The Effects of Hydroxyethyl Starch 130/0.

4 (6%) on Blood Loss and Use of Blood Products in Major Surgery: A Pooled Analysis of Randomized Clinical Trials
Sibylle A. Kozek-Langenecker* Cornelius Jungheinrich** Wilhelm Sauermann Philippe Van der Linden
BACKGROUND: The effects of different types of hydroxylethyl starch (HES) on blood coagulation closely depend on their physicochemical properties. HES with lower molar substitution and a lower in vivo molecular weight interferes relatively little with hemostasis and therefore results in lower perioperative blood losses and red blood cell (RBC) transfusion. To test this hypothesis, we analyzed pooled data from all available studies in major surgery comparing 6% HES 130/0.4 and 6% HES 200/0.5 from waxy maize starch. METHODS: Estimated blood loss, drainage loss, calculated blood loss, transfused blood product volumes, and coagulation variables were examined for 24 h after the start of surgery. Groups were compared using analysis of variance, evaluating several covariates. RESULTS: Four-hundred-forty-nine patients from seven clinical trials were analyzed, 228 received HES 130/0.4, and 221 received HES 200/0.5. For HES 130/0.4 patients, when compared to HES 200/0.5 patients, the estimated blood loss was reduced by 404 mL [P 0.006], drainage loss was 272 mL less [P 0.009], and calculated RBC loss was 149 mL less [P 0.003]. RBC transfusion volumes were also lower for HES 130/0.4 by 137 mL [P 0.004]. In the early postoperative phase, HES 130/0.4 was found to exert significantly less effect on measures of coagulation, especially activated partial thromboplastin time and von Willebrand factor (antigen and ristocetin cofactor), than HES 200/0.5. CONCLUSIONS: Blood loss and transfusion requirements can be significantly reduced in major surgery when using third generation HES 130/0.4 (Voluven) compared to second generation waxy maize starch HES 200/0.5. Since HES 130/0.4 and HES 200/0.5 were found similar regarding volume efficacy in other studies, HES 130/0.4 is recommended in this clinical setting.
(Anesth Analg 2008;107:38290)

aintaining adequate circulating blood volume and tissue perfusion is important during major surgery. Both crystalloids and colloids can be used but may influence coagulation beyond hemodilution.1,2 Crystalloids have been reported to have pro-coagulant properties at low degrees of hemodilution.2 Among colloids, hydroxyethyl starch (HES) products have potential effects on clot formation,35 humoral coagulation factors,6 platelet function,711 and clot polymerization.12,13 These effects have been reviewed14 and
From the *Department of Anesthesiology, General Intensive Care and Pain Control, Vienna Medical University, Vienna, Austria; **Medical Affairs, Fresenius Kabi, Bad Homburg, Germany; DATAMAP GmbH (Biostatistics Institute), Freiburg, Germany; and Department of Anesthesiology, CHU Brugmann-HUDERF, Brussels, Belgium. Accepted for publication April 15, 2008. Supported by Fresenius Kabi. Address of correspondence and reprint requests to Sibylle KozekLangenecker, Department of Special Anesthesiology and Pain Management, Vienna Medical University, Wa hringer Gu rtel 18-20, 1090 Vienna, Austria. Address e-mail to sibylle.kozek@meduniwien.ac.at. Copyright 2008 International Anesthesia Research Society
DOI: 10.1213/ane.0b013e31817e6eac

depend on the pharmacokinetic properties of the specific HES type used, which in turn determine the HES plasma concentrations over time, present or absent plasma accumulation, in vivo molecular weight (Mw), and maximum doses.1517 Since the first HES generation (hetastarch, labeled e.g. as HES 450/0.7, 550/0.7, 670/0.75), new formulations have been developed to improve the safety profile of HES, especially regarding coagulation. Until recently, pentastarch (HES 200/0.5), a second generation HES, was used as a standard in intravascular volume therapy with artificial colloids in many European countries for about 20 yr. HES 130/0.4 is the latest generation of the commercially available HES solutions. It is characterized by a mean in vitro Mw of 130,000 20,000 Da, a molar substitution (MS) of 0.4, and a C2/C6 ratio of about 9:1. The low MS is the primary determinant of increased metabolic degradation, the in vitro Mw playing a less important role. The increased C2/C6 ratio partially offsets the effect of the reduced Mw, since a high C2/C6 ratio decreases the rate of hydrolysis by -amylase. Such a HES solution is therefore expected to affect coagulation less and reduce
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Figure 1. Search strategy. *Reviews, Case Reports, Letters,

