3.5% urea-linked gelatin is as effective as 6% HES 200/0.5 for volume management in cardiac surgery patients

PURPOSE: To compare the efficacy of volume expansion with 3.5% gelatin and 6% hydroxyethyl starch 200/0.5 in patients undergoing cardiac surgery. The second objective was to compare the two colloids in terms of blood losses and allogeneic blood transfusion exposure rate. METHODS: In this open-label controlled study, patients were randomly allocated to receive either 3.5% urea-linked gelatin (GEL group: n = 55) or 6% hydroxyethyl starch 200/0.5/5.1 (HES group: n = 55) for per- (including priming of the bypass machine) and postoperative volume management with a maximum dosage of 30 +/- 3 mL.kg(-1).day(-1). Volume replacement was guided according to routine per- and postoperative care based on cardiac index, mixed venous oxygen saturation, and diuresis. If additional colloid was required, 4.5% albumin had to be given. The study period comprised per- and postoperative investigations up to 18 hr after surgery. RESULTS: All hemodynamic variables were comparable in both groups. Total study drug was 25.8 +/- 4.8 mL.kg(-1) in the GEL group and 24.5 +/- 6.0 mL.kg(-1) in the HES group. There was no difference in the number of patients receiving albumin solution or in the amount of albumin administered. Total blood loss was higher in the HES than in the GEL group (11.0 +/- 7.8 mL.kg(-1) vs 8.7 +/- 4.0 mL.kg(-1); P < 0.05) resulting in a higher need for allogeneic blood transfusion (HES: nine patients received 12 units, GEL two patients received 3 units; P = 0.026). CONCLUSION: In the conditions of the present study, HES was not associated with a better plasma expansion effect than GEL. HES could result in a higher need for allogeneic blood transfusion.     

Failure of Autologous Fresh Frozen Plasma to Reduce Blood Loss and Transfusion Requirements in Coronary Artery Bypass Surgery

Background: Previous studies failed to demonstrate any benefit from prophylaxis with fresh frozen plasma (FFP) after cardiopulmonary bypass (CPB). The results, however, were limited by either retrospective study design or use of FFP in subtherapeutic doses (2-3 units). The authors evaluated whether a therapeutic dose (15 ml/kg) of FFP reduces blood loss and transfusion requirements in elective coronary artery bypass surgery. The risks of multiple allogeneic blood donor exposure were circumvented by using autologous plasma.

Methods: Sixty adult patients scheduled for elective primary coronary artery bypass grafting were randomized to receive, after CPB, an intravenous infusion of 15 ml/kg of either autologous FFP (30 patients) or 6% hydroxyethyl starch 450/0.7 (HES; 30 patients). Autologous plasma was obtained by platelet-poor plasmapheresis several weeks before surgery. Perioperative blood transfusions were administered per protocol. Postoperative blood loss was defined as the chest tube drainage during the first 24 h after surgery.

Results: The data from 56 patients (FFP group, 27 patients; HES group, 29 patients) who completed the study according to protocol were analyzed. Median postoperative blood loss was 630 ml (range, 450-1,840 ml) and 830 ml (range, 340-1,980 ml) in the FFP and HES groups, respectively (P = 0.08). Both postoperative (0-24 h) and total perioperative erythrocyte transfusion requirements did not differ significantly between the groups (P = 0.32 and 0.14, respectively).     

Failure of autologous fresh frozen plasma to reduce blood loss and transfusion requirements in coronary artery bypass surgery

