The effects of hydroxyethyl starch solutions on thromboelastography in preoperative male patients

BACKGROUND: Hydroxyethyl starches (HES) have been shown to decrease clot strength and to increase coagulation times assessed by thromboelastography (TEG). HES with minimal anticoagulant side-effects is beneficial for plasma volume expansion in the perioperative setting. A comparison of the in vivo effects of high, middle and low molecular weight HES solutions on TEG variables has not been performed so far. METHODS: Blood was obtained before and after intravenous infusion (10 ml kg-1) of either saline, HES 70/0.5/4 (molecular weight in kDa/degree of substitution/C2:C6 ratio), HES 130/0.4/9, HES 200/0.6/9.4, or HES 450/0.7/4.6 in 50 otherwise healthy patients. Thromboelastography was performed in 360 micro l of 1% celite activated citrated whole blood after recalcification. RESULTS: HES 450/0.7/4.6 prolonged reaction time indicating impairment of the plasmatic coagulation system. TEG parameters indicative for platelet function, including angle alpha, maximum amplitude and coagulation time, deteriorated after infusion of HES 450/0.7/4.6 and HES 70/0.5/4. HES 200/0.6/9.4 and HES 130/0.4/9 impaired platelet contribution to hemostasis only partially, decreasing two or one TEG platelet parameters, respectively. CONCLUSION: Infusion of HES 450/0.7/4.6 compromises TEG parameters more than the other solutions tested, whereas HES 130/0.4/9 has the smallest effect. Further outcome-related studies are needed in order to assess the clinical relevance of our findings.     

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.     

The effect of the combined administration of colloids and lactated Ringer's solution on the coagulation system: an in vitro study using thrombelastograph coagulation analysis (ROTEG

Gelatin solutions are often given in clinical practice once the maximal dose of a median-weight hydroxyethyl starch (HES) has been reached. Colloids are usually combined with lactated Ringer's solution (RL). Whether the combined administration of colloids and/or crystalloids affects blood coagulation is not known. We diluted blood by 20%, 40%, and 60% with RL, gelatin (Gelofusin), 6% HES 130/0.4 (Voluven), and 6% HES 200/0.5 (Iso-Hes), as well as with combinations of these solutions at a ratio of 1:1 (gelatin/RL, 6% HES 130/0.4:RL, 6% HES 200/0.5:RL, 6% HES 130/0.4:gelatin, 6% HES 200/0.5:gelatin). Thereafter, blood was analyzed by using modified thrombelastograph coagulation analysis (ROTEG) and clotting time, clot formation time, and maximal clot firmness were determined. RL had the least effect on hemostasis. Gelatin administered alone impaired the coagulation system significantly less than each median-weight HES administered alone. We conclude that gelatin combined with 6% HES 200/0.5 or 6% HES 130/0.4 decreases hemostasis <6% HES 200/0.5 or 6% HES 130/0.4 administered alone. IMPLICATIONS: The effect of the combined administration of different colloids and/or crystalloids on coagulation is not known. We show that hemostasis is less impaired using a combination of gelatin and median-weight starches than using median-weight starches alone. Furthermore, the combination of lactated Ringer's solution and gelatin decreases the coagulation system to the same extent as the combination of lactated Ringer's solution and 6% hydroxyethyl starch 130/0.4.     

In vitro effects of different medium molecular hydroxyethyl starch solutions and lactated Ringer's solution on coagulation using SONOCLOT

