丙泊酚或与腺苷联合预处理对犬心脏缺血-再灌注损伤的作用

目的 观察丙泊酚预处理及与腺苷联合预处理对犬心脏缺血-再灌注损伤的作用。方法 21只杂种犬随机分为丙泊酚预处理组（A组）、丙泊酚与腺苷联合预处理组（B组）和缺血-再灌注组（C组）,每组7只。C组经历稳定60min,左前降支结扎60min与松开结扎再灌注120min;A组在缺血前30min持续输注丙泊酚直至冠脉结扎前,再行上述缺血-再灌注;B组在丙泊酚输注期间、缺血前10min推注腺苷后续缺血-再灌注处理同C组。于缺血前、缺血15、30、60min及再灌注30、60、120min时抽取冠状静脉窦血样检测乳酸脱氢酶（LDH）和肌酸激酶（CK）的活性。实验结束后用Even’s蓝与TTC双染法测量危险及梗死的心肌面积。结果 从缺血30min起,各组血清CK显著升高直至实验结束;A、B组在缺血与再灌注期间CK显著低于C组（P〈0．05,0．01）。各组心脏间危险面积无显著性差异,而A、B组梗死面积显著低于C组（P〈0．01）。上述各指标A、B组间无显著性差异。结论 丙泊酚单纯预处理与联合腺苷预处理均可减轻麻醉犬心脏缺血-再灌注损伤,缩小梗死面积。腺苷对丙泊酚预处理的心脏保护作用无附加影响。     

吡那地尔预处理对体外循环犬心肌的保护效果

目的 探讨ATP敏感性钾通道开放剂(KCOs)吡那地尔(Pinacidil)药物预处理对常温及低温犬体外循环(CPB)晶体高钾停搏液间断灌注心肌的保护效果。方法 18条犬随机分为三组,每组6条,分别建立犬的常温及低温CPB全心缺血Pinacidil预处理模型。对照组(A组):低温CPB,主动脉根部灌注4℃St.Thomas停搏液(K~+16mmol/L)10ml/kg,阻断30min复灌一次(1/2首量);B组:常温CPB,主动脉根部灌注37℃含氧Pinacidil液(0.083mg/kg);C组:低温CPB,主动脉根部灌注液同B组。三组心脏均接受60min缺血和30min再灌注。阻断主动脉前,开放后15min、30min测血液动力学改变;并循环5min,阻断循环30min、60min及开放循环20min于左心室取心肌组织,测定心肌腺苷酸含量。结果 再灌注期间C组的血液动力学指标明显好于A、B组(P<0.01),而B组又较A组好(P<0.01)。缺血及再灌注期间C组心肌的ATP含量也明显高于A、B组(P<0.01),B组又高于A组(P<0.01)。结论 Pinacidil预处理时对CPB下缺血心肌具有良好的保护效果,低温的效果优于常温。     

异丙酚对心肌缺血再灌注兔胃粘膜pH值的影响

目的 观察兔心肌缺血再灌注后胃粘膜pH值(pHi)的变化,并探讨异丙酚对心肌缺血再灌注后兔内脏器官微循环灌注的影响。方法20只健康家兔,麻醉后随机分为生理盐水对照组(A组)及异丙酚组(B组,术中5mg·kg-1·h-1)。于基础状态(T0),心肌缺血60min(T1),再灌注后60min(T2)、90min(T3)和180min(T4)分别记录收缩压(SBP)、舒张压(DBP)、心率(HR)和pHi值。结果 两组动物5个不同时点的HR、SBP、DBP无显著差异(P>0.05)。两组动物缺血及再灌注后HR、SBP、DBP均有显著性下降(P<0.01)。pHi变化:与A组相比,B组动物T3点pHi值较低(P<0.05);组内,两组动物缺血及再灌注后pHi值均有显著性下降(P<0.01)。两组动物收缩压(SBP)及HR与pHi的变化均具有显著意义的相关性。结论 兔心肌缺血再灌注后,pHi持续显著降低,且pHi与血流动力学变化趋势一致,具有显著意义相关性。兔缺血再灌注期间,5mg·km-1·h-1异丙酚持续静注并不能改善胃肠道微循环灌注,甚至有可能加重胃肠道的低灌注及氧合障碍。     

缺血预处理对大鼠心肌细胞凋亡的影响及其机制

目的 观察心肌细胞凋亡及其机制在大鼠心肌缺血再灌注损伤和缺血预处理中的作用.方法 将40只大鼠随机分成4组:对照组(A组)、60min缺血再灌注组(B组)、120min缺血再灌注组(C组)、缺血预适应组(D组);应用TUNEL法检测心肌组织的凋亡;心脏病理改变用光学和电子显微镜观察;检测肿瘤坏死因子(TNF)-α、bcl-2和bax因子.结果 D组心肌细胞凋亡指数(11.36±4.23)%明显优于B组(18.14±7.69)%和C组(15.59±6.31)%,D组TNF-α、bel-2和bax的表达也明显优于B、C二组.结论 缺血预处理可减轻大鼠心肌缺血再灌注后心肌细胞的凋亡;TNF-α、bcl-2和bax表达的抑制与缺血预处理保护机制有关.     