BACKGROUND: Previous studies failed to demonstrate any benefit from prophylaxis with fresh frozen plasma (FFP) after cardiopulmonary bypass (CPB). The results, however, were limited by either retrospective study design or use of FFP in subtherapeutic doses (2-3 units). The authors evaluated whether a therapeutic dose (15 ml/kg) of FFP reduces blood loss and transfusion requirements in elective coronary artery bypass surgery. The risks of multiple allogeneic blood donor exposure were circumvented by using autologous plasma. METHODS: Sixty adult patients scheduled for elective primary coronary artery bypass grafting were randomized to receive, after CPB, an intravenous infusion of 15 ml/kg of either autologous FFP (30 patients) or 6% hydroxyethyl starch 450/0.7 (HES; 30 patients). Autologous plasma was obtained by platelet-poor plasmapheresis several weeks before surgery. Perioperative blood transfusions were administered per protocol. Postoperative blood loss was defined as the chest tube drainage during the first 24 h after surgery. RESULTS: The data from 56 patients (FFP group, 27 patients; HES group, 29 patients) who completed the study according to protocol were analyzed. Median postoperative blood loss was 630 ml (range, 450-1,840 ml) and 830 ml (range, 340-1,980 ml) in the FFP and HES groups, respectively (P = 0.08). Both postoperative (0-24 h) and total perioperative erythrocyte transfusion requirements did not differ significantly between the groups (P = 0.32 and 0.14, respectively). CONCLUSION: The prophylactic administration of a therapeutic dose (15 ml/kg) of autologous FFP after CPB failed to reduce blood loss and transfusion requirements in patients undergoing uncomplicated, elective, primary coronary artery bypass surgery.     

Hemostatic effects of tranexamic acid in elective thoracic aortic surgery: a prospective,randomized, double-blind,placebo-controlled study

OBJECTIVE: We studied the hemostatic effects of tranexamic acid in patients undergoing elective surgery involving the thoracic aorta. METHODS: In a double-blind, randomized fashion, 60 consecutive patients were assigned to two treatment groups: 30 patients (placebo group) received infusion of saline solution, and 30 (treatment group) received tranexamic acid (1 g before skin incision, an infusion of 400 mg/h during the operation, and 500 mg in the pump priming). Perioperative bleeding was considered as a primary outcome. Perioperative allogeneic transfusions, major thrombotic complications (myocardial infarction, pulmonary embolism, renal insufficiency), and surgical outcomes were also considered. RESULTS: Patients treated with tranexamic acid showed significant reductions in postoperative bleeding, both in terms of the amount collected during the first 4 postoperative hours (median 307 mL, interquartile range 253-361 mL in the placebo group vs median 211 mL, interquartile range 108-252 mL in the treatment group, P =.002) and in terms of total bleeding (median 722 mL, interquartile range 574-952 mL in the placebo group vs median 411 mL, interquartile range 313-804 mL in the treatment group, P =.04). Consequently, the number of patients transfused differed significantly between groups (21 patients [72.4%] in the placebo group vs 13 [44.8%] in the treatment group, P =.033). Patients in the treatment group showed significant reductions in the total amount for the entire group of packed red cells transfused (13,500 mL in the treatment group vs 28,000 mL in the placebo group, P =.012) and in the total amount of allogeneic transfusions (23,400 mL in the treatment group vs 53,000 mL in the placebo group, P =.024). No differences in perioperative thrombotic complications were found. CONCLUSIONS: In this initial series of patients undergoing thoracic aortic surgery, tranexamic acid appeared effective in reducing perioperative bleeding, with a significant reduction in the need for allogeneic transfusions and without any increased risk of thrombotic complications.     

多次给予羟乙基淀粉或高渗氯化钠溶液对实验性脑出血大鼠脑水肿的影响

目的 评价多次给予羟乙基淀粉或高渗氯化钠溶液对实验性脑出血(ICH)大鼠脑水肿的影响.方法 清洁级雄性SD大鼠167只,体重260～300 g,随机分为假手术组(S组,n=20)、ICH组(M组,n=38)、氯化钠组(N组,n=55)和羟乙基淀粉组(H组,n=54).采用立体定向技术向大鼠右侧尾状核注入自体血50μl建立ICH模型,S组仅刺入基底节,但不注血.N组分别于ICH后2、24、48、72 h前5～10 min静脉输注7.5%氯化钠溶液5 ml/kg,H组分别于ICH后2、24、48、72 h前45～50 min静脉输注6%羟乙基淀粉130/0.4 30 ml/kg,速率均为0.2 ml/min.S组和M组分别于ICH后2、24、48、72 h随机取5只大鼠断头处死,N组和H组则在上述各时点输液前、后随机取5只大鼠处死,采用干湿重法测定脑含水量;各组每天行行为学评分,观察大鼠生存情况.结果 与M组比较,N组和H组ICH后2、24、48、72 h输液后注血侧皮层和基底节脑含水量、ICH后24、48 h时行为学评分降低,ICH后24、48、72 h时生存率升高(P<0.05);与N组比较,H组ICH后72 h时生存率升高(P<0.05).结论 多次给予6%羟乙基淀粉130/0.4或7.5%氯化钠溶液可改善ICH后大鼠脑水肿.     

