Objective To investigate the clinical significance of Child-Pugh grading of liver function in patients with general anesthesia induced by propofol induction. Methods The 126 patients with liver cirrhosis undergoing elective abdominal surgery were divided into group A, B, C, which meet the standard of Child-Pugh A, B, C grade respectively according to the classification of Child-Pugh liver function, with 42 patients in each. In addition, 42 patients with normal liver function and elective abdominal surgery were selected as the control group. All patients with general anesthesia were induced by propofol target controlled infusion anesthesia. When reaching the same sedative effect [alert sedation (OAA/S) score ≤1], the indexes of liver metabolism [alanine aminotransferase (ALT) and aspartate aminotransferase (AST), albumin (ALB), total bilirubin (T-BiL), prothrombin time (PT)], hemodynamics[systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR)], arterial blood gas monitoring [arterial oxygen saturation (SaO2), arterial oxygen pressure (PaO2), arterial carbon dioxide pressure (PaCO2)], BIS and propofol concentration in four groups were compared. Results The content of ALB in the control group, group A, B and C tended to decreased, and the content of T-BiL, PT showed an increasing trend (P<0.05). When the OAA/S score was less than 1 points, four groups of SBP, DBP, MAP, BIS were below baseline (P<0.05). In all the groups, group A, B and C, the SBP, DBP, MAP and effect-site concentration of propofol, tended to decrease (P<0.05). The incidence of hypotension in group B and C was significantly higher than that in control group (P<0.05). The incidence of bradycardia and myocardial ischemia in group A and B was significantly higher than that in group C (P<0.05). Conclusion It is beneficial to control the dosage of propofol, reduce the adverse event, and improve surgical safety and prognosis in patients with general anesthesia by evaluating the liver function using Child-Pugh grading.
Compared with control group, ALB:*1t=11.894-31.291, T-BiL:*1t=7.527-27.765, PT:*1t=4.767-6.733, all*1P <0.05;compared with A group, ALB:*2t=7.777-18.033, T-BiL:*2t=9.588-21.724, PT:*2t=3.964-5.886, all *2P<0.05;compared with B group, ALB:*3t=15.770, T-BiL:*3t=12.419, PT:*3t=2.082, all*3P <0.05
表2
4组患者术前ALT、AST、ALB、T-BiL、PT比较
Tab.2
Comparison of preoperative ALT, AST, ALB, T-BiL and PT among four groups of patients x¯±s,n=42
表3
4组患者血流动力学、动脉血气监测指标、BIS及丙泊酚效应室浓度比较
Tab.3
Comparison of hemodynamics, arterial blood gas monitoring, BIS and propofol concentration among four groups of patients x¯±s,n=42
Compared with basal value, SBP:*1t=19.570-26.972, DBP:*1t=16.301-29.076, MAP:*1t=14.333-31.892, BIS:*1t=35.016-39.922, all*1P <0.05;compared with control group, SBP:*2t=6.067-15.388, DBP:*2t=3.445-15.790, compartment concentration of propofol:*2t=4.278-10.053, all*2P <0.05;compared with A group, SBP:*3t=5.101~8.911, DBP:*3t=5.002~12.256, MAP:*3t=8.241-19.489, compartment concentration of propofol:*3t=3.335-6.069, all*3P <0.05;compared with B group, SBP:*4t=4.213, DBP:*4t=8.550, MAP:*4t=10.417, compartment concentration of propofol:*4t=2.670, all *4P<0.05