异丙酚对大鼠缺血再灌注心肌Toll样受体4、NF-κB及血清IL-6的影响

目的 探讨异丙酚对大鼠缺血再灌注心肌Toll样受体4(TLR4)、核转录因子κB(NF-κB)和血清白细胞介素-6(IL-6)的影响.方法 健康雄性SD大鼠40只,体重200～250 g,随机分为4组,每组10只,假手术组(A组)左冠状动脉前降支只穿线;缺血再灌注组(B组)左冠状动脉前降支穿线结扎30 min后,再灌注120 min;A组和B组在缺血前10 min经股静脉注射生理盐水5 ml/kg后以5 ml·kg-1·h-1持续静脉输注至再灌注120 min;低剂量异丙酚组(C组)缺血前10 min经股静脉注射异丙酚5mg/kg后以5 mg·kg-1·h-1持续静脉输注至再灌注120 min,余处理同B组;高剂量异丙酚组(D组)缺血前10 min经股静脉注射异丙酚10 mg/kg后以10 mg·kg-1·h-1持续静脉输注至再灌注120 min,余处理同B组.再灌注120 min后,测定血清IL-6的浓度及心肌TLR4 mRNA、NF-κB蛋白的表达.结果 与A组比较,B组、C组及D组心肌TLR4 mRNA、NF-κB蛋白表达上调,血清IL-6水平升高;与B组比较,C组和D组心肌TLR4 mRNA、NF-κB蛋白表达下调,血清IL-6水平降低;与C组相比,D组心肌TLR4 mRNA、NF-κB蛋白表达下调,血清IL-6水平降低.结论 静脉注射异丙酚可抑制大鼠缺血再灌注心肌TLR4 mRNA、NF-κB的表达及血清IL-6浓度的升高,呈剂量依赖性.     

腺苷预处理对大鼠缺血-再灌注心肌NF-κB和TNF-α的影响

目的 通过研究腺苷预处理对大鼠缺血心肌核转录因子（NF）-κB活性和肿瘤坏死因子（TNF）-α水平的影响，探讨腺苷对心肌缺血-再灌注损伤保护的分子机制。方法 18只健康成年SD大鼠(300～350g)随机分为三组，每组6只。C组为对照组；Ⅰ组为缺血心肌组，缺血30min再灌注2h；P组为腺苷预处理组，腺苷预处理加缺血30min再灌注2h。大鼠开胸阻断左冠状动脉前室间支建立心肌缺血模型，取心尖部心肌组织提取胞核蛋白质，用Western blotting法测定胞核中NF-κB的活性并进行灰度扫描；用ELISA法测定TNF-α水平。结果 腺苷预处理后30min再行缺血-再灌注，NF-κB活性和TNF-α的含量与未处理组相比有明显下降；与对照组相比较，仅有少许升高，无显著差异。结论 腺苷可抑制缺血大鼠心肌的NF-κB活性和TNF-α水平，并由此推测腺苷对缺血大鼠心肌NF-κB活性的抑制可能是使TNF-α水平下调的分子机制。     

异丙酚对脑缺血再灌注损伤大鼠海马组织细胞间粘附分子-1及核转录因子-κB表达的影响

目的观察异丙酚对大鼠脑缺血再灌注损伤后海马组织细胞问粘附分子-1(ICAM-1)及核转录因子-κB(NF-κB)基因表达的影响,探讨异丙酚脑保护作用的机制。方法雄性Wistar大鼠40只,随机分为假手术组(A组)、缺血再灌注对照组(B组)和缺血再灌注异丙酚预处理组(C组),按异丙酚用量又分为50mg·kg-1、100mg·kg-1和150mg·kg-1三个亚组,缺血前10min腹腔注射。全脑缺血10min再灌注24h时,断头处死大鼠。用逆转录-聚合酶链反应技术检测海马组织ICAM-1与NF-κBmRNA的表达,用免疫组织化学方法检测海马组织ICAM-1及NF-κB蛋白的表达,用电镜检测海马组织超微结构的改变。结果脑缺血再灌注后海马组织ICAM-1与NF-κBmRNA的表达水平增高,异丙酚可下调ICAM-1与NF-κBmRNA的表达;缺血再灌注亦可明显诱导ICAM-1与NF-κB蛋白在海马的表达,异丙酚预处理可显著抑制ICAM-1与NF-κB蛋自在海马的表达;缺血再灌注后海马线粒体超微结构发生明显损害,异丙酚可减轻海马线粒体的损伤程度。结论异丙酚可能通过抑制:ICAM-1与NF-κB基因的表达而对脑缺血再灌注损伤起一定的保护作用。     