Low- and Medium-molecular-weight Hydroxyethyl Starches: Comparison of Their Effect on Blood Coagulation

Background: High-molecular-weight hydroxyethyl starch (HES) compromises blood coagulation more than medium-molecular-weight HES. The authors compared medium molecular weight HES (200 kd [HES200]) and low-molecular-weight HES (70 kd [HES70]).

Methods: In a prospective, double-blind, randomized-sequence crossover study, 22 male volunteers received 15 ml/kg HES200 and HES70. Blood samples were taken before and 5 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after infusion. The following parameters were analyzed at all time points: prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII, antigenetic and functional von Willebrand factor, platelets, Thrombelastograph(R) analysis parameters (reaction time, coagulation time, maximum amplitude, angle [alpha], and clot lysis 30 and 60 min after maximum amplitude), ionized calcium, hematocrit, HES plasma concentration, molecular weight (weight average and number average), molar substitution, and polydispersity (weight average/number average). Repeated-measures analysis of variance (P < 0.05) was used to compare the response of the aforementioned parameters to the infusion of HES70 and HES200.

Results: Both HES solutions had a significant impact on all parameters. A slightly greater compromise with HES200 was found in activated partial thromboplastin time (P = 0.010), factor VIII (P = 0.009), antigenetic von Willebrand factor (P = 0.041), functional von Willebrand factor (P = 0.026), maximum amplitude (P = 0.008), and angle [alpha] (P = 0.003). No difference was established with the other parameters. HES concentration (P < 0.001), weight average (P < 0.001), number average (P < 0.001), and polydispersity (P < 0.001) were higher with HES200. There was no difference with molar substitution (P = 0.091).     

患者静脉输注羟乙基淀粉130/0.4或羟乙基淀粉200/0.5的药代动力学

目的 比较患者静脉输注6%羟乙基淀粉(HES)130/0.4和HES 200/0.5的药代动力学.方法 择期手术患者20例,ASA Ⅰ级,随机分为2组,HES 130/0.4组和HES 20010.5组,每组10例.分别在30min内静脉输注500 ml HES 130/0.4或HES 200/0.5,蒽酮比色法测定输注后各时点血清中胶体浓度,采用3P97软件计算其药代动力学参数.结果 二室模型权重为1时计算药代动力学参数最符合HES 130/0.4和HES 200/0.5的体内特点,HES 130/0.4主要的药代动力学参数如下:t1/2α=1.7 h、t1/2β=10 h、K10:0.13 h-1、K12=0.133 h-1、K21=0.210 h-1、CL(s)=10.77 L/h、AUC=46 mg·h·ml-1.HES200/0.5主要药代动力学参数如下:t1/2α=3.2 h、t1/2β=164 h、K10=0.09 h-1、K12=0.120 h-1、K21=0.010h-1、CL(s)=0.19 L/h、AUC=53 mg·h·ml-1.结论 HIES 130/0.4和HES 200/0.5在血管内停留时间均较长,HES 130/0.4较HES 200/0.5具有更好的药代动力学特点,其消除半衰期短、在血液内无蓄积.     

A comparison of the haemodynamic effects of 4% succinylated gelatin, 6% hydroxyethyl starch (200/0.5) and 4% human albumin after cardiac surgery.