Hydroxyethyl starch (HES) solutions are widely used to replace intravascular volume. HES solutions differ from each other with regard to molecular weight and mode of hydroxyl substitution (degree of hydroxylation, C2:C6 hydroxyethyl ratio, concentration), factors which may have varying effects on coagulation. We studied, in vitro, three different HES preparations (molecular weight/degree of hydroxylation/concentration/C2:C6 ratio of substitution 70.000/0. 5/6%/3.2; Pharmacia & Upjohn Co., Erlangen, Germany; 130.000/0. 4/6%/11.2 and 200.000/0.5/6%/4.6; Fresenius Co., Bad Homburg, Germany) and, for comparison, lactated Ringer's solution (RL) at 33% and 66% dilution with whole blood. The influence of hemodilution was measured by using routine laboratory variables and SONOCLOT (Sonoclot II Coagulation and Platelet Function Analyzer, Sienco Co.) analysis, using a viscoelastic test, on the cellular as well as on the plasmatic hemostatic system. For statistical analysis of quantitative data, we used nonparametric analysis of variance and adequate post hoc tests. Qualitative data were analyzed by using the nonparametric Kruskal-Wallis test. A P value below 0.05 was considered significant. In contrast to the control group with RL, the liquid phase of coagulation (activated clotting time) was slightly affected by the 33% diluted HES solutions. HES 70.000, 130. 000, and 200.000 interfered significantly with the early stage of coagulation as expressed by the clot rate (gel/fibrin formation). Clot maturation and speed of maturation (time to peak) were strongly affected by HES 70.000 at all grades of dilution. HES 130.000 showed a faster clot formation process compared with the other HES solutions. HES 130.000 diluted 33% showed a better clot retraction as compared with the other HES solutions. In conclusion, in vitro hemodilution comparing different medium molecular weight HES solutions reveals that HES 130.000 seems preferable regarding some aspects of clot formation and retraction. RL affected clot formation only minimally, except for the early activation of clotting, which was measured by a shortened activated clotting time. IMPLICATIONS: We investigated the effect of different hydroxyethyl starch (HES) solutions (70.000, 130.000, 200.000) on coagulation. Regarding clot formation and retraction, HES 130.000 had some advantages over the other tested HES solutions. Lactated Ringer's solution affected coagulation only minimally, except for the early stage of clot formation.     

Effects of a new modified,balanced hydroxyethyl starch preparation (Hextend) on measures of coagulation

Background. Hydroxyethyl starch (HES) may affect blood coagulation.We studied the effects of a modified, balanced, high-molecularweight [mean molecular weight (MW) 550 kDa], high-substituted[degree of substitution (DS) 0.7] HES preparation (Hextend^®)on coagulation in patients undergoing major abdominal surgery. Methods. Patients were allocated randomly to receive Hextend^®(n=21), lactated Ringer’s solution (RL, n=21) or 6% HESwith a low MW (130 kDa) and a low DS (0.4) (n=21). Theinfusion was started after induction of anaesthesia and continueduntil the second postoperative day to maintain central venouspressure between 8 and 12 mm Hg. Activated thrombelastography(TEG) was used to assess coagulation. Different activators wereused (extrinsic and intrinsic activation of TEG) and aprotininwas added to assess hyperfibrinolytic activity (ApTEG). We measuredonset of coagulation [coagulation time (CT=reaction time, r)],the kinetics of clot formation [clot formation time (CFT=coagulationtime, k)] and maximum clot firmness (MCF=maximal amplitude,MA). Measurements were performed after induction of anaesthesia,at the end of surgery, 5 h after surgery and on the morningsof the first and second days after surgery. Results. Significantly more HES 130/0.4 [2590 (SD 260)ml] than Hextend^® [1970 (310) ml] was given. Blood losswas greatest in the Hextend^® group and did not differ betweenRL- and HES 130/0.4-treated patients. Baseline TEG datawere similar and within the normal range. CT and CFT were greaterin the Hextend^® group immediately after surgery, 5 hafter surgery and on the first day than in the two other groups.ApTEG MCF also changed significantly in the Hextend^® patients,indicating more pronounced fibrinolysis. Volume replacementusing RL caused moderate hypercoagulability, shown by a decreasein CT. Conclusion. A modified, balanced high-molecular weight HES witha high degree of substitution (Hextend^®) adversely affectedmeasures of coagulation in patients undergoing major abdominalsurgery, whereas a preparation with a low MW and low DS affectedthese measures of haemostasis less. Large amounts of RL decreasedthe coagulation time. Br J Anaesth 2002; 89: 722–8     