异丙酚、芬太尼对离体心肌缺血再灌注损伤的影响

目的 评价异丙酚、芬太尼对离体心肌缺血再灌注损伤的作用。方法 采用离体鼠Langendroff脏模型,SD大鼠 32只,取心脏用 K-H液恒温恒压主动脉逆灌、平衡 15min,随机分为 4组:（A）脂肪乳剂对照组;（B）5μg·ml-1异丙酚组;（C）10ng·ml-1芬太尼组;（D）5μg·ml-1异丙酚加10ng·ml-1芬太尼组。用含相应药液的 K-H液灌注 10min,常温全心停灌30min,然后用含相应药液的K-H液恢复灌注30min,记录各组用药前、停灌前1min、再灌30min时心脏机械功能变化、冠脉流量以及测定再灌注30min冠脉流出液里乳酸脱氢酶（LDH）活性。结果 再灌30min时B、C、D组心功能的恢复明显好于A组,D组明显好于B、C组。LDH活性B、C、D组明显低于A组,D组明显低于B、C组。结论5μg·ml-1异丙酚、10ng·ml-1芬太尼能抑制离体心肌缺血再灌注损伤,两者复合应用其作用更强。     

异氟醚预处理和异丙酚预处理对大鼠心肌缺血再灌注损伤的影响

目的 评价异氟醚预处理和异丙酚预处理对大鼠心肌缺血再灌注损伤的影响.方法 雄性Wistar大鼠36只,体重250～300 g,随机分为4组(n=9):缺血再灌注组(I/R组)、异氟醚预处理组(Ⅰ组)、异丙酚预处理组(P组)和异氟醚预处理联合异丙酚预处理组(I+P组).Ⅰ组异氟醚预处理方法:吸入1.6%异氟醚10 min,停止吸入5 min,共重复2次;P组异丙酚预处理方法:静脉输注异丙酚37.5 mg·kg~(-1)·h~(-1) 10 min,停止输注5 min,共重复2次;I+P组同时进行异氟醚预处理和异丙酚预处理.预处理后立即结扎左冠状动脉前降支60 min,随后松开进行再灌注,I/R组只进行缺血再灌注.再灌注120 min时每组取1只大鼠,取心肌组织,透射电镜下观察心肌细胞超微结构;各组其余大鼠处死后,取左心室,采用TUNEL法测定心肌细胞凋亡情况,计算凋亡指数,并测定心肌细胞线粒体活性氧(ROS)水平.结果 各组均可见凋亡小体,I组、P组和I+P组心肌损伤程度轻于I/R组.与I/R组比较,I组、P组和I+P组心肌细胞凋亡指数和ROS水平降低(P＜0.05),而I组、P组和I+P组间上述指标比较差异无统计学意义(P＞0.05).结论 异氟醚预处理或异丙酚预处理及两种方法联合应用时减轻大鼠心肌缺血再灌注损伤的效应相似.     

不同剂量丙泊酚预处理对大鼠离体心脏缺血-再灌注损伤的保护作用

目的观察丙泊酚预处理对大鼠离体心脏缺血-再灌注的量效关系。方法建立大鼠离体心脏Langendorff灌流模型,随机分为六组(n=8):缺血-再灌注组(A组)行平衡35min、停灌30min与再灌注120min;丙泊酚预处理组(B、C、D、E组)与脂肪乳预处理组(F组)在平衡15min后依次以12·5、25、50、100μmol/L丙泊酚及脂肪乳预处理10min,冲洗10min,停灌、复灌与A组相同。记录各组心率、机械功能及冠脉流量变化,并对再灌注期间的心律失常进行评分。结果(1)与平衡期比,再灌注后各组心率、机械功能及冠脉流量均显著下降(P<0·01)。与A组比,C、D、E组不同程度减轻上述变化,且D组最显著(P<0·05,P<0·01)。(2)D、E组心律失常评分优于A组。结论丙泊酚预处理改善离体大鼠心脏缺血-再灌注后心脏机械功能与冠脉受损及再灌性心律失常的发生,该作用与其溶剂脂肪乳无关。     