BACKGROUND AND AIMS: The goal for volume replacement therapy is to maintain stable haemodynamics after cardiac surgery. We hypothesized that a short term infusion of hydroxyethyl starch results in better haemodynamic response than an infusion of lower molecular weight gelatin. MATERIAL AND METHODS: 45 patients received a predetermined fixed dose of 15 ml kg(-1) of either 4% succinylated gelatin (GEL) or 6% hydroxyethyl starch (HES) or 4% human albumin (HA) after cardiac surgery. RESULTS AND CONCLUSIONS: Pulmonary capillary wedge pressure was more increased in GEL and HES groups [mean (SD) 153% (54) and 168% (57) of pre-infusion value] than in HA group [122% (23)] (P = 0.031) after completion of infusion, but no differences in cardiac index (CI) and stroke volume index (SVI) were observed. At 2 and 18 hours after end of study infusions SVI was more increased in HES [143% (38) and 148% (41) of pre-infusion values] and HA [143% (35) and 163% (42) of pre-infusion values] groups than in GEL [116% (23) and 125% (30)] group (P = 0.047 at 2 hours and P = 0.033 at 18 hours). In early postoperative phase after cardiac surgery, HES and HA infusions improve haemodynamics more and longer period than GEL infusion.     

Low- and medium-molecular-weight hydroxyethyl starches: comparison of their effect on blood coagulation

BACKGROUND: High-molecular-weight hydroxyethyl starch (HES) compromises blood coagulation more than medium-molecular-weight HES. The authors compared medium molecular weight HES (200 kd [HES200]) and low-molecular-weight HES (70 kd [HES70]). METHODS: In a prospective, double-blind, randomized-sequence crossover study, 22 male volunteers received 15 ml/kg HES200 and HES70. Blood samples were taken before and 5 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after infusion. The following parameters were analyzed at all time points: prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII, antigenetic and functional von Willebrand factor, platelets, Thrombelastograph analysis parameters (reaction time, coagulation time, maximum amplitude, angle alpha, and clot lysis 30 and 60 min after maximum amplitude), ionized calcium, hematocrit, HES plasma concentration, molecular weight (weight average and number average), molar substitution, and polydispersity (weight average/number average). Repeated-measures analysis of variance (P < 0.05) was used to compare the response of the aforementioned parameters to the infusion of HES70 and HES200. RESULTS: Both HES solutions had a significant impact on all parameters. A slightly greater compromise with HES200 was found in activated partial thromboplastin time (P = 0.010), factor VIII (P = 0.009), antigenetic von Willebrand factor (P = 0.041), functional von Willebrand factor (P = 0.026), maximum amplitude (P = 0.008), and angle alpha (P = 0.003). No difference was established with the other parameters. HES concentration (P < 0.001), weight average (P < 0.001), number average (P < 0.001), and polydispersity (P < 0.001) were higher with HES200. There was no difference with molar substitution (P = 0.091). CONCLUSIONS: Low-molecular-weight hydroxyethyl starch (70 kd) compromises blood coagulation slightly less than HES200, but it is unclear whether this is clinically relevant.     

快速降解的羟乙基淀粉溶液损害心脏手术后凝血功能：一项前瞻性随机化试验研究

背景羟乙基淀粉溶液（hydroxyethyl starch,HES）对凝血功能的影响一直受到关注。因此诞生了对血块强度影响较小的快速降解羟乙基淀粉溶液。由于体外循环后出血的风险增加,因此作者研究了心脏手术后给予这些类型的羟乙基淀粉溶液是否会产生凝血功能的变化。方法本研究在45例择期接受心脏大手术的患者中比较了给予2种新型的快速降解的羟乙基淀粉溶液与人血白蛋白对凝血功能的影响。住入心脏外科重症监护病房后,患者随机短时（70～240分钟）输注低分子量羟乙基淀粉溶液15ml／kg（6％HES200／0．5或6％HES130／0．4）或4％的人血白蛋白溶液。结果输注2种羟乙基淀粉溶液的研究组中的血栓弹性描记法检测结果显示：血块生成时间延长且最大血凝块强度降低,这种损害在完成输液2小时后的血栓形成描记中可部分恢复（使用InTEM和ExTEM凝血激活因子）。所有治疗组中,血小板在血块最大硬度中的作用均不受影响。羟乙基淀粉溶液不会引起纤维蛋白溶解。输注人血白蛋白组在血栓形成描记上无显著变化。研究中各组胸导管引流情况大致相同。结论心脏手术后短时间内输注迅速降解的羟乙基淀粉溶液对纤维蛋白的生成和血栓弹性描记中血凝块的强度有削弱作用。而本临床研究中,人血白蛋白不影响止血功能。     

