内质网应激与缺血后处理的心肌保护

内质网应激(endoplasmic reticulum stress,ERS)是细胞对各种伤害性刺激的适应性反应.在心肌缺血/再灌注(ischemia/reperfusion,I/R)过程中,过度的ERS引起心肌细胞凋亡导致心肌损伤.缺血后处理(ischemic postconditioning,I-postC)是心肌对抗I/R损伤的内源性保护现象,可通过多条信号转导途径发挥心肌保护作用,对ERS的调节是其重要方面.现将从ERS的角度探讨I-postC的心肌保护机制.     

内质网应激与缺血后处理的心肌保护

内质网应激(endoplasmic reticulum stress,ERS)是细胞对各种伤害性刺激的适应性反应.在心肌缺血/再灌注(ischemia/reperfusion,I/R)过程中,过度的ERS引起心肌细胞凋亡导致心肌损伤.缺血后处理(ischemic postconditioning,I-postC)是心肌对抗I/R损伤的内源性保护现象,可通过多条信号转导途径发挥心肌保护作用,对ERS的调节是其重要方面.现将从ERS的角度探讨I-postC的心肌保护机制.     

内质网应激与缺血后处理的心肌保护

内质网应激(endoplasmic reticulum stress,ERS)是细胞对各种伤害性刺激的适应性反应.在心肌缺血/再灌注(ischemia/reperfusion,I/R)过程中,过度的ERS引起心肌细胞凋亡导致心肌损伤.缺血后处理(ischemic postconditioning,I-postC)是心肌对抗I/R损伤的内源性保护现象,可通过多条信号转导途径发挥心肌保护作用,对ERS的调节是其重要方面.现将从ERS的角度探讨I-postC的心肌保护机制.     

自噬与沉默信息调节因子蛋白家族对心肌缺血/再灌注的影响

背景自噬是一种细胞本体的降解过程.它以溶酶体的方式参与或老化非正常的细胞蛋白及细胞本身的降解.许多研究证实自噬水平在心肌缺血/再灌注(ischemia/reperfusion,I/R)中增高,但对于自噬在再灌注中的作用,现在争议较大.同时有研究证实新发现的与长寿相关的沉默信息调节因子蛋白(silent information regulator protein,Sirt)家族可能参与了自噬对I/R的调节.目的了解Sirt家族、自噬及I/R这三者间的联系.内容对自噬的基本过程,自噬的分子机制,自噬在心肌I/R中的作用,自噬与Sirt家族的关系作一综述.趋向促进对自噬的深入了解,期望对Sirt家族在心肌保护方面的作用提供新的认识.     

大电导钙激活钾通道与心血管保护

背景 大电导钙激活钾通道(large conductance Ca2+-activated K+ channels,BKCa)可能是各类心脏疾病的重要治疗靶点. 目的 主要阐述如何通过调节心肌及血管平滑肌的BKCa通道而发挥保护心肌作用及其相关机制. 内容 在心肌细胞的线粒体上,BKCa通道能够有效地调节线粒体的活性氧、Ca2+和呼吸作用.在血管平滑肌细胞,BKCa通道能调节血管紧张度,促进血管扩张. 趋向 BKCa通道在心肌缺血/再灌注(ischemia/reperfusion,I/R)损伤中有着重要的作用,包括改善心肌功能和减少梗死面积.     

蛋白激酶C在未成熟心肌预处理中的作用

目的为进一步加强未成熟心肌保护和临床应用的可行性,探讨蛋白激酶C(PKC)在未成熟心肌预处理保护中的作用。方法建立兔Langendorff灌注模型,将24只幼兔随机分为4组:缺血再灌注组(I/R组)、心脏缺血预处理组(MIP组)、PKC阻滞组(CLT组)和PKC激活剂组(PKC组),观察4组幼兔血流动力学、生化、心肌超微结构等指标。结果 MIP组和PKC组心功能恢复、心肌含水量优于I/R组和CLT组(P0.01),三磷酸腺苷(ATP)含量、超氧化物歧化酶活性、心肌线粒体Ca2+-ATPase活性、心肌线粒体合成ATP的能力优于I/R组和CLT组(P0.01),丙二醛含量、血清肌酸激酶和乳酸脱氢酶漏出率、心肌细胞内Ca2+含量、心肌线粒体Ca2+含量低于I/R组和CLT组(P0.01),心肌超微结构损伤较I/R组和CLT组明显减轻。结论心肌缺血预处理对未成熟心肌具有明显的保护作用,其机制可能是通过PKC的激活起作用。     

