Tsai

Stroke Volume Variation Derived by Arterial Pulse Contour Analysis Is a Good Indicator for Preload Estimation During Liver Transplantation

BACKGROUND Accurate determination of preload during liver transplantation is essential. Continuous right ventricular end diastolic volume index (RVEDVI) has been shown to be a better preload indicator during liver transplantation than the filling pressures. However, recent evidence has shown that dynamic variables, in this case stroke volume variation (SVV), are also good indicators of preload responsiveness. In this study, we evaluated the correlation between SVV, which we derived from arterial pulse contour analysis and RVEDVI. METHODS In this study, we looked for possible relationships between SVV obtained through FloTrac/Vigileo monitor, central venous pressure (CVP), pulmonary arterial occlusion pressure (PAOP), and RVEDVI in 30 patients undergoing liver transplantation. Measurements were taken at 11 defined points during different phases across liver transplantation. Each set of measurement was taken during a steady state, which means at least 15 minutes elpased after any changes occured in either the infusion rate of catecholamines or ventilator settings. Pearsons test was used for correlation estimation. RESULTS There was a statistically significant (P<.01) relationship between SVV and RVEDVI with a correlation coefficient of -0.87. The correlations between CVP (r=0.42), PAOA (r=0.46), and RVEDVI were less strong. CONCLUSION We conclude that SVV is a good indicator for preload estimation during liver transplantation. A higher SVV value is associated with a more hypovolemic fluid status.

Cardiac Output Derived From Arterial Pressure Waveform Analysis: Validation of the Third-Generation Software in Patients Undergoing Orthotopic Liver Transplantation

BACKGROUND The upgraded third-generation software (version 3.02) for the FloTrac/Vigileo system has been developed to particularly improve the accuracy of cardiac output (CO) measurements in hyperdynamic conditions. The aim of our study was to compare the CO values obtained using the FloTrac/Vigileo system during orthotopic liver transplantation (OLT) with those obtained in the same circumstances using a Swan-Ganz catheter (bolus thermodilution method). METHODS Twenty consecutive recipients scheduled for OLT were studied. Simultaneous CO values measured by both devices were obtained at 10 predefined time points throughout the surgery. A percentage error of not more than 30% was established as the criterion for device interchangeability. RESULTS A total of 200 paired measurements were obtained. The CO values derived from the FloTrac/Viligeo ranged from 2.8 to 10.9 L/min, with a mean of 5.91±1.81 L/min. The values from bolus thermodilution ranged from 2.2 to 13.2 L/min, with a mean of 6.12±2.07 L/min. The bias was 0.22, and the limits of agreement were -3.13 to 3.56 L/min. The percentage error between the FloTrac/Viligeo and bolus thermodilution measurements was 54.93%. The percentage errors of paired measurements in three surgical phases by subgroup analysis were 43.50% (dissecting phase), 62.9% (anhepatic phase), and 56.05% (reperfusion phase), respectively. CONCLUSION CO measurements obtained using the less invasive arterial waveform FloTrac/Vigileo system upgraded with the third-generation software had poor intraoperative agreement with pulmonary artery thermodilution CO measurements in patients undergoing OLT.

Sirtinol Inhibits Neutrophil Elastase Activity and Attenuates Lipopolysaccharide-Mediated Acute Lung Injury in Mice

