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BJA Advance Access originally published online on December 10, 2008
British Journal of Anaesthesia 2009 102(2):191-197; doi:10.1093/bja/aen353
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2008. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Influence on coagulation of a potato-derived hydroxethylstarch (HES 130/0.42) and a maize-derived hydroxethylstarch (HES 130/0.4) in patients undergoing cardiac surgery

J. Boldt*, S. Suttner, C. Brosch, A. Lehmann and A. Mengistu

Department of Anaesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany

* Corresponding author. E-mail: boldtj{at}gmx.net

Accepted for publication November 10, 2008.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
Background: This study compared the effects of a potato-based hydroxyethyl starch (HES) with those of a maize-derived HES preparation on coagulation in cardiac surgery patients.

Methods: Sixty patients undergoing elective cardiac surgery with cardiopulmonary bypass were allocated randomly to receive either a potato-derived HES (6% HES 130/0.42) (n=30) or a waxy-maize-derived HES (6% HES 130/0.4) (n=30) given to keep pulmonary capillary wedge pressure/central venous pressure between 12 and 14 mm Hg until the second postoperative day (POD). A four-channel thrombelastography analyzer was used to measure rotation thrombelastometry (ROTEM®) and whole blood aggregometry was used to assess the effects on platelet function.

Results: Potato HES 2990 (340) ml and maize HES 2890 (350) ml were given on the second POD. Standard coagulation (e.g. fibrinogen and antithrombin III) did not differ between the groups. Blood loss and need for transfusion of blood/blood products did not differ. Coagulation time (intrinsic/extrinsic CT) and clot formation time (intrinsic/extrinsic CFT) increased similarly after surgery and after 5 h, but recovered completely by the first and second POD. Clot firmness was similar in both groups. Platelet function induced by three inductors decreased significantly after surgery, but without significant differences between the two groups. Platelet function had recovered fully by the first POD.

Conclusions: Both HES preparations showed similar effects on thrombelastometry and platelet function. As blood loss and need for the use of blood products were also similar, both potato- and maize-derived HES preparations can be safely used in cardiac surgery with regard to haemostasis.

Keywords: blood, coagulation; complications, coagulopathy; fluids, i.v.; pharmacology, hydroxyethyl starch; surgery, cardiac


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 References
 
Hydroxyethyl starch (HES) is a widely used plasma substitute for correcting hypovolaemia.1 HES preparations differ with regard to concentration (hypo-oncotic: 3%; iso-oncotic: 6%; and hyper-oncotic: 10%), mean molecular weight [MW, low-molecular weight-HES: 70 kDa; medium-molecular weight-HES: 130–260 kDa; and high-molecular weight (HMW)-HES: >450 kDa], molar substitution [MS (low: <0.5; medium: 0.5; and high: >0.5)], ratio of the C2/C6 hydroxyethylation, the solvent (balanced vs unbalanced HES prepared in saline), and the origin (potato or waxy-maize starch). There have been reports that HES from different plant sources may have different physico-chemical characteristics that lead to different clinical properties,2–4 especially with regard to coagulation.5 As the influence of the origin of HES on coagulation in the clinical setting is still an open issue, this study was designed to compare the influence of potato- or waxy-maize-derived HES on coagulation, including platelet function in patients undergoing cardiac surgery.


   Methods
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 Abstract
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 Methods
Results
 Discussion
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After approval of the Institutional Review Board (IRB) and written informed consent, 50 consecutive patients undergoing elective, first-time cardiac surgery using cardiopulmonary bypass (CPB) were studied. Serum creatinine concentration of >2.0 g dl–1, chronic oliguric/anuric renal dysfunction requiring dialysis, liver dysfunction (aspartate amino-transferase >40 U litre–1 and alanine aminotransferase >40 U litre–1), and chronic use of corticosteroids were exclusion criteria.

Before operation, the patients were randomized using a sealed envelope system to receive either a potato-derived HES preparation with an MW of 130 kDa, an MS of 0.42, and a C2/C6 ratio of 6:1 dissolved in saline solution (6% HES 130/0.42; Venofundin®; B. Braun, Melsungen, Germany) (n=25) or a waxy-maize-derived HES preparation with an MW of 130 kDa, an MS of 0.42, and a C2/C6 ratio of 9:1 dissolved in saline solution (6% HES 130/0.4; Voluven®; Fresenius-Kabi, Bad Homburg, Germany) (n=25). Fluids were administered perioperatively and during the first 48 h after surgery, when mean arterial pressure (MAP) was <60 mm Hg and pulmonary capillary wedge pressure (PCWP) or central venous pressure [CVP, after removal of the pulmonary artery catheter at the second postoperative day (POD)] was <10 mm Hg (aim: 12–16 mm Hg). In addition to HES, Ringer's lactate (RL) was given in a 1:1 ratio. During surgery, 250 ml h–1 of RL was administered routinely in both groups.