尼克酰胺磷酸核糖转移酶对心肌缺血/再灌注的影响研究进展

背景 尼克酰胺磷酸核糖转移酶(nicotinamide phosphoribosyltransferase,NAMPT)是合成烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide,NAD)的限速酶.NAMPT可存在于细胞内和细胞外,它们的作用不尽相同.NAMPT在心血管系统中发挥着重要作用,但在心肌缺血/再灌注(ischemia/reperfusion,I/R)中的作用尚存争议. 目的 进一步了解NAMPT的心血管作用及对心肌I/R的影响. 内容 就目前研究对NAMPT的来源及潜在的心血管作用、细胞内NAMPT(intracellular NAMPT,iNAMPT)及细胞外NAMPT(extracellular NAMPT,eNAMPT)、以及对心肌I/R的影响作一综述. 趋向 促进对NAMPT的作用及机制的了解,NAMPT有望成为治疗心肌I/R损伤的新靶点.     

蛋白激酶C和线粒体ATP敏感性钾通道在未成熟心肌预处理中的作用

目的探讨蛋白激酶C(PKC)和线粒体三磷酸腺苷敏感性钾通道(mitoKATP)在未成熟心肌预处理保护中的作用。方法采用Langendorff离体心脏灌注模型,30只新生日本长耳大白兔分为5组:缺血/再灌注组(I/R组),心脏缺血预处理组(E1组),蛋白激酶C(PKC)阻滞剂chelerythrine(CLT) 心脏缺血预处理(E2组),mitoKATP阻滞剂5-hydroxydecanoate(5-HD) 心脏缺血预处理(E3组),mitoKATP通道开放剂Diazoxide(Diaz)预处理组(E4组)。以血流动力学、生化指标、心肌超微结构等作为观察指标。结果E1和E4组心功能恢复、心肌含水量优于I/R、E2和E4组(P<0.05),三磷酸腺苷含量、超氧化物歧化酶活性、心肌线粒体Ca2 -ATPase活性、心肌线粒体合成三磷酸腺苷(ATP)的能力优于I/R、E2和E4组(P<0.01),丙二醛含量、血清肌酸激酶和乳酸脱氢酶漏出率、心肌细胞内Ca2 含量、心肌线粒体Ca2 含量低于I/R、E2和E4组(P< 0.01),心肌超微结构损伤较I/R、E2和E4组明显减轻。结论心肌缺血预处理对未成熟心肌具有明显的保护作用,其机制可能是通过PKC的激活和mitoKATP通道的开放起作用。     

依那普利后处理对肢体缺血再灌注诱发大鼠心肌损伤的影响

目的 评价依那普利后处理对肢体缺血再灌注诱发大鼠心肌损伤的影响.方法 健康雄性SD大鼠36只,体重200 ～ 250 g,采用随机数字表法,将其分为3组(n=12)∶假手术组(S组)、缺血再灌注组(I/R组)和依那普利后处理组(EP组).I/R组和EP组采用橡皮带环绕结扎大鼠双后肢根部3h,再灌注3h的方法制备肢体缺血再灌注模型.再灌注前30 min时,EP组经颈内静脉注射依那普利0.04 mg/kg,S组和I/R组经颈内静脉注射等容量生理盐水.再灌注3h时,处死大鼠,取心肌组织,采用TUNEL法检测心肌细胞凋亡,计算细胞凋亡指数;采用免疫组化法测定Bcl-2和Bax的蛋白表达;采用黄嘌呤氧化酶法测定SOD活性;采用硫代巴比妥法测定MDA含量.结果 与S组比较,I/R组和EP组心肌细胞凋亡指数和MDA含量升高,Bax蛋白表达上调,Bcl-2蛋白表达下调,SOD活性降低(P＜0.05);与I/R组比较,EP组心肌细胞凋亡指数和MDA含量降低,Bax蛋白表达下调,Bcl-2蛋白表达上调,SOD活性升高(P＜0.05),心肌病理学损伤减轻.结论 依那普利后处理可减轻肢体缺血再灌注诱发大鼠心肌损伤,其机制可能与减少心肌细胞凋亡和减轻脂质过氧化反应有关.     