Conference Papers as defined by the data bases; non-human, in vitro, ex vivo, case reports, reviews (not pre-defined in the data bases); pharmacokinetics, pharmacodynamics, volunteers, retrospective studies, meta-analyses. **Studies not using hydroxyethyl starch (HES) made of waxy maize starch, control drug other than HES, comparison other than HES 130/0.4 versus HES 200/0.5, uncontrolled studies. ***No perioperative blood loss or no blood loss data; more than one publication of the same study population.

blood loss and blood transfusion when compared to older HES solutions, such as pentastarch (HES 200/0.5), characterized by a higher MS and Mw. The purpose of this pooled analysis was to compare HES 130/0.4 (Voluven) and HES 200/0.5 (HAESsteril) from waxy maize starch in terms of perioperative blood loss, allogeneic blood product requirements and coagulation variables in patients undergoing major surgical procedures.

HES, an(a)emia, orthop(a)edic, surgery, volume replacement, blood loss, cardiopulmonary bypass, substitution, and coronary artery bypass. The time period was limited from 1988 to 2006 (wk 50). No language or study design constrains were adopted in conducting the searches. Relevant studies were also included by manual searching for unpublished studies, e.g., all studies used for international regulatory purposes, meeting abstracts. Two-hundred-three articles for more detailed evaluation were available after exclusion of: 1) reviews, case reports, letters, and conference papers as defined by the databases, 2) non-human studies, in vitro, and ex vivo studies still contained in the results despite limiting the search to human studies only, 3) case reports and reviews contained in the results which were not clearly defined as such in the publication type of the searched databases, 4) pharmacokinetic, pharmacodynamic studies, studies with volunteers, 5) retrospective studies, 6) meta-analyses, and 7) studies using starches other than HES. The remaining 129 articles were further checked if they provided comparative data for HES 130/0.4 and HES 200/0.5. Other starch sources (one study using potato starch) were excluded because of the pharmacological differences and the products not being bioequivalent to starch products. Nine articles remained for further consideration. Of these, two studies had to be excluded because they were not at least partially blinded, and no data on blood loss of individual patients were available. The manual search for unpublished data complying with the search profile yielded one study performed for regulatory purposes (HS-1324-DE) that was included in the pooled analysis. Consequently, data from seven studies were finally included in the analysis.1722 All of these studies were at least partially blinded or even fully double-blind (all five studies with preplanned equal colloid volumes in both groups).

Statistical Analysis
The pooled analysis was based on the original single patient data of the seven studies. In contrast, a meta-analysis is only based on mean values and standard deviations for the single studies, mostly taken from publications. A pooled analysis is superior to a meta-analysis, since more information is available and since it allows analyzing the effect of explanatory variables on the response variables. Further, it allows one to define response variables and explanatory variables consistently for all studies. Differences between studies can be accounted for and analyzed by including a study in the statistical model. Response variables were blood loss, drainage loss, calculated red blood cell (RBC) loss, transfused RBC volume, transfused platelets, transfused fresh frozen plasma, and coagulation variables during the first 24 h after the start of surgery. Transfused RBC volume was
2008 International Anesthesia Research Society

METHODS
Studies and Patients
All prospective, randomized, clinical studies comparing 6% HES 130/0.4 (Voluven) and the control solution, 6% HES 200/0.5 (HAES-steril both Fresenius Kabi, Bad Homburg, Germany) have been evaluated. Only trials with surgical indications were considered, since no blood loss in either group was to be expected in situations of hypervolemic treatment, e.g., for sudden hearing loss or stroke. Published and unpublished studies were included only if individual patient data could be retrieved. We used the following search strategy (Fig. 1): 293 publications were identified after consolidation of the EMBASE and MEDLINE search results using the search terms hydroxyethyl starch, hydroxyethylstarch,
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Table 1. Studies Included in the Pooled Analysis Study number

HS-1313-DE (Jungheinrich17) HS-1314-NL (Gallandat18) HS-1318-BE (lckx19) HS-1319-FR (Langeron20) HS-1321-DE (Boldt21) HS-1324-DE Kasper et al. 200322 Total
HES hydroxyethyl starch.