A comparative study of the postoperative allogeneic blood-sparing effect of tranexamic acid versus acute normovolemic hemodilution after total knee replacement

Both acute normovolemic hemodilution (NVHD) and tranexamic acid (TA) are potentially useful allogeneic blood conservation strategies after total knee replacement. However, the relative efficacy of these blood-sparing techniques is unknown. Therefore, to compare the postoperative allogeneic blood sparing of NVHD and TA after total knee replacement, we investigated 40 patients in a prospective, single-blinded study protocol. In Group TA, 30 min before deflating the limb tourniquet, an IV infusion of TA, 15 mg/kg, was administered over a 30-min period. Thereafter, a constant IV infusion of 10 mg x kg(-1) x hr(-1) was administered until 12 h after deflation of the limb tourniquet. Before induction of anesthesia, NVHD patients were bled to a target hematocrit of approximately 28%. Intravascular blood volume was maintained with lactated Ringer's solution. All autologous blood was transfused at the end of the surgery. Postoperatively, hematocrit was measured daily. In all cases, a hematocrit <27% was the postoperative transfusion trigger. Before discharge, deep vein thrombosis was excluded by Echo Doppler. Three months after surgery, the incidence of delayed thromboembolic events was assessed. The two groups were demographically comparable. In Group NVHD, 843 mL+/-289 of autologous blood was removed. Despite autologous blood transfusion, during the early postoperative period and until the third postoperative day, the NVHD group had significantly (P < 0.01) lower mean hematocrits when compared with the TA group. Thereafter, because of a significantly (P < 0.0008) greater allogeneic blood requirement in the NVHD group, no statistically significant difference in mean hematocrit recordings was noted among the groups. Blood accumulation in the surgical drain 12 h postoperatively, was significantly (P < 0.0008) higher in the NVHD group (259 mL+/-156) when compared with the TA group (110 mL+/-62). Significantly (P < 0.0008) more allogeneic blood was transfused in the NVHD group (19 U/13 patients) when compared with the TA group (2 U/2 patients). No abnormal Echo Doppler studies were reported. During the 3-mo follow-up period, a deep vein thrombosis and pulmonary embolus were documented in one patient in the NVHD group. We conclude that perioperative hemodynamic stability and allogeneic blood sparing is superior after tranexamic acid administration when compared with normovolemic hemodilution. IMPLICATIONS: For total knee replacement, when compared with normovolemic hemodilution, tranexamic acid administration is associated with superior perioperative hemodynamic stability and allogeneic blood sparing.     

Tranexamic acid compared with high-dose aprotinin in primary elective heart operations: effects on perioperative bleeding and allogeneic transfusions

OBJECTIVE: Since excessive fibrinolysis during cardiac surgery is frequently associated with abnormal perioperative bleeding, many authors have advocated prophylactic use of antifibrinolytic drugs to prevent hemorrhagic disorders. We compared the effects of tranexamic acid (a synthetic antifibrinolytic drug) with aprotinin (a natural derivative product with antifibrinolytic properties) on perioperative bleeding and the need for allogeneic transfusions. METHODS: In a single-center prospective randomized unblinded trial, 1040 consecutive patients undergoing primary, elective cardiac operations with cardiopulmonary bypass received either high-dose aprotinin or tranexamic acid. The aprotinin group (518 patients) received 280 mg in 20 minutes before the skin incision, 280 mg in the priming solution of the extracorporeal circuit, and a continuous infusion of 70 mg/h throughout the operation. The tranexamic acid group (522 patients) received 1 g in 20 minutes before the skin incision, 500 mg in the priming solution of the extracorporeal circuit, and a continuous infusion of 400 mg/h during the operation. Postoperative bleeding, perioperative transfusions, and hematologic variables were evaluated at fixed times. Postoperative thrombotic complications, intubation time, intensive care unit stay, and hospital stay were recorded. RESULTS: Postoperative bleeding was similar in the 2 groups: aprotinin 250 mL (150-400 mL) versus tranexamic acid 300 mL (200-450 mL) (median and 25th-75th quartiles), median difference of 50 mL (95% confidence intervals, 0-50 mL). The number of transfusions and the outcome did not differ. CONCLUSIONS: Tranexamic acid and aprotinin show similar clinical effects on bleeding and allogeneic transfusion in patients undergoing primary elective heart operations. Since tranexamic acid is about 100 times cheaper than aprotinin, its use is preferable in this type of patient.     