表3
4组患者血流动力学、动脉血气监测指标、BIS及丙泊酚效应室浓度比较
Tab.3
Comparison of hemodynamics, arterial blood gas monitoring, BIS and propofol concentration among four groups of patients x¯±s,n=42
Compared with control group, hypotension:*1χ2=3.896-9.722, arrhythmia:*1χ2=4.086, *1P<0.05;compared with A group, bradycardia:*2χ2=6.098, arrhythmia:*2χ2=4.974, *2P<0.05;compared with B group, bradycardia:*3χ2=7.265, arrhythmia:*3χ2=6.098,*3P<0.05
表4
4组患者麻醉诱导期血流动力学事件发生率比较
Tab.4
Comparison of the incidence of hemodynamics events during anesthesia introduction among four groups of patients
目的：探讨肝功能 Child-Pugh 分级及不同肝功能指标与清醒时 BIS 值的相关性。方法择期行上腹部手术的患者65例,按照术前肝功能 Child-Pugh 分级将患者分为三组：A 组（n =27）肝功能正常；B 组（n=21）轻度肝功能不全,Child-Pugh 分级 A 级；C 组（n=17）重度肝功能不全, Child-Pugh 分级 B~C 级。记录术前总胆红素（TBIL）、间接胆红素（DBIL）、直接胆红素（IBIL）、谷丙转氨酶（ALT）、谷草转氨酶（AST）、白蛋白（ALB）、乳酸脱氢酶（LDH）、凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）、纤维蛋白原（FIB）,以及患者入室后静卧5 min 的 BIS 值（BISwake）。结果 B组和 C 组 TBIL、DBIL、IBIL、ALT、AST、ALB 明显高于 A 组（P 〈0.05或 P 〈0.01）,C 组 PT和 APTT 明显长于 A 组和 B 组（P 〈0.01）。C 组 BISwake 为94.1±3.0,明显低于 A 组的96.2±1.7（P 〈0.01）和 B 组的95.6±0.8（P 〈0.01）。多因素相关性分析显示,BISwake 与 TBIL 呈负相关（r=-0.26,P =0.039）。结论终末期肝病患者清醒时的 BIS 值明显低于轻度肝功能不全及肝功能正常的患者。血清总胆红素水平与清醒时 BIS 值的关系较为紧密。
KIVLEHANF,CHAUME,LINDNERE.Propofol detection and quantification in human blood:the promise of feedback controlled,closed-loop anesthesia[J].Analyst,2015,140(1):98-106.
DEL-GIUDICEA,LEGGIOC,BALASCON,et al.Ibuprofen and propofol cobinding effect on human serum albumin unfolding in urea[J].J Phys Chem B,2014,118(34):10043-10051.
The unfolding pathway of the defatted human serum albumin (HSA) binding ibuprofen and propofol has been studied by using small-angle X-ray scattering (SAXS) and the support of circular dichroism data. A set of HSA solutions with urea concentrations between 0.00 and 9.00 M was analyzed, and the singular value decomposition method applied to the complete SAXS data set allowed us to distinguish four different states in solution. Besides the native and unfolded forms, two intermediates I1 and I2 have been identified, and the low-resolution structures of these states were obtained by exploiting both ab initio and rigid body fitting methods. The I1 structure was characterized by only one open domain (domain I, which does not host a binding site for either of the ligands), whereas I2 presents only one closed domain (domain III). A direct comparison with the unfolding pathway of the HSA:Ibu complex (Galantini et al. Biophys. Chem. 2010, 147, 111-122) pointed out that the presence of propofol as a second ligand, located in subdomain IIIB, leads to the appearance of an intermediate with two closed domains (domains II and III), which are those that accommodate the ligands. Moreover, the equilibrium between I2 and the unfolded form is slightly shifted toward higher urea concentrations. These results suggest that the cobinding significantly hinders the unfolding process.
BALERK,MARTIN OA,CARIGNANO MA,et al.Elec-trostatic unfolding and interactions of albumin driven by pH changes:a molecular dynamics study[J].J Phys Chem B,2014,118(4):921-930.