Effects of albumin 5% and artificial colloids on clot formation in small infants

Albumin is often cited in textbooks as the gold standard for fluid replacement in paediatrics, but in practice artificial colloids are more frequently used. Although one concern with the use of artificial colloids is their intrinsic action on haemostasis, the available data in children are inconclusive for 6% hydroxyethyl starch 130/0.4 (HES) and no data exist for gelatine solution with respect to coagulation. A total of 42 children (3-15 kg) undergoing surgery and needing colloid replacement were randomly assigned to receive 15 mlxkg(-1) of either albumin 5%, 4% modified gelatine solution or 6% hydroxyethyl starch 130/0.4 solution. Standard coagulation tests and modified thrombelastography (ROTEM) were performed. After colloid administration, routine coagulation test results changed significantly and comparably in all groups, although activated partial thromboplastin time values increased more with gelatine and HES. Coagulation time was unchanged in the children who received albumin or gelatine but other activated modified thrombelastography values were significantly impaired in all groups. After gelatine and after albumin the median clot firmness decreased significantly but remained within the normal range. Following HES, coagulation time increased significantly, and clot formation time, alpha angle, clot firmness, and fibrinogen/fibrin polymerisation were significantly more impaired than for albumin or gelatine, reaching median values below the normal range. From a haemostatic point of view it might be preferable to use gelatine solution as an alternative to albumin; HES showed the greatest effects on the overall coagulation process.     

Influence of a new hydroxyethylstarch preparation (HES 130/0.4) on coagulation in cardiac surgical patients.

OBJECTIVE: To compare volume therapy with HES 130/0.4, a new hydroxyethylstarch (HES) solution with a gelatin-based fluid replacement strategy. DESIGN: Prospective, randomized, safety study. SETTING: Urban, university-affiliated hospital (single institution). PARTICIPANTS: Forty-two patients undergoing elective cardiac surgery. INTERVENTIONS: Patients were prospectively randomized into 2 groups: In group 1 (n = 21), gelatin was given perioperatively for volume support until the 1st postoperative day to keep the central venous pressure (CVP) between 10 and 14 mmHg; in group 2 (n = 21) HES 130/0.4 was administered using the same protocol as in group 1. MEASUREMENTS AND MAIN RESULTS: Standard coagulation variables and modified thromboelastography (TEG) were used. Using different activators for extrinsic and intrinsic activation and heparin inactivation by heparinase, the onset of coagulation (coagulation time), kinetics of clot formation (clot formation time), and maximum clot firmness were measured. Measurements were performed after induction of anesthesia (T0), at the end of surgery (T1), 4 hours after surgery (T2), and on the morning of the 1st postoperative day (T3). A total of 3310 +/- 810 mL of gelatin and 3070 +/- 570 mL of HES 130/0.4 were used in the 2 groups during the study period. The 2 groups did not differ with regard to postoperative bleeding or in use of packed red blood cells or fresh frozen plasma. Standard coagulation variables were similar between the 2 groups. All TEG variables were within the normal range at baseline. Coagulation time and clot formation time data were significantly elevated after surgery and in the intensive care unit, without showing specific differences between the 2 volume replacement groups. Intrinsic TEG and heparinase TEG clot formation times remained significantly higher until the end of the study period. No differences were seen between HES-treated and gelatin-treated patients. CONCLUSIONS: Volume replacement with the new HES preparation was as safe as gelatin-based volume replacement with regard to coagulation in cardiac surgical patients. HES 130/0.4 is an alternative plasma substitute to treat volume deficits.     

小容量高渗氯化钠羟乙基淀粉40注射液对小鼠局灶性脑缺血/再灌注损伤的影响

目的研究高渗氯化钠羟乙基淀粉40注射液(hypertomic sodiam chloride hydroxyethyl starch 40 injection,HSH)对小鼠局灶性脑缺血/再灌注损伤（ischemia/reperfusion injury,I/RI）的影响。方法30只昆明种小鼠,应用随机排列表进行随机分...     

In cardiac surgery patients does Voluven(R) impair coagulation less than other colloids?

Hydroxyethyl starch (HES) solutions are commonly used for volume replacement in cardiac surgery patients. The degree of impairment of the haemostatic system depends on the molecular weight and substitution degree of HES solutions. It is claimed that as HES 130/0.4 (Voluven(?)) exhibits a lower in vitro molecular weight and a lower degree of hydroxyethyl substitution than HES 200/0.5 (HAES-steril(?)) therefore it has less impact on haemostasis. A best evidence topic in cardiac surgery was written according to a structured protocol to verify this statement. The question addressed was: in cardiac surgery patients does volume replacement with Voluven(?) impair coagulation less than other colloids? Using the reported search 12 papers, three in vitro and nine clinical studies, were found to represent the best evidence to answer the clinical question. The nine clinical studies were all randomised controlled trials. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The in vitro studies suggest that HES 130/0.4 has no significant effect on platelet variables, shows a faster clot formation process and a better clot retraction as compared with the other HES solutions. On the other hand, current best available evidence (level 1b) from clinical studies, limited by heterogeneity predominantly in terms of dosage of HES 130/0.4 administered and the sample size of individual trials, overwhelmingly suggests that HES 130/0.4 compared with HES 200/0.5 or gelatin-based volume replacement fluid affects coagulation to the same extent resulting in similar degree of blood loss. It can be concluded that contrary to in vitro studies HES 130/0.4 in clinical practice has comparable effects on blood loss after cardiac surgery.     