Setting
Orthopedic surgery Cardiac surgery Urologic surgery Orthopedic surgery Cardiac surgery Cardiac surgery Cardiac surgery

Number of patients HES 130/0.4

26 30 20 52 10 31 59 228

Number of patients HES 200/0.5

26 29 20 48 10 30 58 221

defined as the sum of all transfused RBC volumes multiplied by their respective hematocrit (HCT), which was either contained in the database or was assumed to be 0.7 for packed RBC and 0.6 for salvaged blood. Calculated RBC loss, using a modification of the method of Mercuriali and Inghilleri,23 was defined as estimated blood volume (HCT0 hHCT24 h) transfused RBC volume, whereby blood volume was estimated by the formula of Nadler et al.24 Estimated blood loss was defined as the sum of objective losses, e.g., via drainage and swabs plus clinically estimated additional losses. Several possible explanatory variables were analyzed to assess their influence on the response variables. Results were reported as mean sd (SD), median, range and number of observations (N) (quantitative variables) or as absolute and relative frequencies (qualitative variables). The statistical analysis was performed by an analysis of variance with treatment group, study, and explanatory variables as effects. During the analysis planning phase, 22 possible explanatory variables were defined, each of which divided the total patient sample into subgroups. Many of these explanatory variables either led to small subgroups, were confounded with one of the other explanatory variables, or were not considered true explanatory variables in the sense that their outcome was measured after start of treatment (i.e., was a response rather than an explanatory variable). These variables were excluded from the analysis. The model which contained all remaining explanatory variables was termed full model and included treatment group, study and the explanatory variables age, sex, duration of surgery, aspirin administration, and aprotinin at day of surgery. Interactions were investigated for significant variables to assess the uniformity of the treatment effect over subgroups defined by the explanatory variables. Single models including only one explanatory variable and additional treatment group and study were also investigated in order to assess the goodness of fit of the full model and possible confounding of explanatory variables. Statistical results presented here are based on the full model. Data were analyzed using SAS Version 8.2, SAS Institute Inc., Cary, NC.
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Table 2. Demographic Data Variable

n Age (yr) Sex (F/M) Weight (kg) Height (cm) BMI

HES 130/0.4 (6%)

228 60.3 11.4 74/154 76.7 11.1 169.7 8.8 26.6 3.4

HES 200/0.5 (6%)

221 62.4 9.9 75/146 75.6 11.0 169.4 9.4 26.4 3.3

P
0.04* 0.76 0.23 0.64 0.34

Data are presented as mean SD unless otherwise noted. BMI Body Mass Index; n number of patients in the pooled analysis; HES hydroxyethyl starch. P-values are two-sided from Fishers exact test (sex) and an ANOVA with study and treatment as effects (all other parameters). * P 0.05.

Table 3. Volumes of HES Solutions Infused Variable

n HES volume (mL) 2.5 L infused (n) 2.5 L infused (n) HES volume (mL/ kg BW) 35 mL/kg BW (n) 35 mL/kg BW (n)

HES 130/0.4 HES 200/0.5

228 2,546 1,075 129 57% 99 43% 33.2 13.2 133 58% 95 42% 221 2,104 622 183 83% 38 17% 28.0 7.9 194 88% 27 12%

P
0.01* 0.01*

Data are presented as mean SD unless otherwise noted. Higher volumes per kg body weight of HES 130/0.4 compared to HES 200/0.5 were allowed by several study protocols, which expectedly led to a higher exposure to HES 130/0.4. HES hydroxyethyl starch; BW body weight; n number of patients in the pooled analysis. P-values are two-sided from an ANOVA with study and treatment as effects. * P 0.05.

RESULTS
Seven clinical trials fulfilled the pre-defined selection criteria and are listed in Table 1. Four-hundredforty-nine patients were therefore analyzed in a pooled fashion, 228 in the HES 130/0.4 and 221 in the HES 200/0.5 group. All seven studies were prospectively randomized and conducted in settings where high surgical blood losses were anticipated, specifically in cardiac surgery (four studies), major orthopedic surgery (two studies), and urologic surgery (one study). All but two studies were double-blind and had similar maximum doses of study colloids. Studies HS-1324-DE and Kasper et al.22 were blinded until a dose of 33mL/kg body weight, and unblinded only
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Table 4. Blood Loss and Transfusions by Type of Surgery Variable, type of surgery
Estimated blood loss (mL) Cardiac Orthopedic Urologic Total Drainage loss (mL) Cardiac Orthopedic Urologic Total Calculated RBC loss (mL) Cardiac Orthopedic Urologic Total Transfused RBC volumes (mL) Cardiac Orthopedic Urologic Total Transfused platelets (mL) Cardiac Orthopedic Urologic Total Fresh frozen plasma (mL) Cardiac Orthopedic Urologic Total

n
128 78 20 226 118 78 20 216 128 75 20 223 128 78 20 226 128 78 20 226 128 78 20 226