A better understanding of protein aggregation is bound to translate into critical advances in several areas, including the treatment of misfolded protein disorders and the development of self-assembling biomaterials for novel commercial applications. Because of its ubiquity and clinical potential, albumin is one of the best-characterized models in protein aggregation research; but its properties in different conditions are not completely understood. Here, we carried out all-atom molecular dynamics simulations of albumin to understand how electrostatics can affect the conformation of a single albumin molecule just prior to self-assembly. We then analyzed the tertiary structure and solvent accessible surface area of albumin after electrostatically triggered partial denaturation. The data obtained from these single protein simulations allowed us to investigate the effect of electrostatic interactions between two proteins. The results of these simulations suggested that hydrophobic attractions and counterion binding may be strong enough to effectively overcome the electrostatic repulsions between the highly charged monomers. This work contributes to our general understanding of protein aggregation mechanisms, the importance of explicit consideration of free ions in protein solutions, provides critical new insights about the equilibrium conformation of albumin in its partially denatured state at low pH, and may spur significant progress in our efforts to develop biocompatible protein hydrogels driven by electrostatic partial denaturation.
COOPER DJ,MYBURGHJ,HERITIERS,et al.Albumin resuscitation for traumatic brain injury:is intracranial hypertension the cause of increased mortality?[J].J Neurotrauma,2013,30(7):512-518.
Abstract Mortality is higher in patients with traumatic brain injury (TBI) resuscitated with albumin compared with saline, but the mechanism for increased mortality is unknown. In patients from the Saline vs. Albumin Fluid Evaluation (SAFE) study with TBI who underwent intracranial pressure (ICP) monitoring, interventional data were collected from randomization to day 14 to determine changes in ICP (primary outcome) and in therapies used to treat increased ICP. Pattern mixture modelling, designed to address informative dropouts, was used to compare temporal changes between the albumin and saline groups, and 321 patients were identified, of whom 164 (51.1%) received albumin and 157 (48.9%) received saline. There was a significant linear increase in mean ICP and significantly more deaths in the albumin group compared with saline when ICP monitoring was discontinued during the first week (1.30±0.33 vs. -0.37±0.36, p=0.0006; and 34.4% vs. 17.4%; p=0.006 respectively), but not when monitoring ceased during the second week (-0.08±0.44 vs. -0.23±0.38, p=0.79; and 18.6% vs. 12.1%; p=0.36 respectively). There were statistically significant differences in the mean total daily doses of morphine (-0.42±0.07 vs. -0.66±0.0, p=0.0009), propofol (-0.45±0.11 vs. -0.76±0.11; p=0.034) and norepinephrine (-0.50±0.07 vs. -0.74±0.07) and in temperature (0.03±0.03 vs. 0.16±0.03; p=0.0014) between the albumin and saline groups when ICP monitoring ceased during the first week. The use of albumin for resuscitation in patients with severe TBI is associated with increased ICP during the first week. This is the most likely mechanism of increased mortality in these patients.
SHITYAKOVS,ROEWERN,FORSTERC,et al.In silico investigation of propofol binding sites in human serum albumin using explicit and implicit solvation models[J].Comput Biol Chem,2017,70(1):191-197.
Abstract All-atom molecular dynamics (MD) simulations are presented on general anesthetic propofol bound to human serum albumin (HSA) due to the drug pharmacokinetics and pharmacodynamics in the circulatory system. We implemented the explicit and implicit solvation models to compare the binding affinity of propofol at the different binding sites (PR1 and PR2) in the HSA protein. Only the implicit solvation models provided the evidence in accordance with the experimental data indicating that the HSA-ligand interactions are dominanted by hydrophobic forces due to the higher drug affinity at the PR1 position with a 0200G MM-PB/SA value of -23.44kcalmol -1 . Overall, this study provides important information on the accuracy of explicit and implicit solvation models to characterize the propofol interaction with different HSA binding sites. Copyright 0008 2017 Elsevier Ltd. All rights reserved.
KOJIMAA,BAIJY,ITOY,et al.Serum albumin attenuates the open-channel blocking effects of propofol on the human Kv1.5 channel[J].Eur J Pharmacol,2016,783(1):117-126.