miRNA在缺血预处理保护心肌缺血/再灌注损伤中的研究进展

背景microRNAs(miRNAs)是一类由动物、 植物和病毒基因组编码的约由22个核苷酸组成的小分子单链RNA.近年来发现它在缺血预处理(ischemic preconditioning,IPC)中发挥着重要作用,有望成为研究治疗心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)的新靶点.目的 阐述不同miRNA在IPC保护心肌I/RI中的作用及其可能机制.内容IPC是经典的保护心肌I/RI的方法,IPC后心肌中miRNA表达谱发生改变,其中miR-1、miR-21、miR-133b-5p、miR-199a、miR-144/451可能通过不同的基因调节机制影响IPC保护心肌I/RI.趋向将miRNA与靶基因、 信号调节通路相结合将是未来研究miRNA调节IPC保护心肌I/RI的重要趋势.     

Is the recovery profile of mivacurium independent of the rate of decay of its plasma concentration in patients with normal plasma cholinesterase activity?

Background: The duration of action of muscle relaxants is poorly correlated to the rate of decay of their plasma concentration. The plasma concentration of mivacurium may rapidly decrease below its active concentration because of the extensive hydrolysis of mivacurium. By inflating a tourniquet on one upper limb for 3 min after the administration of atracurium, mivacurium or vecuronium, we studied the influence of the initial decline of their plasma concentration on their effect. Methods: In 50 patients anaesthetised with thiopental, isoflurane and fentanyl, the effect of bolus doses of 0.15 or 0.25 mg . kg^?1 mivacurium (MIV 15, MIV 25), 0.3 or 0.5 mg . kg^?1 atracurium (ATR 30, ATR 50) and 0.06 or 0.1 mg . kg^?1 vecuronium (VEC 06, VEC 10) were measured on both arms (evoked response of the adductor pollicis to train-of-four stimulation every 12 s), a tourniquet being applied on one arm just before and during 3 min after the muscle relaxant bolus. Results: Tourniquet inflation of 3 min almost abolished the neuromuscular effect of mivacurium. In the vecuronium groups and in the ATR 50 group, tourniquet inflation did not modify the maximum degree of depression of the twitch response. Also, the duration of action of vecuronium was unaffected by the tourniquet. In the ATR 30 group, times to return of the twitch response to 25% (duration 25%) and 75% (duration 75%) of control response were significantly shorter in the cuffed arm, 23 min vs 27 min, and 41 min vs 45 min, respectively. In the ATR 50 group, only duration 25% was significantly shorter in the cuffed arm (41 min vs 45 min). Conclusion: The results suggest that the rate of decline of the plasma concentration of mivacurium is so rapid, that a very low and almost clinically ineffective concentration is present as soon as 3 min after its administration. The results also indicate that the recovery from a mivacurium-induced neuromuscular blockade is not influenced by the rate of decay of its plasma concentration in patients with genotypically normal plasma cholinesterase.     

Membranes in Artificial Organs

Abstract: Membrane processes play a pivotal and enabling role in modern replacement therapy for acute and chronic organ failure and in the management of immunologic diseases. In fact, virtually all contemporary extracorporeal blood purification methods employ membrane devices, and the next generation of artificial organs and tissue engineering therapies are almost certain to be similarly grounded in membrane technology. In this short essay, we comment on the similarities and differences among synthetic membranes and their natural counterparts and also provide a critical overview of the demographics and technology of hemodialysis, hemofiltration, apheresis, oxygenation, and emerging membrane technologies and applications.     