HES 130/0.4
1601 1714 2415 1430 1971 748 1915 1597 930 539 779 639 1971 748 972 679 860 409 798 514 761 241 830 436 383 329 616 505 12 55 430 421 8.6 46.6 0.0 0.0 0.0 0.0 4.9 35.3 116 315 226 438 40 179 147 358

n
127 74 20 221 117 74 20 211 122 73 20 215 127 74 20 221 127 74 20 221 127 74 20 221

HES 200/0.5
1603 1486 3112 2295 3340 3861 2266 2213 1050 850 980 825 3340 3861 1242 1565 930 492 989 842 1109 840 967 664 464 491 786 813 280 775 555 663 12.6 72.4 15.9 98.0 10.0 44.7 13.5 79.8 192 594 156 377 80 358 170 511

P
0.77 0.01* 0.25 0.01* 0.05* 0.07 0.25 0.01* 0.09 0.08 0.20 0.01* 0.06 0.13 0.27 0.01* 0.39 0.39 0.53 0.21 0.13 0.35 0.82 0.47

Data are presented as mean SD unless otherwise noted. HES hydroxyethyl starch; RBC red blood cell; n number of patients for the respective parameter. P-values are two-sided, based on an ANOVA (full model). * P 0.05.

after the colloid dose of 33 mL/kg was reached. In both studies, the HES 130/0.4 group could then receive more study colloid until 50 mL/kg, whereas the HES 200/0.5 control groups had to switch to gelatin. Demographic variables are summarized in Table 2. There was no significant difference in baseline characteristics between the two groups of patients except a slightly higher age in the control group. Table 3 displays the HES volumes given in both groups. Due to the two protocols which mandated unequal HES volumes, the number of patients receiving larger amounts of HES (2.5 L or 35 mL/kg) was about threefold in the HES 130/0.4 group (99 vs 38, and 95 vs 27). Therefore, mean exposure to HES 130/0.4 study solution was higher than to the HES 200/0.5 control solution. Table 4 shows raw means sd for blood loss and transfusion variables, stratified by type of surgery. Results of the pooled statistical analysis are displayed in Figures 25, always referring to the HES 130/0.4HES 200/0.5 difference. Perioperative blood loss was significantly less in the HES 130/0.4 group than in the HES 200/0.5 group. For the clinically evaluated blood loss, the mean estimated difference [95% confidence interval] derived from analysis of variance was 404 [689; 119] mL (P 0.006, Fig. 2). For drainage loss, the mean estimated difference
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Figure 2. Estimated blood loss in pooled analysis and in

single studies, differences hydroxyethyl starch (HES) 130/0.4 HES 200/0.5. Negative values mean less blood loss in the HES 130/0.4 group. Total: Least squares estimates and 95% confidence interval based on Analysis of Variance full model; single study strata: raw means and 95% confidence intervals. For information on single studies refer to Table 1.

was 272 [474; 70] mL (P 0.009; Fig. 3). For the calculated RBC loss, the mean estimated difference was 149 [247; 50] mL (P 0.003; Fig. 4).
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Figure 3. Drainage loss in pooled analysis and in single

studies, differences hydroxyethyl starch (HES) 130/0.4 HES 200/0.5. Negative values mean less drainage loss in the HES 130/0.4 group. Total: Least squares estimates and 95% confidence interval based on Analysis of Variance full model; single study strata: raw means and 95% confidence intervals. For information on single studies refer to Table 1.

Figure 5. Transfused red blood cell volume in pooled analysis and in single studies, differences hydroxyethyl starch (HES) 130/0.4 HES 200/0.5. Negative values mean lower transfused red blood cell volumes in the HES 130/0.4 group. Total: least squares estimates and 95% confidence interval based on Analysis of Variance full model; single study strata: raw means and 95% confidence intervals. For information on single studies refer to Table 1. groups (Table 5). Significant differences were found for the early postoperative phase at 4 8 h after end of surgery. Activated partial thromboplastin time (P 0.02) was shorter in the HES 130/0.4 group, von Willebrand factor-ristocetin cofactor (P 0.04) and von Willebrand factor-antigen (P 0.04) were significantly higher for HES 130/0.4. Mean Factor VIII was also higher for the HES 130/0.4 group but did not reach significance in this pooled analysis. Platelet counts were slightly but significantly higher for HES 130/0.4 patients at this time point and at the end of surgery (P 0.03). Quick values were also slightly higher at 24 h in the HES 130/0.4 group.