Weight-related doses of sufentanil, midazolam, and pancuronium bromide were used for induction and maintenance of anaesthesia. A non-pulsatile pump and a membrane oxygenator were used for CPB. The circuit was primed with 1000 ml of RL and 500 ml of the allocated potato-derived 6% HES 130/0.42 or maize-derived 6% HES 130/0.4. Tranexamic acid (2 g as a bolus after induction of anaesthesia followed by a continuous infusion of 6 mg kg–1 h–1, 1 g added to the priming) was used in all patients. Temperature was kept at mild hypothermia (bladder temperature >33oC) and a flow rate of 2.4 litre min–1 m–2 was used. MAP was kept between 50 and 70 mm Hg with norepinephrine as required. To maintain the filling volume of the circuit, the allocated HES was added. If the haemoglobin (Hb) decreased to <7 g dl–1, packed red blood cells (PRBC) were given. During weaning off bypass, as much pump blood as necessary to keep PCWP between 10 and 14 mm Hg was infused. At the end of CPB, the blood from the CPB circuit was salvaged (cell saving system) and re-transfused after sternal closure. Shed mediastinal blood was not re-transfused in the postoperative period.

After surgery, all patients were transferred to the intensive care unit (ICU) and controlled mechanical ventilation was continued. The trachea was extubated when the patient was haemodynamically stable, temperature was >36oC, and adequate spontaneous respiration was maintained. Blood loss by suction (intraoperatively) and drainage (after operation) was also documented.

After operation, the respective HES was given when MAP was <60 mm Hg and PCWP (first POD) or CVP (after removal of the pulmonary artery catheter) was <10 mm Hg. PRBC were given if haemoglobin was <9 g dl–1, fresh frozen plasma (FFP) was given only when bleeding occurred with an activated partial thromboplastin time (aPTT) >60 s, despite a normal activated clotting time. Epinephrine or dobutamine were used when MAP was <60 mm Hg and cardiac index (CI) was <2.5 litre min–1 m–2 in spite of sufficient volume infusion (target for CI: 2.5–3.0 litre min–1 m–2). Norepinephrine was administered when systemic vascular resistance (SVR) was <600 dyn s cm–5 and MAP was <60 mm Hg (target for SVR: 600–800 dyn s cm–5). The patient’s perioperative management was carried out by physicians blinded to the purpose of the study.

Haemodynamics
Heart rate, MAP, pulmonary artery pressure, PCWP, CVP, and cardiac output (using a pulmonary artery catheter) were monitored and derived haemodynamic measures (SVR and CI) were calculated using the standard formulae.

Thrombelastography
A four-channel thrombelastography analyzer was used to measure rotation thrombelastometry (ROTEM®, Pentapharm, Munich, Germany). The ROTEM® system uses a different power transduction system to conventional thrombelastography (TEG®) machines that makes it less susceptible to mechanical stress, movement, and vibrations.6 ROTEM® analysis relies on continuous measurement of clot firmness, allowing the determination of the onset of coagulation [coagulation time (CT), standard TEG®: reaction time (r)], kinetics of clot formation [clot formation time (CFT), standard TEG®: CT (k)], clot strengthening [slope of tangent at 2 mm amplitude (standard TEG®: alpha slope between r and k)], and maximum clot firmness (MCF), standard TEG®: maximum amplitude (MA)]. Clot formation was measured after recalcification of 300 µl of whole blood (20 µl of calcium chloride 0.2 M) and adding thromboplastin-phospholipid (20 µl) to monitor the intrinsic system IntrinsicROTEM® is similar to aPTT in whole blood. Clot formation was also monitored after addition of calcium chloride to 300 µl of whole blood and addition of liquid stable thromboplastin reagent derived from rabbit brain (i.e. tissue factor+phospholipids) (20 µl) for monitoring the extrinsic system (ExtrinsicROTEM®). All measurements were performed at 37°C 60 min after blood withdrawal by the same (blinded) individual.