The intravenous anesthetic propofol modulates various ion channel functions. It is generally accepted that approximately 98% of propofol binds to blood constituents and that the free (unbound) drug preferentially affects target proteins including ion channels. However, modulatory effects of propofol on ion channels have not been previously explored in the presence of serum albumin. This study was designed to investigate the effects of serum albumin on the blocking action of propofol on the human Kv1.5 (hKv1.5) current. Whole-cell patch-clamp method was used to record the hKv1.5 channel current, heterologously expressed in Chinese hamster ovary cells, in the absence and presence of bovine serum albumin (BSA). Propofol induced a time-dependent decline of the hKv1.5 current during depolarizing steps and slowed the time course of tail current decay upon repolarization, supporting that propofol acts as an open-channel blocker. This blocking effect was reversible and concentration-dependent with an IC50of 62.93.1 M (n= 6). Bath application of 1% BSA markedly reduced the blocking potency of propofol on hKv1.5 current (IC50of 1116.0491.4 M;n= 6). However, in the presence of BSA, the propofol-induced inhibition of hKv1.5 current was also accompanied by a gradual decline of activated current during depolarization and deceleration of deactivating tail current upon repolarization. The presence of BSA greatly attenuated the blocking potency of propofol on hKv1.5 channel without affecting the mode of action of propofol on the channel. Serum albumin thus appears to bind to propofol and thereby reducing effective concentrations of the drug for inhibition of hKv1.5 channel.
目的:探讨经颈静脉肝内门体分流术(transjugular intrahepatic portosystemic shunt,TIPS)治疗肝硬化顽固性腹水的临床疗效及影响预后因素。方法:23例肝硬化顽固性腹水患者术后随访1~26月(平均9.7月),观察患者腹水缓解情况(腹水量)、临床血清学指标(血小板计数、白蛋白、总胆红素、凝血酶原时间、肌酐等)、生存率等。采用配对t检验、非参数检验分析术前术后临床血清学指标的变化情况,Kaplan-Merier方法计算生存率,术前危险因素预测3个月腹水疗效采用logistic回归分析,术前危险因素对术后生存情况的影响采用COX多因素回归模型分析,受试者工作曲线(receiver operating characteristic,ROC)及曲线下面积(area under the curve,AUC)判断最佳预测界值。结果:术后1年的各个随访期患者的腹水与术前比较明显改善,82.6%的患者术后1月腹水得到有效控制,52.4%患者在术后3月仅存少量腹水,术后6月在访的所有患者腹水均为少量。术后1周肝功能存在短期损害凝血酶原时间延长,中值(最小值,最大值)=19.6(14.0,28.7),Z=-2.419,P=0.016;Child-Pugh评分增加,x±s=9.87±1.71,t=-2.714,P=0.013;总胆红素升高,Z=-3.711,P=0.000,中值(最小值,最大值)=37.0(13.2,204.3),之后逐渐恢复。术后3个月、6个月及1年的累积生存率为95.5%、85.9%、78.1%。COX回归多因素分析显示血钠(P=0.027,HR=0.677,95%CI=0.479~0.956)、总胆红素(P=0.007,HR=1.049,95%CI=1.012~1.086)是影响预后的独立危险因素。运用ROC及AUC分析提示总胆红素AUC为0.676,95%CI为0.335~1.000,总胆红素37μmol/L(敏感性66.7%,特异性94.1%)为最佳预测界值。Kaplan-Merier生存率分析显示总胆红素≥37μmol/L及总胆红素37μmol/L时的1年生存率分别为25%、92.3%。结论:TIPS是治疗肝硬化顽固性腹水的有效方案,术后存在短期的肝功能损害;总胆红素≥37μmol/L是预测肝硬化顽固性腹水患者TIPS术后1年生存率的危险因素,可为术前判断患者预后提供临床依据。
, 周伟, 张强