DISCUSSION
Figure 4. Calculated red blood cell loss in pooled analysis
and in single studies, differences HES 130/0.4 HES 200/0.5. Negative values mean less red blood cell loss in the HES 130/0.4 group. Total: Least squares estimates and 95% confidence interval based on Analysis of Variance full model; single study strata: raw means and 95% confidence intervals. For information on single studies refer to Table 1.

In line with the results regarding RBC loss, transfused RBC volume was also significantly lower in the HES 130/0.4 group, with a mean estimated difference of 137 [231; 43] mL (P 0.004; Fig. 5). Differences in calculated RBC loss and transfused RBC volume between the two HES groups appeared to increase with the duration of the surgical procedure. Differences in the transfused volume of platelets (7.4 [19.0; 4.1] mL, P 0.21) and FFP (30 [113; 53] mL, P 0.47) were not significant. In the early postoperative period, the coagulation profile also appeared different between the two
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HES 130/0.4 Reduces Bleeding

Our pooled analysis of the different studies having compared HES 130/0.4 and HES 200/0.5 in major surgical procedures demonstrated that the use of HES 130/0.4 is associated with a significant reduction in perioperative blood loss, resulting in a decrease in allogeneic blood transfusion equivalent to about one RBC unit per patient. A pooled analysis of the available single patient data was possible, and not merely a meta-analysis of published data. Results were remarkably homogeneous between studies and consistent for the different variables, with a reduced calculated RBC loss of 149 mL with HES 130/0.4, almost equal to a decreased transfused RBC volume of 137 mL in the same group during the first 24 h after the beginning of surgery. The duration of surgery appeared to be an important factor, since the differences between the two groups became larger with increased surgery time. Univariate analyses, as described in the Methods section, yielded results consistent with the full model.
ANESTHESIA & ANALGESIA

Table 5. Coagulation Variables Variable, time

aPTT (s) End of surgery (EOS) 48 h after EOS 24 h after start Quick (%) (prothrombin time) End of surgery (EOS) 48 h after EOS 24 h after start Thombin time (s) End of surgery (EOS) 48 h after EOS 24 h after start von Willebrand factor (ristocetin cofactor activity, %) End of surgery (EOS) 48 h after EOS 24 h after start von Willebrand factor (antigen, %) End of surgery (EOS) 48 h after EOS 24 h after start Factor VIII C (chromogenic method, %) End of surgery (EOS) 48 h after EOS 24 h after start Fibrinogen (g/L) End of surgery (EOS) 48 h after EOS 24 h after start Platelets ( times 109/L) End of surgery (EOS) 48 h after EOS 24 h after start

HES 130/0.4
46.1 2.7 34.8 1.2 38.8 1.7 71.9 2.3 77.3 1.6 82.0 1.8 14.8 1.3 18.4 2.1 13.6 1.2 52.1 28.2 124.6 6.6 197.7 37.7 100.4 4.4 111.8 6.2 139.2 30.7 80.5 11.0 104.7 6.2 115.2 17.7 1.78 0.10 1.85 0.11 3.17 0.16 158 5 168 5 166 5

HES 200/0.5
48.5 2.7 38.3 1.2 39.7 1.8 72.4 2.3 73.7 1.6 79.3 1.9 16.2 1.3 20.2 2.2 13.4 1.3 46.5 27.2 107.4 6.8 164.0 35.4 95.9 4.5a 96.1 6.4 127.1 28.1 80.5 10.4 90.7 6.3 116.8 16.3 1.71 0.10 1.80 0.11 3.18 0.17 150 5 155 5 160 5

HES 130/0.4- HES 200/0.5 95% CI

2.4 6.1; 1.2 3.5 6.5; 0.6 0.9 3.3; 1.5 0.5 3.2; 2.2 3.6 0.2; 7.5 2.7 0.3; 5.2 1.4 4.1; 1.2 1.8 7.0; 3.4 0.2 2.5; 2.9 5.6 12.3; 23.6 17.2 1.0; 33.4 33.7 0.7; 68.1 2.1 10.2; 14.5 15.7 0.6; 30.8 12.1 17.7; 41.9 0.0 9.0; 9.0 14.0 0.7; 28.7 1.6 17.8; 14.7 0.08 0.06; 0.21 0.05 0.16; 0.25 0.01 0.25; 0.22 8 1; 15 13 2; 25 6 1; 13

P
0.19 0.02* 0.47 0.71 0.06 0.03* 0.29 0.49 0.87 0.54 0.04* 0.06 0.73 0.04* 0.42 1.00 0.06 0.85 0.27 0.64 0.92 0.03* 0.03* 0.10

Data are presented as least squares means SE , unless otherwise noted, generated from the ANOVA full model as explained in the methods section. CI condence interval; aPTT activated partial thromboplastin time; HES hydroxyethyl starch. a Estimates SE for this time point from model including treatment and study (because of too low n for full model estimation). * P 0.05.