Molar substitution and C2/C6 ratio of hydroxyethyl starch: influence on blood coagulation

Background. Development of hydroxyethyl starches (HES) witha low impact on blood coagulation but a long intravascular persistenceis of clinical interest. A previous in vitro study showed thatlow substituted high molecular weight HES does not compromiseblood coagulation more than medium molecular weight HES. Inthe present study we assessed the individual effects on bloodcoagulation of molar substitution and C2/C6 ratio of a highmolecular weight HES. Methods. Blood was obtained from 30 healthy patients undergoingelective surgery and mixed with six high molecular weight (700kDa) HES solutions differing in their molar substitution (0.42and 0.51) and C2/C6 ratio (2.7, 7 and 14) to achieve 20, 40and 60% dilution. Blood coagulation was assessed by Thrombelastograph^®analysis (TEG) and plasma coagulation tests.Data were comparedusing a three-way analysis of variance model with repeated measureson the three factors. Results. Higher molar substitution compromised blood coagulationmost (for all TEG parameters, P<0.05). The lowest C2/C6 ratiowas associated with the lowest effect on blood coagulation;r (P<0.001), angle     

The effect of In vitro hemodilution with gelatin, dextran, hydroxyethyl starch, or Ringer's solution on Thrombelastograph

To determine the effects of progressive in vitro hemodilution with various plasma substitutes on whole blood coagulation, blood was obtained from six healthy volunteers. The Thrombelastograph((R)) (TEG; Haemoscope Corp., Morton Grove, IL) variables of reaction time, coagulation time, maximum amplitude, and growth angle were determined. The following plasma substitutes were tested: two gelatin solutions (4% gelatin polysuccinate and 5.5% oxypolygelatin); two dextrans (10% dextran 40 and 6% dextran 60); and five hydroxyethyl starch (HES) preparations (6% HES 70/0.5-0.55, 3% HES 200/0.5, 6% HES 200/0.5, 10% HES 200/0.5, and 6% HES 450/0.7). Ringer's solution was also tested to assist analyzing the intrinsic effect of colloid molecules on blood coagulation. The dilution ratios of citrated blood volume to plasma substitute volume were 10:2, 10:4, and 10:10. Blood coagulation was affected by plasma substitutes when the dilution ratios of citrated blood volume to colloid solution volume were 10:4 and 10:10. TEG variables did not change significantly after in vitro hemodilution with lactated Ringer's solution. The tested gelatin solutions showed less intrinsic effect on blood coagulation than other plasma substitutes. All HES preparations showed similar intrinsic effects as 6% dextran 60. The plasma substitute of 10% dextran 40 had the strongest effect on coagulation. Coagulation time was the most markedly affected TEG variable. Blood coagulation may be compromised when the dilution ratio of blood volume to colloid solution volume is >10:4. Whereas gelatin solutions have less intrinsic effect on blood coagulation, 10% dextran 40 has the strongest effect on coagulation. IMPLICATIONS: Blood coagulation may be compromised when the dilution ratio of blood volume to colloid solution volume is >10:4. Whereas gelatin solutions have less intrinsic effect on blood coagulation than hydroxyethyl starch or dextran, 10% dextran 40 has the strongest effect on coagulation.     