Hypertonic/hyperoncotic fluid resuscitation after hemorrhagic shock in dogs.

We compared canine systemic and cerebral hemodynamics after resuscitation from hemorrhagic shock with 4 mL/kg (a volume approximating 12% of shed blood volume) of 7.2% saline (HS; 1233 mEq/L sodium), 20% hydroxyethyl starch (HES) in 0.8% saline, or a combination fluid consisting of 20% hydroxyethyl starch in 7.2% saline (HS/HES). Eighteen endotracheally intubated mongrel dogs (18-24 kg) were ventilated to maintain normocarbia with 0.5% halothane in nitrous oxide and oxygen (60:40). After a 30-min period of hemorrhagic shock (mean arterial blood pressure = 40 mm Hg), extending from time T0 to T30, animals received one of three randomly assigned intravenous resuscitation fluids: HS, HES, or HS/HES. Data were collected at baseline, at the beginning and end of the shock period (T0 and T30), immediately after fluid infusion (T35), and at 60-min intervals for 2 h (T95, T155). After resuscitation, mean arterial blood pressure and cardiac output increased similarly in all groups, but failed to return to baseline. Intracranial pressure decreased during shock and increased slightly, immediately after resuscitation in all groups. During shock, cerebral blood flow (cerebral venous outflow method) declined in all groups. After resuscitation, cerebral blood flow increased, exceeding baseline in the HS and HS/HES groups but remaining low in the HES group (P less than 0.05 HS vs HES at T35). We conclude that small-volume resuscitation (4 mL/kg) with HS, HS/HES, or HES does not effectively restore or sustain systemic hemodynamics in hemorrhaged dogs. In dogs without intracranial pathology, the effects on cerebral hemodynamics are also comparable, except for transiently greater cerebral blood flow in the HS group in comparison with the HES group.     

Physiologic effects of intravenous fluid administration in healthy volunteers

Dose regimens in perioperative fluid management are rarely evidence based. Therefore, we investigated responses to an IV fluid infusion in healthy volunteers to assess basic physiologic effects of a fluid infusion per se. In a prospective, double-blinded, cross-randomized study, 12 healthy volunteers with a median age of 63 yr (range, 59-67 yr) received an infusion of lactated Ringer's solution 40 mL/kg (median, 2820 mL) or 5 mL/kg (median, 353 mL; background infusion) in random order on two separate occasions. The study was designed to mimic the perioperative course with preoperative fasting, infusion of the fluid over 3 h in the morning, and additionally 24-h hospitalization under standardized conditions. Primary outcome assessments were pulmonary function (spirometry), exercise capacity (submaximal treadmill test), balance function (BalanceMaster), and weight. Infusion of 40 mL/kg of lactated Ringer's solution compared with the background infusion (5 mL/kg) resulted in a significant decrease in pulmonary function and a significant weight gain of median 0.85 kg (range, -0.2-1.6 kg; P = 0.003) persisting 24 h after the infusion. Exercise capacity and balance function were not influenced by fluid administration. These findings may serve as a basis for clinical studies applying the same type of fluid in different amounts to determine the optimal amount of perioperative fluid in various surgical procedures. IMPLICATIONS: Infusion of 40 mL/kg of lactated Ringer's solution in volunteers led to a significant decrease in pulmonary function and a significant weight gain for 24 h but without effects on exercise capacity. These findings may serve as basis information for clinical studies of perioperative fluid management.     

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.     

