健康志愿者6%羟乙基淀粉130/0.4的容量动力学

目的 探讨健康志愿者6%羟乙基淀粉130/0.4的容量动力学.方法健康志愿者7名,性别不限,年龄18～32岁,体重46～84 kg.经60 min静脉输注6%羟乙基淀粉130/0.4 30ml/kg.采用Matlab 6.0版软件包进行容量动力学分析,采用F检验选择房室模型.结果 一室模型参数:基础清除率(3.5±1.3)ml/min,清除率(19±11)ml/min,一室模型分布容积(5746±1371)ml;二室模型参数:清除率(63±29)ml/min,交换系数(11±4)ml/min,中央室目标容积(1551±995)ml,外周室目标容积(908±398)ml,二室模型分布容积(2460±1332)ml.6%羟乙基淀粉130/0.4扩张、转运、分布及消除等体内过程符合容量动力学一室模型(F值为3.81,P＞0.05).4 h清除率为(75±10)%.容量动力学一室模型分布容积与健康志愿者血容量比较差异无统计学意义(P＞0.05).结论 健康志愿者6%羟乙基淀粉130/0.4急性扩容符合容量动力学一室模型,提示羟乙基淀粉快速输注主要分布在血液,有效扩容时间4 h.

Abstract：

Objective To investigate the volume kinetics of 6% hydroxyethyl starch 130/0.4 in healthy volunteers.Methods Seven healthy volunteers aged 18-32 yr weighing 46-84 kg were selected in this study. 6% hydroxyethyl starch 130/0.4 30 ml/kg was infused over 60 min. Volume kinetics analysis of 6% hydroxyethyl starch 130/0.4 was performed with Matlab 6.0 software, compartment model was determined by F test.Results One-compartment model parameters: basic clearance, clearance and distribution volume of one-compartment model were (3.5 ± 1.3) ml/min,(19± 11) ml/min and (5746 ± 1371) ml respectively. Two-compartment model parameters: clearance, K1, the volume of central compartment, the volume of peripheral compartment, distribution volume of two-compartment model were (63 ±29) ml/min,(11 ±4) ml/min, (1551 ± 995) ml, (908 ±398) ml,(2460 ± 1332) ml respectively. There was no difference between the distribution volume of one-compartment model and blood volume of healthy volunteers ( P ＞ 0.05) .The distribution of infused 6% hydroxyethyl starch 130/0.4 was accordant with one-compartment model (F value was 3.81, P ＞ 0.05)and 4 h clearance was (75 ± 10)% .Conclusion The distribution of infused 6% hydroxyethyl starch 130/0.4 for volume expansion is accordant with one-compartment model, and the effective duration of plasma volume expansion is 4 h.     

The effect of hydroxyethyl starch 6% 130/0.4 compared with gelatin on microvascular reactivity

We compared the effects on microvascular reactivity of hydroxyethylstarch (Volulyte^®) and gelatin (Geloplasma^®) during acute haemodilution. The hypothesis was that Volulyte would provide better microvascular reactivity than Geloplasma. Forty patients undergoing elective cardiac surgery were randomly assigned to receive either Volulyte or Geloplasma as the exclusive priming solution of the cardiopulmonary bypass. To evaluate microvascular reactivity, postocclusive reactive hyperaemia was examined before and after cardiopulmonary bypass. Microvascular reactivity assessments included the rate of the occlusion and reperfusion slopes and reperfusion times. After cardiopulmonary bypass, increases in reperfusion time were significantly smaller in the Volulyte group (3 (?27 to 9 [?35 to 33]%) vs 29 (?17 to 76 [?34 to 137]%) in the Geloplasma group, p = 0.02 between groups). Rate of reperfusion increased in the Volulyte group (26 (?17 to 43 [?59 to 357])%), whereas it decreased in the Geloplasma group (?22 (?47 to 16 [?84 to 113])%), p = 0.02 between groups. The shorter reperfusion times and increased reperfusion rate suggest that Volulyte maintains better microvascular reactivity than Geloplasma.     