羟乙基淀粉130/0.4体外不同程度血液稀释对凝血功能的影响

目的 探讨羟乙基淀粉130/0.4体外不同程度血液稀释对凝血功能的影响.方法 采集20名健康志愿者空腹静脉血样,采用6%羟乙基淀粉130/0.4氯化钠注射液作为稀释液,按容量稀释比例(全血∶稀释液)分为6组:10∶0组(未稀释组)、9∶1组(10%组)、8∶2组(20%组)、7∶3组(30%组)、6∶4组(40%组)、5∶5组(50%组).每名志愿者采血23 ml(前3 ml血弃用),其中15 ml用于测定红细胞压积(Hct)、血小板计数(PLT)、凝血酶原时间(PT)、活化部分凝血活酶时间(AFIT)和纤维蛋白原(Fjb);剩余的5 ml抗凝后,采用血栓弹力描记仪检测血栓弹力描记图(TEG)指标:反应时间(R)、凝血时间(K)、α角和最大振幅(MA).结果 Hct、PLT和Fib随稀释程度的增加而下降(P＜0.05);与未稀释组比较,30%组、40%组和50%组PT和APTT延长,且随稀释程度的增加而延长(P＜0.01).与未稀释组和10%组比较,20%组、30%组和40%组R和K缩短,α角增大,50%组R延长,MA减小(P＜00.05);与20%组、30%组和40%组比较,50%组R和K延长,α角和MA减小(P＜0.05).结论 羟乙基淀粉130/0.4体外不同程度血液稀释对凝血功能的影响不同:10%稀释时,对凝血功能无影响;20%～40%稀释时,活化凝血初始阶段,凝血块形成时间缩短,速率增快;50%稀释时,抑制凝血因子活性,凝血块强度降低.     

Effects of two different hydroxyethyl starch solutions (HES200/0.5 vs. HES130/0.4) on the expression of platelet membrane glycoprotein

BACKGROUND: There are various hydroxyethyl starch (HES) solutions with different degrees of hydroxylation and different molecular weights. HES200/0.5 solution is most commonly used. HES130/0.4 is a new HES solution and is the 'state-of-the-art' in volume substitution. However, the mechanism of the observed anticoagulation action of HES has not been fully delineated. The objective of this study was to further investigate the effect of HES200/0.5 and HES130/0.4 on platelet coagulation. METHODS: Sixty ASA I-II patients undergoing elective minor surgery were randomly allocated to receive an intravenous infusion (20 ml/kg) of lactated Ringer's solution (group L), HES200/0.5 (group H) or HES130/0.4 (group V) after the induction of anesthesia. The expression of CD42b, CD41/61 and CD62p in vivo was assessed on non-stimulated platelets and adenosine diphosphate (ADP) agonist-activated platelets using flow cytometry. RESULTS: Resting glycoprotein expression of the non-stimulated platelets was observed. HES200/0.5 and HES130/0.4 reduced the CD42b, CD41/61 and CD62p expression of ADP-agonist-activated platelets at 15 min after intravenous infusion. At 6 h after intravenous infusion, the trend of decreasing expression of activated CD42b, CD41/61 and CD62p was maintained in group H. However, CD42b, CD41/61 and CD62p expression returned to the pre-operative level in group V. CONCLUSION: This study showed that both HES200/0.5 and HES130/0.4 can inhibit platelet coagulation. Platelet dysfunction experienced a faster recovery after the infusion of HES130/0.4 than after HES200/0.5. Liquid resuscitation with HES130/0.4 may decrease the risk of hemorrhage in the operative period.     

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。     

Artificial colloids impair haemostasis. An in vitro study using thromboelastometry coagulation analysis