Hydroxyethyl starch as a priming solution for cardiopulmonary bypass impairs hemostasis after cardiac surgery

We investigated the influence of hydroxyethyl starch (HES) as a priming solution for the cardiopulmonary bypass (CPB) circuit on postoperative hemostasis in 45 patients undergoing elective coronary artery bypass grafting. In a randomized sequence, 20 mL/kg of low-molecular-weight HES (HES 120; molecular weight 120,000 daltons), high-molecular-weight HES (HES 400; molecular weight 400,000 daltons), or 4% human albumin (ALB) was used as the main component of the CPB priming solution. The thromboelastographic values indicating the speed of solid clot formation (alpha-angle) and the strength of the fibrin clot (maximum amplitude and shear elastic modulus) were decreased up to 2 h after CPB in both HES groups. Four hours after the operation, blood loss through the chest tubes had increased in the HES groups: HES 120, mean 804 mL (range, 330-1390 mL); HES 400, mean 1008 mL (range, 505-1955 mL); and ALB, mean 681 mL (range, 295-1500 mL) (P < 0.05 between the HES 400 and ALB groups). We conclude that HES solutions, when given in doses of 20 mL/kg in connection with the CPB prime, compromise hemostasis after cardiac surgery. This effect appears related to formation of a less stable thrombus compared with that formed in the presence of ALB. IMPLICATIONS: The influence of hydroxyethyl starch (HES) on postoperative hemostasis was investigated in cardiac surgery. The thromboelastographic values indicated that HES solutions, when given in connection with the cardiopulmonary bypass prime, compromise hemostasis after cardiac surgery. This effect seems to occur through the formation of a less stable clot.     

Hemostatic changes in patients receiving hydroxyethyl starch: the influence of ABO blood group

Hydroxyethyl starches (HES) interfere with coagulation because of their molecular structure and the amount infused during surgery. Coagulation defects include platelet dysfunction and a decrease of the VIII/von Willebrand factor complex (VIII/vWF). We examined the effects of 6% HES 200/0.6 on hemostasis by using an in vitro platelet function analyzer, the usual coagulation tests, the VIII/vWF complex assessment, and TEG analysis in patients undergoing abdominal surgery. The influence of the blood group was investigated. HES infusion induced primary hemostasis alterations, assessed by a prolonged platelet function analyzer closure time in the presence of epinephrine and adenosine diphosphate, which was not correlated with the platelet count. The decrease in VIII/vWF complex was proportional to the volume of infused HES (20 and 30 mL/kg) and was more pronounced in patients of the O blood group. The preoperative hypercoagulability status assessed by TEG analysis was reversed 24 h after HES infusion. In conclusion, 6% HES 200/0.6 induced immediate hemostasis alterations. Patients of the O blood group were likely to develop a von Willebrand-like syndrome after HES infusion. We conclude that intraoperative use of 6% HES 200/0.6 should be restricted in patients of the O blood group undergoing surgical procedures with high risk for bleeding.     

The effects of hydroxyethyl starches of varying molecular weights on platelet function

We evaluated the effect of various hydroxyethyl starch (HES) solutions on platelet function. Blood was obtained before and after the IV infusion (10 mL/kg) of saline (n = 10), HES 70/0.5--0.55 (molecular weight in kD/degree of substitution; n = 10), HES 130/0.38--0.45 (n = 10), HES 200/0.6--0.66 (n = 10), or HES 450/0.7--0.8 (n = 10) in otherwise healthy patients scheduled for elective surgery. Collagen and epinephrine were used as agonists for assessment of platelet function analyzer closure times. Flow cytometry was used to assess agonist-induced expression of activated glycoprotein IIb/IIIa complex and P-selectin. Infusion of HES 450/0.7--0.8, HES 200/0.6--0.66, and HES 70/0.5--0.55 prolonged closure times and reduced glycoprotein IIb/IIIa expression, whereas saline and HES 130/0.38--0.45 had no significant effect on platelet variables. P selectin expression was not affected by any solution tested. In vitro experiments demonstrated a less inhibiting effect of HES 130/0.38--0.45 on closure times when compared with other HES solutions. This study shows that HES 450/0.7--0.8, HES 200/0.6--0.66, and HES 70/0.5--0.55 inhibit platelet function by reducing the availability of the functional receptor for fibrinogen on the platelet surface. Our data indicate that fluid resuscitation with HES 130/0.38--0.45 may reduce the risk of bleeding associated with synthetic colloids of higher molecular weight and degree of substitution.     