Vasopressor hormone response following mesenteric traction during major abdominal surgery

Background : We investigated the vasopressor hormone response following mesenteric traction (MT) with hypotension due to prostacyclin (PGI₂) release in patients undergoing abdominal surgery with a combined general and epidural anesthesia. Methods : In a prospective, randomized, placebo-controlled study we administered 400 mg ibuprofen (i.v.) in 42 patients scheduled for abdominal surgery. General anesthesia was combined with epidural anesthesia (T4-L1). Before as well as 5, 15, 30, 45, and 90 min after MT we recorded plasma osmolality, hemodynamics and measured 6-keto-PGFlα (stabile metabolite of PGI₂), TXB₂ (stabile metabolite of thromboxane A₂) active renin, and arginine vasopressin (AVP) plasma concentrations by radioimmunoassay. Catecholamine levels were assessed by high-pressure liquid chromatography (HPLC) with electrochemical detection. Results : Following MT, arterial hypotension occurred along with a substantial PGI₂ release. This was completely abolished by ibuprofen administration. Although plasma levels of 6-keto-PGF_1α (1133 (708) vs. 60 (3) ng/L, median (median absolute deviation), P=0.0001, placebo vs. ibuprofen) remained significantly elevated, blood pressure was restored within 30 min after MT in the placebo group. At the same point in time plasma concentrations of TXB² (164 (87) vs. 58 (1) ng/L, P=0.0001), epinephrine (46 (33) vs. 14 (6) ng/L, P=0.001), AVP (41 ± (18) vs. 12 (7) ng/L, P=0.0004), and active renin (27 (12) vs. 12 (4) ng/L, P = 0.001) were significantly higher in placebo-treated patients. Conclusion : Under combined general and epidural anesthesia arterial hypotension following MT due to endogenous PGI₂ release is associated with enhanced release of AVP, active renin, epinephrine and thromboxane A₂, presumably contributing to hemodynamic stability within 30 min after MT.     

A comparison of the inhibitory effects of four volatile anaesthetics on the metabolism of chlorzoxazone, a substrate for CYP2E1, in rabbits

Background: Halothane inhibits in vitro and in vivo activity of cytochrome P-450 (CYP) 2E1. There are several fluorinated volatile anaesthetics besides halothane, and most of them are defluorinated by CYP2E1. It is unclear whether other fluorinated anaesthetics inhibit the in vivo activity of CYP2E1.
Methods: We compared the inhibitory effects of therapeutic concentrations of four inhalational anaesthetics, halothane, enflurane, isoflurane, and sevoflurane, on chlorzoxazone metabolism in rabbits receiving artificial ventilation.
Results: All four inhalational anaesthetics decreased arterial blood pressure and increased plasma chlorzoxazone concentration. However, no significant differences in the plasma chlorzoxazone concentration were found between the four anaesthetics. The estimated chlorzoxazone clearance increased after beginning inhalation with all four agents, but no significant difference in clearance was noted between agents.
Conclusions: At therapeutic concentrations, the in vivo inhibitory effect on chlorzoxazone metabolism was similar for all four inhalational anaesthetics examined, even though their chemical characteristics and extent of hepatic metabolism differ considerably.     

Microspheres Based Detoxification System: A New Method in Convective Blood Purification

Abstract: A variety of protein-bound or hydrophobic substances, accumulating as a result of pathologic conditions such as exogenous or endogenous intoxications, are removed poorly by conventional detoxification methods because of low accessibility (hemodialysis), insufficient adsorption capabilities (hemosorption), low efficiency (peritoneal dialysis), or economic limitations (high-volume plasmapheresis). Combining advantages of existing methods with microspheric technology, a module-based system was designed. Major operating parameters of the latter can be modified to allow for adjustment to individual clinical situations. An extracorporeal blood circuit including a plasmafilter is combined with a secondary high-velocity plasma circuit driven by a centrifugal pump. Different microspheric adsorbers can be combined in one circuit or applied in sequence. Thus, a prolonged treatment can be tailored using specially designed selective adsorber materials. Comparing this system with existing methods (high-flux hemodialysis, molecular adsorbent recycling system), results from our in vitro studies and animal experiments demonstrate the superior efficiency of substance removal.     

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.     