肾移植术中输注6%羟乙基淀粉130/0.4或琥珀酰明胶患者术后肾功能的比较

目的 比较肾移植术中输注6%羟乙基淀粉130/0.4或琥珀酰明胶患者术后肾功能.方法 同种异体单侧肾移植术患者70例,ASA Ⅲ或Ⅳ级,年龄23～64岁,体重43～65 kg,随机分为羟乙基淀粉组(H组)和琥珀酰明胶组(C组),每组35例.两组麻醉后分别静脉输注6%羟乙基淀粉130/0.4或4%琥珀酰明胶15 ml/kg.术中常规监测有创动脉血压、心率、中心静脉压、心电图及脉搏血氧饱和度.于术前(T0)、肾动静脉开放后5 min(T1)、术毕(T2)及术后1、3、7、14 d(T3～6)抽取肘静脉血,检测血清β2-微球蛋白(β2-MG)水平;T0、T3～6取新鲜晨尿,检测尿β2-MG、α1-微球蛋白(α1-MG)、微量白蛋白(mALB)浓度,同时抽取肘静脉血测定血清尿素氮(BUN)和肌酐(Cr)浓度,记录尿量.结果 与C组比较,H组T5,6时血清α2-MG浓度降低,T4,5时血清BUN浓度降低,T3～6时血清Cr浓度降低,T4～6尿β2-MG和mALB浓度降低,T6时尿α1-MG浓度降低(P＜0.01).结论 肾移植术中输注6%羟乙基淀粉130/0.4较4%琥珀酰明胶更利于患者术后移植肾功能的恢复.     

Neurotoxicity of intrathecal 6% hydroxyethyl starch 130/0.4 injection in a rat model

Epidural blood patch is the gold standard treatment for post‐dural puncture headache, although hydroxyethyl starch may be a useful alternative to blood if the latter is contraindicated. The aim of this experimental study was to assess whether hydroxyethyl starch given via an indwelling intrathecal catheter resulted in clinical or histopathological changes suggestive of neurotoxicity. The study was conducted in rats that were randomly allocated to receive three 10‐μl injections on consecutive days of either saline or hydroxyethyl starch administered via the intrathecal catheter. Eight rats were given injections of saline 0.9% and 11 were given 6% hydroxyethyl starch 130/0.4 derived from thin boiling waxy corn starch in 0.9% sodium chloride (Voluven^®). Daily clinical evaluation, activity measured by actimetry and neuropathological analysis of the spinal cord were subsequently performed to assess for signs of neurotoxicity. No clinical or actimetric changes were observed in either group following intrathecal saline or hydroxyethyl starch administration. Histopathological examination showed non‐specific changes with no differences between the two groups. This experimental study in the rat suggests that repeated intrathecal injection of hydroxyethyl starch is not associated with neurotoxicity.     

The influence of two different hydroxyethyl starch solutions (6% HES 130/0.4 and 200/0.5) on blood viscosity

We performed the current study to investigate the influence of 2 different hydroxyethyl starch (HES) solutions, the novel medium molecular weight HES 130/0.4 (6%) and HES 200/0.5 (6%), on plasma and whole blood viscosity in vitro and ex vivo in patients with severe head injury. For the in vitro experiments, blood was incubated with increasing concentrations (0%-50% vol/vol plasma) of either 6% HES 130/0.4 or 6% HES 200/0.5 solution. Plasma viscosity and whole blood viscosity (hematocrit [Hct] 45%) at high (94.5 s(-1)) and low (0.1 s(-1)) shear rates were determined. Both HES solutions increased plasma viscosity, but HES 130/0.4 to a lesser extent than HES 200/0.5. Whole blood viscosity was significantly less with HES 130/0.4 than with HES 200/0.5 at concentrations of 37.5% and larger. In the ex vivo study on 31 patients with severe cranio-cerebral trauma treated randomly with either HES 130/0.4 or HES 200/0.5 over several days, frozen plasma samples were thawed and plasma viscosity was determined. Blood was reconstituted with normal erythrocytes (0, Rh neg, Hct 45%) for whole blood viscosity measurements. In both groups plasma and blood viscosity tended to increase over time without statistical significance. Although the prominent effects found in vitro are not in keeping with the ex vivo data, they are likely to reflect the true clinical situation during repetitive, large-dose HES administration. We therefore conclude that HES 130/0.4 may have hemorheological advantages over conventional HES 200/0.5 when used in large quantities.     