BACKGROUND: Hydroxyethyl starch (HES) solutions impair haemostatic mechanisms. The impact of the degree of substitution (DS) of a HES solution on thromboelastometry tracings is unclear. Therefore we tested the hypothesis of whether the DS has an effect on the haemostatic defect caused by HES, and assessed whole blood coagulation by thromboelastometry coagulation analysis (ROTEM, Pentapharm Co., Munich, Germany) in serial in vitro haemodilutions of colloids. METHODS: Whole blood was withdrawn from 12 volunteers in a crossover study. Six per cent low-molecular weight HES with a high (HES MW 120 kDa/degree of substitution 0.7) and low (HES MW 130 kDa/0.4) degree of substitution, 4% succinylated gelatin (GEL) or 4% albumin (ALB) was added to citrated venous whole blood samples to make 20, 40, 60 vol.% end-concentrations of each of the solutions. Samples were analyzed by ROTEM. RESULTS: There was a comparable decrease in maximum clot firmness (MCF) and shear elastic modulus [G = 5000 x MCF/(100-MCF)] by HES 120/0.7 and HES 130/0.4 at 20 and 40 vol.% dilutions. At 60 vol.% dilution HES 120/0.7 decreased less alpha-angle and MCF than HES 130/0.4 (P < 0.05). With moderate dilutions all colloids shortened coagulation time (CT). At 20, 40 and 60 vol.% dilutions MCF and G were more decreased in both HES groups than in the ALB and GEL groups (P < 0.05). Furthermore, at 40 and 60 vol.% dilutions G deteriorated more in the GEL than in the ALB group (P < 0.05). CONCLUSION: In vitro the impact of the degree of substitution of HES solution on thromboelastometry coagulation analysis was modest. Haemodilution with gelatin and albumin induced fewer coagulation abnormalities than HES. In addition, the haemodilution with gelatin impaired coagulation more than albumin solution.     

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.     

The effects of in vitro hemodilution with gelatin, hydroxyethyl starch, and lactated Ringer's solution on markers of coagulation: an analysis using SONOCLOT

Blood-saving strategies have recently been established to avoid allogeneic transfusion during surgery or after trauma. This includes an expanding use of crystalloids and colloids. These solutions interfere with coagulation systems, but quantitative measurements are still lacking. The SONOCLOT (Sienco Company, Morrison, CO) analysis (SCT), a viscoelastic test, measures clot formation and includes information on the cellular, as well as the plasmatic coagulation, system. To quantify hemodilutional effects on in vitro coagulation, we studied gelatin (G), hydroxyethyl starch 6% (HES; molecular weight 450,000), and lactated Ringer's solution (RL) in 33% and 66% dilutions measuring routines laboratory and SCT variables. Hemodilution with RL tended to increase in vitro coagulability. Among the tested colloids, G had the least impact on markers of coagulation. G33% did not differ significantly from the undiluted control group. HES had the largest impact on markers of coagulation compared with G and RL. In conclusion, SCT provides a fast and easy to perform bedside test to quantify in vitro hemodilution. IMPLICATIONS: The effects of progressive hemodilution on coagulation are difficult to measure. SONOCLOT analyses provide an easy to perform test with fast information on cellular and plasmatic coagulation properties. Among colloids, hydroxyethyl starch has the largest impact on markers of coagulation compared with gelatin or lactated Ringer's solution.     

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.     

Colloids decrease clot propagation and strength: role of factor XIII-fibrin polymer and thrombin-fibrinogen interactions

Colloid-mediated hypocoagulability is clinically important, but the mechanisms responsible for coagulopathy have been incompletely defined. Thus, my goal was to elucidate how colloids decrease plasma coagulation function. Plasma was diluted 0% or 40% with 0.9% NaCl, three different hydroxyethyl starches (HES, mean molecular weight 450, 220 or 130 kDa), or 5% human albumin. Samples (n=6 per condition) were activated with celite, and diluted samples had either no additions or addition of fibrinogen (FI), thrombin (FIIa) or activated Factor XIII (FXIIIa) to restore protein function to prediluted values. Thrombelastographic variables measured included clot propagation (angle, alpha), and clot strength (amplitude, A; or shear elastic modulus, G). Dilution with 0.9% NaCl significantly decreased alpha, A and G-values compared to undiluted samples. Supplementation with FI, but not FIIa or FXIIIa, resulted in 0.9% NaCl-diluted thrombelastographic variable values not different from those of undiluted samples. FI supplementation of HES 450, HES 220, HES 130 and albumin-diluted samples only partially restored alpha, A and G-values compared to undiluted samples. FIIa addition only improved clot propagation and strength in albumin-diluted samples. FXIIIa supplementation improved propagation in samples diluted with HES 450, HES 220 and albumin, and clot strength improved in HES 450 and albumin-diluted plasma. Considered as a whole, these data support compromise of FIIa-FI and FXIIIa--fibrin polymer interactions as the mechanisms by which colloids compromise plasma coagulation. Investigation to determine if clinical enhancement of FXIII activity and/or FI concentration (e.g. fresh-frozen plasma, cryoprecipitate) can attenuate colloid-mediated decreases in hemostasis is warranted.     

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.