Reduction of Plasma Fibrinogen, Immunoglobulin G, and Immunoglobulin M Concentrations by Immunoadsorption Therapy with Tryptophan and Phenylalanine Adsorbents

Abstract Immunoadsorption (1A) therapy with tryptophan (TR-350) or phenylalanine (PH-350) adsorbents has been used to reduce the concentration of serum antibodies in human lymphocyte antigen (HLA)-immunized patients. Other forms of plasma purification have been reported to reduce the level of fibrinogen, which affects the blood properties. In this study we investigated the effects of IA therapy using both adsorbents on plasma fibrinogen and immunoglobulins G and M in 13 patients (8 patients were treated with TR-350, and 5 patients were treated with PH-350). During each session 1 plasma volume (2.8 ± 0.4 L of plasma) was processed through the immunocolumn and then returned to the patient together with the blood cells. Compared with the pretreatment values, the plasma fibrinogen, IgG, and IgM concentrations were significantly reduced after IA therapy (p < 0.01 for TR-350; p < 0.04 for PH-350). There was a positive correlation between the degree of reduction of plasma proteins and the number of IA treatments given. A nonpara-metric test (Wilcoxon's signed-rank test or the Mann-Whitney test) was used for statistical analysis. We conclude from our study that IA therapy effectively lowers the plasma levels of fibrinogen, IgG, and IgM and thus can be considered a valuable alternative to other blood purification methods.     

Dilemma of Membrane Biocompatibility and Reuse

Abstract: Numerous articles have been published on the multiple use of dialyzers and on the effect of different reprocessing chemicals and techniques on the dialyzer biocompatibility and performance. The results often appear contradictory, especially those comparing standard biocompatibility parameters. Despite this confusion, a discerning review of the published works allows certain limited conclusions to be drawn. Reprocessing of used hemodialyzers changes the biocompatibility profile of a dialyzer as defined by the parameters complement activation. leukopenia, and cytokine release. The effect of reprocessing depends on the chemicals and reprocessing technique applied and also on the type of membrane polymer being subjected to the reprocessing procedure. Reports of pyrogenic reactions indicate that the flux of the membrane also influences how suitable it is for safe reuse. An increased risk of allergic and pyrogenic reactions appears to be associated with dialyzer reuse. Furthermore, there has been a lack of investigations into the immunologic effect of the layer of adsorbed and chemically altered proteins that remains on the inner surface of reprocessed dialyzers. We conclude that the clinical benefit of dialyzer reuse cannot be generally accepted from a biocompatibility point of view.     

The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans

Background : Ketamine in sub-dissociative doses has been shown to have analgesic and phantom-Limb pain, where conventional treatment has often failed. Chronic ischemic pain due to lower extremity arteriosclerosis obliterans often responds poorly to analgesics, and the pain-generating mechanisms are not well understood.
Methods : Eight patients with rest pain in the lower extremity due to arteriosclerosis obliterans were given sub-dissociative doses of 0.15, 0.30, or 0.45 mg/kg racemic ketamine and morphine 10 mg as a 5-min infusion on four separate days in a cross-over, double-blind, randomised protocol. Plasma levels of (S)- and (R)-ketamine and their nor-metabolites were analysed with an enantioselective high-performance liquid chromatography (HPLC) method. Pain levels were evaluated with a visual analogue scale (VAS).
Results : Individual pain levels were highly variable during and after all the infusions but the pooled pain levels showed a dose-dependent analgesic effect of ketamine with a transient but complete pain relief in all patients at the highest dose (0.45 mg/ kg). Side-effects, mainly disturbed cognition and perception, were pronounced and dose-dependent. Morphine 10 mg had an analgesic peak at 20 min and 5/8 patients had complete pain relief. The remaining 3 patients also had high baseline pain scores, indicating a higher analgesic potency for the 0.30 and 0.45 mg/ kg ketamine doses than for morphine 10 mg.
Conclusion : We have demonstrated a potent dose-dependent analgesic effect of racemic ketamine in clinical ischemic pain. Due to a narrow therapeutic window, this analgesic effect is probably best utilised in combination with other analgesics.     