不同剂量6%羟乙基淀粉130/0.4预先给药对大鼠内毒素性急性肺损伤的影响

目的 研究不同剂量6%羟乙基淀粉130/0.4(6% HES 130/0.4)预先给药对大鼠内毒素性急性肺损伤的影响.方法 72只健康清洁级雄性SD大鼠随机分为6组(n=12),对照组(C组)经尾静脉注射生理盐水30 ml/kg;肺损伤组(L组)经尾静脉注射脂多糖(LPS)5 mg/kg;不同剂量6%HES130/0.4组分别经尾静脉注射6%HES 130/0.4 7.5 ml/kg(H1组)、15 ml/kg(H2组)和30 ml/kg(H3组),1 h后再经尾静脉注射LPS 5 mg/kg;H4组经尾静脉注射6%HES 130/0.4 30 ml/kg.各组给药速率均为0.2ml/min.注射LPS后4 h行动脉血气分析,气管插管.每组取6只大鼠,测定肺组织微血管通透性指数(PMPI);每组取6只大鼠,测定支气管肺泡灌洗液(BALF)蛋白浓度、肺组织湿/干重比(W/D)、髓过氧化物酶(MPO)活性,血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-10(IL-10)、丙二醛(MDA)浓度和超氧化物歧化酶(SOD)活性,观察肺组织病理学.结果 与L组比较,H2组血清TNF-α、IL-1β、MDA浓度和肺组织MPO活性降低,血清IL-10浓度和SOD活性升高,H1组IL-1β浓度降低,H1组、H2组和H3组PMPI、BALF蛋白浓度和W/D均降低(P＜0.05);与H2组比较,H1组和H3组血清TNF-α、MDA浓度和肺组织MPO活性升高,血清SOD活性、IL-10浓度降低,H3组血清IL-1β浓度升高(P＜0.05).H1组、H2组和H3组较L组肺组织损伤较轻,其中H2组损伤最轻.结论 15 ml/kg6%HES 130/0.4预先给药可减轻大鼠内毒素性急性肺损伤,其机制可能与抑制炎性因子释放、减少肺内中性粒细胞聚集和氧自由基生成、改善肺微血管通透性有关.     

6%羟乙基淀粉200/0.5氯化钠注射液对外科手术围术期凝血功能和肾功能的影响

目的 探讨围手术期应用6%羟乙基淀粉(Hetastarch,HES)200/0.5氯化钠注射液对外科手术中全麻患者凝血功能及肾功能的影响.方法 限期全麻胃肠道恶性肿瘤手术患者40例,随机分为两组,每组20例:6%HES 130/0.4(A组,万汶)和6%HES200/0.5(B组,代斯).根据晶胶结合(2∶1)的原则补液,全麻术中输实验药物1000ml,术后第1、2天输实验药物量为1000ml/d.术前和术后第3天检测以下指标:血红蛋白(Hb)、血细胞比容(Hct)、血尿素氮(BUN)、血清肌酐(SCr)、凝血酶原时间(PT)、凝血酶时间(TT)、部分凝血活酶时间(APTT)、von Willebrand(vWF)因子活性、Ⅷ因子活性、全血黏度高切变率、全血黏度低切变率、血浆黏度.结果 术后两组患者Hb、Hct均下降,但组间差异无统计学意义(P>0.05).术后两组患者SCr均明显下降,组间、组内差异均有统计学意义(P<0.05),但均在正常范围.两组患者PT、TT、APTT、全血黏度高切变率、血浆黏度、vWF因子活性、Ⅷ因子活性、BUN术前术后改变组间、组内差异无统计学意义(P>0.05).结论 6%羟乙基淀粉200/0.5氯化钠注射液进行容量替代治疗时对外科手术全麻患者凝血功能及肾功能的影响较小.     