Whole blood aggregometry
To assess platelet function, we used a whole blood platelet function analyzer (Multiplate®, Dynabyte Medical, Munich, Germany). This is based on the technique of impedance aggregometry7 and measures electrical impedance between electrodes immersed in whole blood. Blood is stirred using an electromagnetic stirrer by 800 rpm. The attachment of platelet aggregates to the electrodes increases the impedance between them. The change of the impedance is transformed to arbitrary aggregation units (AU) and plotted against time. In contrast to optical aggregometry, centrifugation is not needed and whole blood aggregometry (WBA) tests platelet function under more physiological conditions than platelet aggregometry using platelet-rich plasma. The system allows assessment of platelet function in whole blood samples after activation by adenosine diphosphate (ADP), thrombin receptor-activating protein (TRAP), and collagen (COL). Three hundred microlitres of blood were mixed with 300 µl of pre-warmed isotonic saline solution. After incubation for 3 min, 20 µl of activating substrate was added to the probe. Activated platelet function was recorded for 6 min. The Multiplate® analyzer allows duplicate measurement of each probe. The computer analysed the area under the curve (AUC) of the clotting procedure of each measurement and calculates the mean values. We performed three tests using ADP (ADPTest® 2 mM ml–1, Instrumentation Laboratory, Munich, Germany), TRAP (TRAPTest® 1 mM ml–1, Instrumentation Laboratory, Munich, Germany), and COL (COLTest® 100 µg ml–1, Instrumentation Laboratory, Munich, Germany) for every sample. Measurements were performed within 30 min of blood withdrawal.

Sample size was determined before the study by a power analysis based on a previously published study on HES and coagulation assessed by TEG®.8 To obtain a power of 80% with an estimated difference between the groups of 10% and an SD of 15%, a sample size of 30 patients was determined with a type I error of 0.05. Data are presented as mean and SD unless otherwise indicated. {chi}2 analyses with Fisher’s exact tests were used for categorical data. A non-parametric test (Wilcoxon rank-sum) was used for variables that were not normally distributed (detected by Kolmogorov–Smirnov test; e.g. the use of blood products). Continuous, normally distributed data were compared using paired and unpaired Student’s t-test or analysis of variance for repeated measures (followed by Scheffé’s test). The Bonferroni correction was applied when multiple comparisons were made. Continuous, non-normally distributed data were compared using the Wilcoxon test. A P-value of <0.05 was considered significant.


   Results
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 Methods
 Results
Discussion
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 References
 
All 50 enrolled patients completed the study and their data analysed. The patients did not differ with regard to biometric data, preoperative medication, type and time of surgery, anaesthesia, and outcome. None of the patients died within the study period or during their hospital stay (Table 1).


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  		Table 1 Patient characteristics and data from the perioperative period. CABG, coronary artery bypass grafting; AVR, aortic valve replacement; MVR, mitral valve replacement; f, female; m, male; CPB, cardiopulmonary bypass; LVEF, left ventricular ejection fraction; LVDP, left ventricular end-diastolic pressure; First POD, first postoperative day; ICU, intensive care unit; ACE, angiotensin-converting enzyme; AT, angiotensin; mean (SD)

 
A total of 2990 (340) ml of the potato-derived and 2890 (350) ml of the maize-derived HES were administered by the second POD (Table 2). There was no significant difference with respect to urine output, blood loss, the use of blood (PRBC) and blood products (FFP) between the two groups (Table 2). Haemodynamic measurements, need for inotropic support, and the use of vasopressors did not differ between the groups throughout the study period.


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  		Table 2 Fluid in- and output (cumulative). {dagger}Including priming; HES, hydroxyethylstarch; FFP, fresh frozen plasma; PRBC, packed red blood cells; POD, postoperative day; mean (SD)

 
Standard coagulation variables did not differ between the two groups at any point (Table 3).


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  		Table 3 Standard coagulation data. aPTT, activated partial thromboplastin time; ATIII, antithrombin III

 
Thrombelastography
IntrinsicROTEM®: CT and CFT were within normal range at baseline in both groups (Fig. 1). Both groups showed a similar pattern of change after surgery and at 5 h, with significant increases in CT and CFT. On the first and second POD, both CT and CFT had returned to baseline values. MCF and alpha angle remained normal throughout the study period in both groups (Fig. 2).