Intravenous endotoxin does not increase tissue extravasation of albumin in rats

Background : It is unclear whether activation of the inducible nitric oxide synthase (iNOS) increases or decreases the extravasation of plasma.
Methods : Chloralose anaesthetised male Wistar rats received E. coli lipopolysacharide (LPS), 3 mg kg^-1 i.v., or the corresponding volume of saline, 3 or 5 h before the end of the experiment. Mean arterial pressure (MAP) and heart rate (HR) were recorded. Tissue clearance of radio-labelled albumin, during the last 2 h of each experiment, was determined by a double-isotope method. In separate animals, the serum concentration of nitrite and nitrate was determined, 5 h after LPS or the solvent.
Main Results : LPS initially decreased MAP and lastingly increased HR. In the 3-h LPS animals (n=8), tissue plasma clearance was lower in the heart and calf muscle and increased only in diaphragm, compared to corresponding control animals (n=8). In the 5-h LPS rats, clearance was lowered (n=8) in the entire gastrointestinal tract and in testes, compared to controls (n=8). The serum nitrite/nitrate concentration was higher in animals given LPS (n=6) than in controls (n=6).
Conclusion : After LPS, tissue clearance of albumin was not increased in any major tissue, in spite of increased serum levels of NO end products. Apparently, after activation of iNOS, the augmented release of NO is not necessarily associated with increased albumin extravasation.     

The multiply injured child

Blunt trauma is the principal cause of childhood death in many developed countries. This review outlines the differences between adults and children with respect to resuscitation and treatment of orthopaedic injuries in a child with polytrauma. Recent advances in techniques of fracture stabilization are reported.     

Adrenaline markedly improves thoracic epidural analgesia produced by a low-dose infusion of bupivacaine, fentanyl and adrenaline after major surgery: A randomised, double-blind, cross-over study with and without adrenaline

Background: Basic pharmacological research indicates that there are synergistic antinociceptive effects at the spinal cord level between adrenaline, fentanyl and bupivacaine. Our clinical experience with such a mixture in a thoracic epidural infusion after major surgery confirms this. The objectives of the present study were to evaluate the effects on postoperative pain intensity, pain relief and side effects when removing adrenaline from this triple epidural mixture. Methods: A prospective, randomised, double-blind, cross-over study was carried out in 24 patients after major thoracic or abdominal surgery. Patients with only mild pain when coughing during a titrated thoracic epidural infusion of about 10 ml · h^?1 of bupivacaine 1 mg · ml^?1, fentanyl 2 μg · ml^?1, and adrenaline 2 μg · ml^?1 were included. On the 1^st and 2^nd postoperative days each patient was given a double-blind epidural infusion, at the same rate, with or without adrenaline. The effect was observed for 4 h or until pain when coughing became unacceptable in spite of a rescue analgesic procedure. Rescue analgesia consisted of up to two epidural bolus injections per hour and i.v. morphine if necessary. All patients received rectal paracetamol 1 g, every 8 h. Fentanyl serum concentrations were measured with a radioimmunoassay technique at the start and end of each study period. Main outcome measures were extent of sensory blockade and pain intensity at rest and when coughing, evaluated by a visual analogue scale, a verbal categorical rating scale, the Prince Henry Hospital pain score, and an overall quality of pain relief score. Results: The number of hypaesthetic dermatomal segments decreased (P <0.001) and pain intensity at rest and when coughing increased (P <0.001) when adrenaline was omitted from the triple epidural mixture. This change started within the first hour after removing adrenaline. After 3 h pain intensity when coughing had increased to unacceptable levels in spite of rescue analgesia (epidural bolus injections and i.v. morphine). Within 15–20 min after restarting the triple epidural mixture with adrenaline, pain intensity was again reduced to mild pain when coughing. Serum concentration of fentanyl doubled from 0.22 to 0.45 ng · ml^?1 (P <0.01), and there was more sedation during the period without adrenaline. Conclusions: Adrenaline increases sensory block and improves the pain-relieving effect of a mixture of bupivacaine and fentanyl infused epidurally at a thoracic level after major thoracic or abdominal surgery. Serum fentanyl concentrations doubled and sedation increased when adrenaline was removed from the epidural infusion, indicating more rapid vascular absorption and systemic effects of fentanyl.     

Utilisation des médicaments prokinétiques en réanimation : indications et limites ?

Enteral feeding is often limited by gastric and intestinal motility disturbances in critically ill patients, particularly in patients with shock. So, promotility agents are frequently used to improve tolerance to enteral nutrition. This review summaries the pathophysiology, presents the available pharmacological strategies, the clinical data, the counter-indications and the principal limits. The clinical data are poor. No study demonstrates a positive effect on clinical outcomes. Metoclopramide and erythromycin seems to be the more effective. Considering the risk of antibiotic resistance, the first line use of erythromycin should be avoided in favor of metoclopramide.