Enhanced activity of neutrophil elastase leads to a protease–antiprotease imbalance, and plays an essential pathogenic role in acute lung injury (ALI) and acute respiratory distress syndrome. We assayed the pharmacological effects and mechanisms of the action of sirtinol in human neutrophils, and in neutrophil elastase (HNE)-induced paw edema and lipopolysaccharide (LPS)-mediated ALI in mice. Sirtinol significantly inhibited the activity of HNE from human neutrophils in response to various stimulators. The inhibitory effects on HNE activity were not mediated through protein kinase A, calcium, extracellular-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, Akt, or Src family kinases. Analysis of enzymatic activities showed that sirtinol inhibited HNE activity in a concentration-dependent manner. These results demonstrate that sirtinol does not affect neutrophil function and is an HNE inhibitor. In addition, administration of sirtinol significantly inhibited HNE-induced paw edema, and attenuated the myeloperoxidase activity and reduced pulmonary wet/dry weight ratio in the LPS-induced ALI mouse model. Our study indicates that sirtinol has anti-inflammatory effects through direct inhibition of HNE activity and attenuates HNE-induced and LPS-mediated tissue or organ injury in vivo. Sirtinol is a novel HNE inhibitor and may have the potential for clinical application in the treatment of inflammatory lung diseases.

Cardiac output derived from arterial pressure waveform analysis in patients undergoing liver transplantation: validity of a third-generation device.

BACKGROUND Hemodynamic monitoring is essential to a successful liver transplantation procedure. FloTrac, a hemodynamic monitor that uses arterial-waveform-based pulse contour analysis for cardiac output (CO) measurement, has proven useful in many clinical settings. One of the primary foci of FloTracs recent third-generation software upgrade was improving its accuracy in low systemic vascular resistance status. We evaluated the accuracy of the upgraded FloTrac monitor during liver transplantation. MATERIALS AND METHODS Twenty-eight patients undergoing liver transplantation were enrolled in the study. Two sets of CO were measured with a radial arterial line connected to a FloTrac monitor (COFT) and a pulmonary artery catheter connected to a continuous cardiac output Vigilence monitor (COPAC). Simultaneous CO measurement was performed and recorded every 5 minutes throughout the surgery. Bland-Altman analysis was used to estimate the accuracy. The comparative method and reference method were considered interchangeable if the limits of agreement did not exceed a threshold set a priori at the greater of ±1 L/min, or a percentage error of lesser than 30%. RESULTS In all, 3234 paired data were collected. The bias was -0.8 L/min and the limits of agreements were -5.6 to 4.0 L/min. Percentage error was 75%. Regression analysis of the systemic vascular resistance index (SVRI) and the bias between COPAC and COFT showed that the bias was inversely related to the SVRI [r2=0.49; P<.001, y=-32.1983+9.9978 Log(x)]. CONCLUSIONS Despite a software upgrade, the effectiveness of the FloTrac artery-derived cardiac output monitor for CO measurement during liver transplantation remains limited.

Protective Effect of Tropisetron on Rodent Hepatic Injury after Trauma-Hemorrhagic Shock through P38 MAPK-Dependent Hemeoxygenase-1 Expression

Tropisetron can decrease inflammatory cell responses and alleviate organ damage caused by trauma-hemorrhage, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase/hemeoxygenase-1 (p38 MAPK/HO-1) pathway exerts anti-inflammatory effects on different tissues. The aim of this study was to investigate whether p38 MAPK/HO-1 plays any role in the tropisetron-mediated attenuation of hepatic injury after trauma-hemorrhage. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35–40 mmHg for 90 min), followed by fluid resuscitation. During resuscitation, several treatment regimens were administered: four doses of tropisetron alone (0.1, 0.3, 1, 3 mg/kg body weight), or a single dose of tropisetron (1 mg/kg body weight) with and without a p38 MAPK inhibitor (SB-203580, 2 mg/kg body weight) or HO antagonist (chromium-mesoporphyrin, 2.5 mg/kg body weight). Various parameters were measured, and the animals were sacrificed at 24 h post-resuscitation. The results showed that trauma-hemorrhage increased the following parameters: plasma concentrations of aspartate (AST) and alanine aminotransferases (ALT), hepatic myeloperoxidase (MPO) activity, and levels of cytokine-induced neutrophil chemoattractant-1 and -3 (CINC-1 and CINC-3), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1α (MIP-1α). These parameters were significantly improved in the tropisetron-treated rats subjected to trauma-hemorrhage. Tropisetron treatment also increased hepatic p38 MAPK and HO-1 expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 or chromium-mesoporphyrin with tropisetron abolished the tropisetron-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of tropisetron administration on alleviation of hepatic injury after trauma-hemorrhage is likely mediated through p38 MAPK-dependent HO-1 expression.