Bariatric Surgery in Some "Central and East-European (former Eastern bloc)"Countries - Current Status and Prediction for the Next Millennium

Background: Obesity is increasing globallly, including in the formerly "Eastern Bloc" countries. Methods: A survey was made of obesity and bariatric surgery. Results: In the 8 East and Central European countries studied, with total population 300 million, roughly 43% of the population was overweight (BMI 25-30), 23% obese (BMI > 30), with about 15 million people morbidly obese (BMI > 40). From 0-10 morbidly obese individuals/100,000/year undergo bariatric surgery. Conclusion: Most countries were found to provide inadequate treatment for obesity.The majority of the morbidly obese are not treated effectively. However, health-care awareness of obesity and bariatric surgeons are slowly increasing.     

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.     

Influence of dopexamine hydrochloride on haemodynamics and regulators of circulation in patients undergoing major abdominal surgery

Background: Catecholaminergic support is often used to improve haemodynamics in patients undergoing major abdominal surgery. Dopexamine is a synthetic vasoactive catecholamine with beneficial microcirculatory properties. Methods: The influence of perioperative administration of dopexamine on cardiorespiratory data and important regulators of macro- and microcirculation were studied in 30 patients undergoing Whipple pancreaticduodenectomy. The patients received randomized and blinded either 2 μg · kg^?1 · min^?1 of dopexamine (n=15) or placebo (n=15, control group). The infusion was started after induction of anaesthesia and continued until the morning of the first postoperative day. Endothelin-1 (ET-1), vasopressin, atrial natriuretic peptide (ANP), and catecholamine plasma levels were measured from arterial blood samples. Measurements were carried out after induction of anaesthesia, 2 h after onset of surgery, at the end of surgery, 2 h after surgery, and on the morning of the first postoperative day. Results: Cardiac index (CI) increased significantly in the dopexamine group (from 2.61±0.41 to 4.57±0.78 1 · min^?1 · m^?2) and remained elevated until the morning of the first postoperative day. Oxygen delivery index (DO₂I) and oxygen consumption index (VO₂I) were also significantly increased in the dopexamine group (DO₂I: from 416±91 to 717±110 ml/m² · m²; VO₂I: from 98±25 to 157±22 ml/m² · m²), being significantly higher than in the control group. pHi remained stable only in the dopexamine patients, indicating adequate splanchnic perfusion. Vasopressive regulators of circulation increased significantly only in the untreated control patients (vasopressin: from 4.37±1.1 to 35.9±12.1 pg/ml; ET-1: from 2.88±0.91 to 6.91±1.20 pg/ml). Conclusion: Patients undergoing major abdominal surgery may profit from prophylactic perioperative administration of dopexamine hydrochloride in the form of improved haemodynamics and oxygenation as well as beneficial influence on important regulators of organ blood flow.     

Synergistic interaction between the effects of propofol and midazolam with fentanyl on phrenic nerve activity in rabbits

Background: It has been shown that the depressive effects of both propofol and midazolam on consciousness are synergistic with opioids, but the nature of their interactions on other physiological systems, e. g. respiration, has not been fully investigated. The present study examined the effect of propofol and midazolam alone and in combination with fentanyl on phrenic nerve activity (PNA) and whether such interactions are additive or synergistic. Methods: PNA was recorded in 27 anaesthetised and artificially ventilated rabbits. In three groups, propofol, fentanyl and midazolam were administered intravenously in incremental doses to construct dose-response curves for the depressant effects of each one on PNA. In another two groups, the effect of pretreatment with either fentanyl 1 μg · kg^?1 i. v. or midazolam 0.05 mg · kg^?1 i. v. on the effects of propofol and fentanyl respectively on PNA were studied. Results: Propofol and fentanyl caused a dose-dependent depression of PNA with complete abolition at the highest total doses of 16 mg · kg^?1 i. v. and 32 μg · kg^?1 i. v., respectively. In contrast, midazolam in incremental doses to a total of 0.8 mg · kg^?1 reduced mean PNA by 63%, but approximately 12% of PNA remained at a total dose as high as 6.4 mg · kg^?1. The mean ED₅₀s, calculated from dose-response curves, were 5.4 mg · kg^?1, 3.9 μg · kg^?1 and 0.4 mg · kg^?1 for propofol, fentanyl and midazolam, respectively. Initial doses of either fentanyl 1 μg · kg^?1 i. v. or midazolam 0.05 mg · kg^?1 i. v. acted synergistically with subsequent doses of either propofol or fentanyl to abolish PNA at total doses of 8 mg · kg^?1 and 8 μg · kg^?1, respectively. Conclusion: Fentanyl has a synergistic interaction with both propofol and midazolam on PNA and hence potentially on respiration.     

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.