The pharmacokinetics and tolerability of an intravenous infusion of the new hydroxyethyl starch 130/0.4 (6%, 500 mL) in mild-to-severe renal impairment

Hydroxyethyl starches (HES) are almost exclusively excreted glomerularly, in part after hydrolysis by amylase. HES 130/0.4 (Voluven; Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany) was developed to improve pharmacokinetics whereas preserving the efficacy of volume effect. We studied the dependency of pharmacokinetics of HES 130/0.4 on renal function. Nineteen volunteers with stable, non-anuric renal dysfunction, ranging from almost normal creatinine clearance (CL(cr)) to severe renal impairment (mean CL(cr): 50.6 mL. min(-1). 1.73 m(-2)), were given a single infusion of 500 mL 6% HES 130/0.4 over 30 min. HES plasma concentrations were determined until 72 h, urinary excretion until 72-96 h. CL(cr) had been obtained at least twice before and twice after dosing. Standard pharmacokinetic calculations and regression analysis were performed. Area under the time concentration curve (AUC(0-inf)) clearly depended on renal function comparing subjects with CL(cr) < 50 with those with CL(cr) > or =50 (ratio 1.73). Peak concentration (C(max), 4.34 mg/mL) as well as terminal half-life (16.1 h, model independent) were not affected by renal impairment. At CL(cr) > or =30, 59% of the drug could be retrieved in urine, versus 51% at CL(cr) 15-<30. The mean molecular weight of HES in plasma was 62,704 d at 30 min, showing lower values with increased renal impairment (P = 0.04). Pre-dose amylase concentrations inversely correlated with baseline CL(cr). Residual HES plasma concentrations after 24 h were small in all subjects (< or =0.6 mg/mL). We conclude that HES 130/0.4 (500 mL 6%) can be safely administered to patients even with severe renal impairment, as long as urine flow is preserved, without plasma accumulation. IMPLICATIONS: Dependency of the pharmacokinetics of hydroxyethyl starch 130/0.4 on renal function was studied. The area under the time concentration curve increased moderately with more severe renal dysfunction; however, small plasma concentrations were observed after 24 h. Terminal half-life and peak concentration remained unaffected by renal impairment.     

The influence of intravascular volume therapy with a new hydroxyethyl starch preparation (6% HES 130/0.4) on coagulation in patients undergoing major abdominal surgery

A new hydroxyethyl starch (HES) preparation with a mean molecular weight of 130,000 daltons and a degree of substitution of 0.4 shows favorable pharmacokinetic properties. We conducted a study of the influence of the new HES specification on coagulation and compared it with another colloidal intravascular volume replacement regimen using gelatin. According to a prospective, random sequence, 42 patients undergoing major abdominal surgery received either HES 130/0.4 (n = 21) or gelatin (n = 21) until the first postoperative day (POD) to keep central venous pressure between 10 and 14 mm Hg. From arterial blood samples, standard coagulation variables were measured, and modified thrombelastogram (TEG) measurements using different activators were performed. A total of 2830 +/- 350 mL of gelatin and 2430 +/- 310 mL of HES 130/0.4 were administered until the morning of the first POD. The use of allogeneic blood/blood products and standard coagulation variables did not differ significantly between the two groups. After induction of anesthesia, all TEG data for both groups were within normal range. Coagulation time and maximum clot firmness did not change significantly in any TEG measurements during the study period. The kinetics of clot formation (clot formation time) significantly increased immediately after surgery, but without showing significant group differences. On the morning of the first POD, the clot formation time returned to almost normal levels, except for aprotinin-activated TEG(R). We conclude that administration of moderate doses of the new HES 130/0.4 preparation in patients undergoing major abdominal surgery results in similar coagulation alterations as those after using an established gelatin-based volume-replacement regimen. IMPLICATIONS: We compared the effects of infusion of a new hydroxyethyl starch preparation (6% hydroxyethyl starch; mean molecular weight 130,000 daltons; degree of substitution 0.4) on coagulation with a gelatin-based intravascular volume replacement regimen in patients undergoing major abdominal surgery. After moderate doses of hydroxyethyl starch (2430 +/- 310 mL until the morning of the first postoperative day), coagulation monitoring, including modified thrombelastography, did not show impaired hemostasis.     