Repetitive large-dose infusion of the novel hydroxyethyl starch 130/0.4 in patients with severe head injury

In this prospective, controlled, randomized, single-center study, we investigated the safety of repetitive large-dose infusion of a novel hydroxyethyl starch solution (6% HES 130/0.4) in cranio-cerebral trauma patients. Patients were randomized to receive either HES 130/0.4 (n = 16) at repetitive doses of up to 70 mL x kg(-1) x d(-1) (which is the largest HES dose reported in the literature) or the control HES 200/0.5 (n = 15) up to its approved dose limit of 33 mL x kg(-1) x d(-1) followed by human albumin up to a total dose (HES 200/0.5 + albumin) of 70 mL x kg(-1) x d(-1). We found no differences between groups in mortality, renal function, bleeding complications, and use of blood products. There were also no major differences in coagulation variables. However, at some time points, factor VIII, von Willebrand factor, and ristocetin cofactor were higher in the HES 130/0.4 group despite the large HES doses administered. We conclude that HES 130/0.4 can safely be used in critically ill head trauma patients over several days at doses of up to 70 mL x kg(-1) x d(-1). IMPLICATIONS: There are concerns that infusion of certain hydroxyethyl starch (HES) types for plasma volume expansion may influence coagulation and renal function. We investigated the safety of the novel HES 130/0.4 in patients with severe cranio-cerebral trauma. The repetitive HES doses administered in this study are the largest reported in the literature.     

术前静脉输注6%羟乙基淀粉200/0.5溶液对患者术后免疫功能的影响

目的 探讨术前静脉输注6%羟乙基淀粉(HES)200/0.5溶液对患者术后免疫功能的影响.方法 择期胆囊切除术患者40例,年龄21～58岁,体重47～79 kg,性别不限,ASA分级Ⅰ或Ⅱ级,采用随机数字表法,将患者随机分为2组(n=20):6%HES 200/0.5组(H组)和复方醋酸钠组(A组).麻醉诱导前经15 min静脉输注6%HES 200/0.5溶液或复方醋酸钠溶液10 ml/kg.于术前、术后1 h、术后1和3 d时取静脉血样,测定血清IL-6、IL-8、TNF-α、IL-2和IL-10以及IgG、IgA和IgM的浓度.结果 与术前比较,两组患者术后血清IL-6、IL-8、TNF-α、IL-2和IL-10浓度均升高,A组术后血清IgA和IgG浓度降低(P＜0.05或0.01),IgM浓度差异无统计学意义,H组上述指标差异无统计学意义(P＞0.05);与A组比较,H组术后血清IL-6、IL-8和TNF-α浓度降低,IL-2、IL-10、IgA和IgG浓度升高(P＜0.05).结论 术前静脉输注6%HES 200/0.5溶液可改善患者术后的免疫功能.

Abstract：

Objective To investigate the effect of 6 % hydroxyethyl starch (HES) 200/0.5 infusion before operation on postoperative immne function in patients. Methods Forty ASA Ⅰ or Ⅱ patients of both sexes aged 21-58 yr weighing 47-79 kg were randomly divided into 2 groups ( n = 20 each): 6% HES 200/0.5 group (group H) and compound sodium acetate group (group A). 6% HES 200/0.5 10 ml/kg or compound sodium acetate solution was infused intravenously over 15 min before anesthesia induction. Anesthesia was induced with iv injection of propofol, fentanyl and vecuronium and maintained with target-controlled infusion of propofol and infusion of remifentanil. Venous blood samples were collected before operation and at 1 h, 1 day and 3 days after operation to detect the serum concentrations of IL-6, IL-8, TNF-α, IL-2, IL-10, IgG, IgA andIgM. Results Serum concentrations of IL-6, IL-8, TNF-α, II-2 and IL-10 were significantly higher after operation in the two groups, and serum concentrations of IgA and IgG were significantly lower after operation in group A than those before operation ( P ＜ 0.05 or 0.01 ). Serum concentrations of IL-6, IL-8 and TNF-α were significantly lower, while serum concentrations of IL-2, IL-10, IgA and IgG were significantly higher after operation in group H than in group A ( P ＜0.05). Conclusion Preoperative infusion with 6% HES 200/0.5 can improve the immune function after operation in patients.