Figure 1
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  		Fig 1 Changes in CT using extrinsic activation (ExtrinsicROTEM®). (A) CT, onset of coagulation (normal value: 42–74 s); (B) CFT, clot formation time (normal value: 46–148 s); mean (SD); *P<0.05 different from baseline data.

 


Figure 2
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  		Fig 2 Changes of (A) alpha angle (slope of tangent at 2 mm amplitude; normal value: 63–81°) and (B) maximum clot firmness (MCF; normal value: 49–72 mm) using extrinsic activation (ExtrinsicROTEM®). Mean (SD).

 
ExtrinsicROTEM®: At baseline, CT and CFT were within normal range in both HES groups (Fig. 3). Both increased significantly after surgery and at 5 h, but without significant differences between the groups. CT and CFT had returned to baseline values on the first and second POD. MCF and alpha angle remained normal throughout (Fig. 4).


Figure 3
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  		Fig 3 Changes in CT using intrinsic activation (IntrinsicROTEM®). (A) CT, onset of coagulation (normal value: 137–246 s); (B) CFT, clot formation time (normal value: 40–100 s). Mean (SD); *P<0.05 different from baseline data.

 


Figure 4
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  		Fig 4 Changes of (A) alpha angle (slope of tangent at 2 mm amplitude; normal value: 71–81°) and (B) maximum clot firmness (MCF; normal value: 52–72 mm) using intrinsic activation (IntrinsicROTEM®). Mean (SD).

 
Whole blood aggregometry
ADP-induced platelet aggregation was normal at baseline in both groups and decreased significantly after surgery in both groups (Fig. 5). After surgery, ADP-induced platelet function significantly decreased in both groups. On the first and second POD, ADP-induced WBA returned to baseline in both groups. Mean ADP-induced platelet aggregation was within normal range throughout the study period.


Figure 5
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  		Fig 5 Changes in WBA using (A) ADP (normal value: 369–1180), (B) TRAP (normal value: 927–1565), and (C) COL (normal value: 546–1134) as stimulators. AUC, arbitrary aggregation units (ohmxmin). Data are presented as box-and-whisker plots (25th and 75th percentiles; 5th and 95th percentiles; dash, median; open square, mean). *P<0.05 different from baseline data; dotted line indicates normal range.

 
In both groups, TRAP-induced WBA was normal at baseline, was significantly lower after surgery (Fig. 5) but had recovered by 5 h after surgery, and was within normal range on the first and second POD. COL-induced WBA was lower than normal in both groups, but showed a similar pattern of decrease and recovery (Fig. 5).


   Discussion
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 Introduction
 Methods
 Results
 Discussion
Funding
 References
 
Objections to the use of HES to correct hypovolaemia in cardiac surgery are mainly due to reports of coagulation disturbances and, consequently, increased bleeding and the use of blood or blood/products.9–12 Studies showing compromised coagulation and increased bleeding are mostly based on the use of a first-generation, HMW-HES preparation (MW >450 kDa) with a high degree of MS (>0.7) (Hetastarch).13 14 This preparation has been demonstrated to induce a type I von Willebrand-like syndrome with decreased factor VIII coagulant activity and von Willebrand’s factor antigen and factor VIII-related ristocitin cofactor. Platelet function is also significantly altered by this type of HES.13 15 As the result of these reports, the Food and Drug Administration (FDA) approved a major change in the labelling of 6% Hetastarch in saline, applying specifically to CPB surgery16 and not recommending its use in this situation. Various modifications to HES have resulted in significantly fewer effects on coagulation.13 17 18 It is apparent that greater adverse effects on blood coagulation are associated with a higher MW, higher MS, and higher C2/C6-ratio.13 19 20 Consequently, HES preparations with a lower MW (130 kDa) and a lower MS (<0.5) have been developed.13

One unresolved issue regarding the safety and efficacy of HES is the effect of the source of the HES preparation. Waxy-maize- and potato-based HES preparations differ with regard to their chemical structure and physico-chemical characteristics.2 Although equivalent to HES 130/0.4/9:1 (maize HES) in terms of colloid oncotic and haemodilution effects, HES 130/0.42/6:1 (potato HES) has the fastest clearance from the circulation.3 The maize-based preparation has a higher mean degree of branching and a lower degree of esterification with phosphoric acid compared with potato-based preparations.3 Potato-derived HES 130/0.42 contains less amylopectin (about 80%) than a maize-derived HES 130/0.4 preparation (about 99%).3 21 Potato-based HES 130/0.42 contains about 20% amylase compared with about 1% in the maize-based HES 130/0.4. The possible influence of these differences on haemostasis was the focus of the present study.