6％羟乙基淀粉130／0．4在小儿腹部手术中容量治疗的临床应用

目的 探讨6％羟乙基淀粉130／0．4在小儿腹部手术中容量治疗的应用效果。方法60例拟行腹部手术的患儿随机分为观察组和对照组,每组各30例。观察组术中容量治疗使用6％羟乙基淀粉130／0．4及晶体液;对照组未使用6％HES130／0．4,所使用的晶体液与观察组相同,可选用胶体液为浓缩红细胞。观察两组患儿手术前后心率、血压．总输液量及晶体液、胶体液、浓缩红细胞输入量等。记录观察组因输注6％羟乙基淀粉可能出现的不良反应,如：过敏（包括低血压、皮疹等）。结果两组输液总量无显著性差异。观察组与对照组相比：胶体液用量、晶体液用量、浓缩红细胞用量均有显著性差异,（P〈0．05）。观察组未发现因输注6％羟乙基淀粉130／0．4而出现的不良反应。结论6％羟乙基淀粉130／0．4可安全、有效的用于小儿腹部大手术中的容量治疗。     

Effect of 6% hydroxyethyl starch 130/0.4 on kidney and haemostatic function in cardiac surgical patients: a randomised controlled trial

Whether third-generation hydroxyethyl starch solutions provoke kidney injury or haemostatic abnormalities in patients having cardiac surgery remains unclear. We tested the hypotheses that intra-operative administration of a third-generation starch does not worsen postoperative kidney function or haemostasis in cardiac surgical patients compared with human albumin 5%. This triple-blind, non-inferiority, clinical trial randomly allocated patients aged 40–85 who underwent elective aortic valve replacement, with or without coronary artery bypass grafting, to plasma volume replacement with 6% starch 130/0.4 vs. 5% human albumin. Our primary outcome was postoperative urinary neutrophil gelatinase-associated lipocalin concentrations, a sensitive and early marker of postoperative kidney injury. Secondarily, we evaluated urinary interleukin-18; acute kidney injury using creatinine RIFLE criteria, coagulation measures, platelet count and function. Non-inferiority (delta 15%) was assessed with correction for multiple comparisons. We enrolled 141 patients (69 starch, 72 albumin) as planned. Results of the primary analysis demonstrated that postoperative urine neutrophil gelatinase-associated lipocalin (median (IQR [range])) was slightly lower with hydroxyethyl starch (5 (1–68 [0–996]) ng.ml⁻¹) vs. albumin (5 (2–74 [0–1604]) ng.ml⁻¹), although not non-inferior [ratio of geometric means (95%CI) 0.91 (0.57, 1.44); p = 0.15] due to higher than expected variability. Urine interleukin-18 concentrations were reduced, but interleukin-18 and kidney injury were again not non-inferior. Of 11 individual coagulation measures, platelet count and function, nine were non-inferior to albumin. Two remaining measures, thromboelastographic R value and arachidonic acid-induced platelet aggregation, were clinically similar but with wide confidence intervals. Starch administration during cardiac surgery produced similar observed effects on postoperative kidney function, coagulation, platelet count and platelet function compared with albumin, though greater than expected variability and wide confidence intervals precluded the conclusion of non-inferiority. Long-term mortality and kidney function appeared similar between starch and albumin.     