Osthol attenuates neutrophilic oxidative stress and hemorrhagic shock-induced lung injury via inhibition of phosphodiesterase 4

Oxidative stress caused by neutrophils is an important pathogenic factor in trauma/hemorrhagic (T/H)-induced acute lung injury (ALI). Osthol, a natural coumarin found in traditional medicinal plants, has therapeutic potential in various diseases. However, the pharmacological effects of osthol in human neutrophils and its molecular mechanism of action remain elusive. In this study, our data showed that osthol potently inhibited the production of superoxide anion (O2(•-)) and reactive oxidants derived therefrom as well as expression of CD11b in N-formylmethionylleucylphenylalanine (FMLP)-activated human neutrophils. However, osthol inhibited neutrophil degranulation only slightly and it failed to inhibit the activity of subcellular NADPH oxidase. FMLP-induced phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) was inhibited by osthol. Notably, osthol increased the cAMP concentration and protein kinase A (PKA) activity in activated neutrophils. PKA inhibitors reversed the inhibitory effects of osthol, suggesting that these are mediated through cAMP/PKA-dependent inhibition of ERK and Akt activation. Furthermore, the activity of cAMP-specific phosphodiesterase (PDE) 4, but not PDE3 or PDE7, was significantly reduced by osthol. In addition, osthol reduced myeloperoxidase activity and pulmonary edema in rats subjected to T/H shock. In conclusion, our data suggest that osthol has effective anti-inflammatory activity in human neutrophils through the suppression of PDE4 and protects significantly against T/H shock-induced ALI in rats. Osthol may have potential for future clinical application as a novel adjunct therapy to treat lung inflammation caused by adverse circulatory conditions.

Osthole attenuates hepatic injury in a rodent model of trauma-hemorrhage.

Recent evidences show that osthole possesses anti-inflammatory properties and protective effects following shock-like states, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase (p38 MAPK) pathway exerts anti-inflammatory effects in injury. The aim of this study was to investigate whether p38 MAPK plays any role in the osthole-mediated attenuation of hepatic injury after trauma-hemorrhage. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35–40 mmHg for 90 minutes), followed by fluid resuscitation. During resuscitation, a single dose of osthole (3 mg/kg, intravenously) with and without a p38 MAPK inhibitor SB-203580 (2 mg/kg, intravenously), SB-203580 or vehicle was administered. Plasma alanine aminotransferase (ALT) with aspartate aminotransferase (AST) concentrations and various hepatic parameters were measured (n = 8 rats/group) at 24 hours after resuscitation. The results showed that trauma-hemorrhage increased hepatic myeloperoxidase activity, intercellular adhesion molecule-1 and interleukin-6 levels, and plasma ALT and AST concentrations. These parameters were significantly improved in the osthole-treated rats subjected to trauma-hemorrhage. Osthole treatment also increased hepatic phospho-p38 MAPK expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 with osthole abolished the osthole-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of osthole administration on alleviation of hepatic injury after trauma-hemorrhage, which is, at least in part, through p38 MAPK-dependent pathway.

Honokiol suppresses TNF-α-induced neutrophil adhesion on cerebral endothelial cells by disrupting polyubiquitination and degradation of IκBα.