This is the first clinical study looking at the effect of the origin of HES preparations on coagulation. The major finding of our study was that ~3 litre of a potato-HES given over 48 h to maintain normovolaemia in cardiac surgery patients had similar effects on thrombelastometry and WBA as a similar volume of a maize-derived HES. Immediately after surgery and at 5 h, clotting time (intrinsic/extrinsic CT), CFT (intrinsic/extrinsic CFT), and platelet aggregation were reduced, mostly, however, without leaving normal range. Markers for clot strengthening (alpha angle) and MCF were not altered significantly by either HES preparation. Blood loss and need of transfusion of PRBC or FFP were not different. These results are in agreement with a study in 20 patients undergoing elective vertebral disc surgery in whom the effects of ~1 litre of 6% HES 200/0.5 from potato were compared with 6% HES 200/0.5 from maize.21 Despite physico-chemical differences of the two HES solutions, there were no clinically apparent effects on plasma coagulation (e.g. factor VIII:c and vWF) and platelet function.

In contrast to our results, an in vitro study of old-style HES preparations on coagulation5 used progressive haemodilution (30% and 60%) with potato-derived 6% HES 200/0.5 and maize-derived 6% HES 200/0.5 on thrombelastography (TEG®) in 80 patients. For all TEG® data, both at 30% and 60% haemodilution, potato HES induced a significantly greater impairment of in vitro coagulation than maize HES (e.g. greater increase in r and k, a more pronounced decrease in MA and alpha angle).

A possible criticism of our study is that not only the source of the two HES preparations differed, but also the C2/C6 ratio was different (potato HES: 6:1; maize HES: 9:1). In vitro coagulation studies (20%, 40%, and 60% dilution) using thrombelastography (TEG®) and different HES preparations demonstrated that increasing MS compromised blood coagulation more than modifications of MW.8 No significant differences on coagulation between HES solutions with the same MS substitution but different C2/C6 ratios were found. Thus, it is unlikely that the results of our study were influenced by the different C2/C6 ratio.

We did not assess effects other than coagulation, for example, accumulation, haemodynamics or organ function, or other safety issues. A large number of studies with maize-derived HES 130/0.4 show its safety in a variety of clinical settings including cardiac surgery patients even when given in high doses.20 22 In contrast, similar safety studies on potato-derived HES 130/0.42 are largely missing.

In conclusion, a volume replacement strategy for cardiac surgery patients using a potato-derived HES 130/0.42 or a maize-derived HES 130/0.4 found no differences in the effect on thrombelastometry and platelet function measured by WBA. As blood loss and the use of blood/blood products were also similar, it would appear that both HES preparations can be used safely in cardiac surgery patients. The equivalence of these preparations with regard to other clinically relevant issues, such as renal function, haemodynamic changes, and safety, still needs to be assessed.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
References
 
This study was supported only by a hospital grant.


   References
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 Abstract
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 Methods
 Results
 Discussion
 Funding
 References
 
1 Schortgen F, Deye N, Brochard L, CRYCO Study Group. Preferred plasma volume expanders for critically ill patients: results of an international survey. Intensive Care Med (2004) 30:2222–9.[CrossRef][Web of Science][Medline]

2 Sommermeyer K, Cech F. Differences in chemical structures between waxy maize- and potato starch-based hydroxyethyl starch volume therapeutics. Transfus Altern Transfus Med (2007) 9:127–33.[CrossRef]

3 Lehmann G, Marx G, Förster H. Bioequivalence comparison between hydroxyethyl starch 130/0.42/6:1 and hydroxyethyl starch 130/0.4/9:1. Drugs R D (2007) 8:229–40.[CrossRef][Medline]

4 Jungheinrich C, Neff TA. Pharmacokinetics of hydroxyethyl starch. Clin Pharmacokinet (2005) 44:681–99.[CrossRef][Web of Science][Medline]

5 Jamnicki M, Zollinger A, Seifert B, Popovic D, Pasch T, Spahn DR. The effect of potato starch derived and corn starch derived hydroxyethyl starch on in vitro blood coagulation. Anaesthesia (1998) 53:638–44.[CrossRef][Web of Science][Medline]