6%羟乙基淀粉130/0.4对患者硬膜外复合全麻诱导期肺循环的影响

Objective To observe the effect of pulmonary circulation by 6% hydroxyethyl starch 130/0.4 during induction period from epidural block combined with general anesthesia. Methods Twenty-six hepatobiliary surgical patients with ASA Ⅰ-Ⅱ, aged 32 y-59 y, weighing 54 kg-73 kg, were randomized into 2 groups(n=13): hydroxyethyl starch 130/0.4 group(HS)and complex acetic acid Ringer's solution (RL). Above-mentioned solutions were infused 7 ml/kg respectively before induction. The pulmonary circulation hemodynamic parameters such as pulmonary arterial systolic pressure (PASP), pulmonary arterial diastolic pressure (PADP), mean pulmonary artery pressure(MPAP), pulmonary artery wedge pressure(PAWP), pulmonary vascular resistance(PVR) and right ventricular stroke work(RVSW) were recorded at base value(T0), 10 min after infusion(T1), 5 min after induction(T2), 5 rain after intubation(T3), 10 rain after intubation(T4)and 20 min after intubation(T5). Results PASP、PADP、MPAP、PAWP and CVP were significantly higher in group HS at T, than the values at T0 (P<0.05); PVR in group HS was obviously lower from T1 to T5 than the value at To (P<0.05 or P<0.01); RVSW was significantly higher in two groups at T1 than base value (P<0.05), but that in group HS was lower than base value (P<0.05 or P<0.01); HR obviously decreased in two groups from T2 to T5 as compared with the value at T0 (P<0.05); MAP was lower from T3 to T5 than the value at To (P<0.05 or P<0.01). PVR was obviously lower in group HS from T1 to T5 than that in group RL (P<0.05 or P<0.01); MAP obviously increased from T2 to T5 in group HS as compared with the value in group RL(P<0.05 or P<0.01). Conclusion 6% hydroxyethyl starch 130/0.4 can obviously reduce PVR during induction pe-riod from epidural block combined with general anesthesia. In all, there is no effect on pulmonary circulation by 6% hydroxyethyl starch 130/0.4.     

6%羟乙基淀粉130/0.4对患者硬膜外复合全麻诱导期肺循环的影响

目的 探讨6%羟乙基淀粉130/0.4对患者硬膜外复合全麻诱导期肺循环血流动力学的影响.方法 26例肝胆外科手术患者,ASA Ⅰ～Ⅱ级,年龄32岁～59岁,体重54 kg～73 kg,随机分为羟乙基淀粉(HS)组和复方醋酸林格液(RL)组,每组13例,硬膜外复合全麻诱导前分别输入上述液体7 ml/kg,于基础值(T0)、输液后10 min(T1)、诱导后5 min(T2)、插管后5 min(T3)、插管后10min(T4)和插管后20min(T5)记录患者肺动脉收缩压(PASP)、肺动脉舒张压(PADP)、肺动脉平均压(MPAP)、肺动脉楔压(PAWP)、肺血管阻力(PVR)、右室心搏作功(RVSW)、中心静脉压(CVP)、心率(HR)、平均动脉压(MAP)等血流动力学参数.结果 两组患者中性别比、年龄、身高、体质量和体表而积均无统计学差异(P>0.05).与T0相比,HS组T1时,PASP、PADP、MPAP、PAWP和CVP增加(P<0.05),PVR值T1到T5时下降(P<0.05或0.01);HS组患者RVSW值T5时下降(P<0.05);两组患者RVSW值T1时均增加(P<0.05或0.01);两组患者HR从T2到T5时下降(P<0.05或0.01),T3到T5时MAP降低(P<0.05或0.01);与RL组相比,HS组PVR值T1到T5时降低(P<0.05或0.01),T2到T5时MAP明显高于RL组(P<0.05或0.01).结论 7 ml/kg 6%羟乙基淀粉130/0.4能明显降低硬膜外复合全麻诱导期PVR,但对肺循环无明显副作用.