Adhesion molecules expressed on cerebral endothelial cells (ECs) mediate leukocyte recruitment and play a significant role in cerebral inflammation. Increased levels of adhesion molecules on the EC surface induce leukocyte infiltration into inflammatory areas and are thus hallmarkers of inflammation. Honokiol, isolated from the Chinese medicinal herb Magnolia officinalis, has various pharmacological activities, including anti-inflammatory effects, yet the nature of honokiol targeting molecules remains to be revealed. Here, we investigated the inhibitory effect of honokiol on neutrophil adhesion and vascular cell adhesion molecule-1 (VCAM-1) expression, which underlie its molecular target, and mechanisms for inactivating nuclear factor κ enhancer binding protein (NF-κB) in mouse cerebral ECs. Honokiol inhibited tumour necrosis factor-α (TNF-α)-induced neutrophil adhesion and VCAM-1 gene expression in cerebral ECs. The inflammatory transcription factor NF-κB was downregulated by honokiol. Honokiol significantly blocked TNF-α–induced NF-κB p65 nuclear translocation and degradation of the proteasome-dependent inhibitor of NF-κB α (IκBα). From docking model prediction, honokiol directly targeted the ubiquitin–ubiquitin interface of Lys48-linked polychains. Moreover, honokiol prevented the TNF-α-induced Lys48-linked polyubiquitination, including IκBα-polyubiquitin interaction. Honokiol has protective anti-inflammatory effects on TNF-α-induced neutrophil adhesion and VCAM-1 gene expression in cerebral ECs, at least in part by directly inhibiting ubiquitination-mediated IκBα degradation and then preventing NF-κB nuclear translocation.

Recipient Age and Mortality Risk after Liver Transplantation: A Population-Based Cohort Study

The aim of the present large population-based cohort study is to explore the risk factors of age-related mortality in liver transplant recipients in Taiwan. Basic information and data on medical comorbidities for 2938 patients who received liver transplants between July 1, 1998, and December 31, 2012, were extracted from the National Health Insurance Research Database on the basis of ICD-9-codes. Mortality risks were analyzed after adjusting for preoperative comorbidities and compared among age cohorts. All patients were followed up until the study endpoint or death. This study finally included 2588 adults and 350 children [2068 (70.4%) male and 870 (29.6%) female patients]. The median age at transplantation was 52 (interquartile range, 43–58) years. Recipients were categorized into the following age cohorts: <20 (n = 350, 11.9%), 20–39 (n = 254, 8.6%), 40–59 (n = 1860, 63.3%), and ≥60 (n = 474, 16.1%) years. In the total population, 428 deaths occurred after liver transplantation, and the median follow-up period was 2.85 years (interquartile range, 1.2–5.5 years). Dialysis patients showed the highest risk of mortality irrespective of age. Further, the risk of death increased with an increase in the age at transplantation. Older liver transplant recipients (≥60 years), especially dialysis patients, have a higher mortality rate, possibly because they have more medical comorbidities. Our findings should make clinicians aware of the need for better risk stratification among elderly liver transplantation candidates.

Ischemic reperfusion injury-induced oxidative stress and pro-inflammatory mediators in liver transplantation recipients.

OBJECTIVE Liver ischemic reperfusion injury is harmful to transplant recipients, and is associated with postoperative morbidity and mortality. Our study was designed to investigate the oxidative stress and pro-inflammatory mediators in liver transplant recipients. METHODS We prospectively analyzed 14 recipients who underwent liver transplantation by measuring their blood levels of malondialdehyde (MDA) and cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, at nine time points perioperatively. We also evaluated the correlations between oxidative stress (MDA levels) and the characteristics of the recipient or the donated graft. RESULTS These parameters significantly increased from 1 minute before reperfusion, and the values peaked within 3 to 30 minutes after reperfusion. On the time point at 5 minutes after reperfusion, the MDA levels which were the highest in the recipients correlated with the values of preoperative direct/and total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), model for end-stage liver disease (MELD) score, international normalized ratio (INR), and surgical blood loss. CONCLUSION The levels of MDA, TNF-α, IL-1β, and IL-6 greatly increased with the ischemic reperfusion insult. Recipients with higher values of preoperative direct/and total bilirubin, AST, ALT, MELD score, INR, and surgical blood loss tended to have higher levels of MDA and may suffer more injury from this insult.