6 Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg (2008) 106:1366–75.[Abstract/Free Full Text]

7 Mengistu AM, Wolf MW, Boldt J, Röhm KD, Lang J, Piper SN. Evaluation of a new platelet function analyzer in cardiac surgery: a comparison of modified thromboelastography and whole-blood aggregometry. J Cardiothorac Vasc Anesth (2008) 22:40–6.[CrossRef][Web of Science][Medline]

8 von Roten I, Madjdpour C, Frascarolo P, et al. Molar substitution and C2/C6 ratio of hydroxyethyl starch: influence on blood coagulation. Br J Anaesth (2006) 96:455–63.[Abstract/Free Full Text]

9 Niemi TT, Suojaranta-Ylinen RT, Kukkonen SI, Kuitunen AH. Gelatin and hydroxyethyl starch, but not albumin, impair hemostasis after cardiac surgery. Anesth Analg (2006) 102:998–1006.[Abstract/Free Full Text]

10 Wilkes MM, Navickis RJ, Sibbald WJ. Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding. Ann Thorac Surg (2001) 72:527–33.[Abstract/Free Full Text]

11 Scharbert G, Deusch E, Kress HG, Greher M, Gustorff B, Kozek-Langenecker SA. Inhibition of platelet function by hydroxyethyl starch solutions in chronic pain patients undergoing peridural anesthesia. Anesth Analg (2004) 99:823–7.[Abstract/Free Full Text]

12 Treib J, Haass A, Pindur G. Coagulation disorders caused by hydroxyethyl starch. Thromb Haemost (1997) 78:974–83.[Web of Science][Medline]

13 Kozek-Langenecker SA. Effects of hydroxyethyl starch solutions on hemostasis. Anesthesiology (2005) 103:654–60.[CrossRef][Web of Science][Medline]

14 de Jonge E, Levi M. Effects of different plasma substitutes on blood coagulation: a comparative review. Crit Care Med (2001) 29:1261–7.[CrossRef][Web of Science][Medline]

15 Franz A, Bräunlich P, Gamsjäger T, Felfernig M, Gustorff B, Kozek-Langenecker SA. The effects of hydroxyethyl starches of varying molecular weights on platelet function. Anesth Analg (2001) 92:1402–7.[Abstract/Free Full Text]

16 Haynes GH, Havidich JE, Payne KJ. Why the Food and Drug Administration changed the warning label for hetastarch. Anesthesiology (2004) 101:560–1.[CrossRef][Web of Science][Medline]

17 Entholzner EK, Mielke LL, Calatzis AN, Feyh J, Hipp R, Hargasser SR. Coagulation effects of a recently developed hydroxyethyl starch (HES 130/0.4) compared to hydroxyethyl starches with higher molecular weight. Acta Anaesthesiol Scand (2000) 44:1116–21.[CrossRef][Web of Science][Medline]

18 Haisch G, Boldt J, Krebs C, Suttner S, Lehmann A, Isgro F. Influence of a new hydroxyethylstarch preparation (HES 130/0.4) on coagulation in cardiac surgical patients. J Cardiothorac Vasc Anesth (2001) 15:316–21.[CrossRef][Web of Science][Medline]

19 Thyes C, Madjdpour C, Frascarolo P, et al. Effect of high- and low-molecular-weight low-substituted hydroxyethyl starch on blood coagulation during acute normovolemic hemodilution in pigs. Anesthesiology (2006) 105:1228–37.[CrossRef][Web of Science][Medline]

20 van Zundert AAJ, Mythen MC, Kerkkamp HEM, Mortier EP. Volume therapy. Is there an ideal colloidal solution? CPD Anaesthesia (2006) 8:131–49.

21 Sefrin P, Rauch S, Zieglmeyer C. Changes in blood coagulation in treatment with hydroxyethyl starch. Anaesthesiol Reanim (1998) 23:149–56.[Medline]

22 Kasper SM, Meinert P, Kampe S, et al. Large-dose hydroxyethyl starch 130/0.4 does not increase blood loss and transfusion requirements in coronary artery bypass surgery compared with hydroxyethyl starch 200/0.5 at recommended doses. Anesthesiology (2003) 99:42–7.[CrossRef][Web of Science][Medline]


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