Therefore, the chosen full model can be judged as robust for this pooled analysis. Differences between HES 130/0.4 and 200/0.5 appear larger than those reported in a previous metaanalysis comparing high in vivo Mw starches (HES 450/0.7), second generation HES 200/0.5, and albumin in cardiac surgery.25 Wilkes et al.25 failed to show a significant difference between HES 200/0.5 and albumin regarding drainage loss (0 included in the 95% CI), but found an overall significant difference of 93 mL (789 487 mL vs 693 350 mL) in favor of albumin compared to the HES products they examined. Although blood product use could not be quantified overall in that meta-analysis, blood product transfusion was lower in the albumin group in about half of the trials included (8/15). Our pooled analysis included three studies performed in cardiac surgery in which drainage loss was reported. In the study in which comparable amounts of study colloids were given (HS-1314-DE), drainage loss was 520 mL less in the HES 130/0.4 group compared to HES 200/0.5 (Fig. 3). In the two other cardiac studies (HS-1324-DE and 22), noninferiority
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of blood loss in the high dose group was proven within these trials, despite a preplanned 50% higher dose of 50 mL/kg HES 130/0.4 compared to 33 mL/kg HES 200/0.5 plus added gelatin. If these high dose HES trials with unequal doses in both groups were removed from the analysis, differences in blood loss and transfusion requirements would have been even higher than observed for the full set of studies. Other studies not covered by our pooled analysis directly compared HES 130/0.4 with crystalloids. In major abdominal surgery, Lang et al. reported similar blood loss and use of blood products for both groups.26 In another study, Boldt et al.1 showed similar blood loss until 24 h for HES 130/0.4 (1180 250 mL) and Ringers lactate solution (1210 350 mL), but higher blood loss for balanced HES 550/0.7 (hetastarch, 1680 270 mL). A similar relation was seen for the use of blood products. Modified thrombelastography was more impaired after hetastarch. A cardiac surgery study by Van der Linden et al.27 compared HES 130/0.4 (n 64; dose 49 18 mL/kg) with modified fluid gelatin (n 68; dose 49 15 mL/kg). Measured blood loss was similar in both
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groups (HES, 19.4 12.3 mL/kg, gelatin, 19.2 14.5 mL/kg), and calculated net RBC loss was also equivalent. Neither the number of patients transfused nor the volume of blood products given differed. This confirmed earlier evidence in cardiac surgery28 and major abdominal surgery.29 Direct comparisons of blood loss after slowly metabolizable hetastarch (MS 0.7) and HES 130/0.4 were performed by Boldt et al.1 and Gandhi et al.30 In the latter study, patients undergoing major orthopedic surgery received either hetastarch in saline (n 51) or HES 130/0.4 (n 49) in a double-blind fashion. RBC transfusion was significantly higher in the hetastarch group (13.8 12.9 mL/kg) compared to HES 130/0.4 (8.0 6.4 mL/kg). The coagulation variables reported in our pooled analysis provide some mechanistic hints to explain the lower blood loss and transfusion requirements observed in patients receiving HES 130/0.4 compared to those receiving HES 200/0.5. Partial thromboplastin time, von Willebrand factor antigen and ristocetin cofactor activity were significantly higher in the early postoperative phase in HES 130/0.4 patients compared to HES 200/0.5 patients. In addition, there was a strong trend in the same direction for Factor VIII. These differences indicated a lower impact of HES 130/0.4 on the plasmatic coagulation system than HES 200/0.5. However, it must be recognized that global coagulation variables alone, such as partial thromboplastin time, Quick (prothrombin time) and thrombin time have a poor sensitivity to predict bleeding complications.31 Slight but statistically significant differences in platelet counts (13/nL at 4 8 h postoperatively) occurred after HES 130/0.4 versus HES 200/0.5 administration (Table 5). Since the static test of platelet count does not correlate to platelet function, this finding allows no definite conclusion on a potential plateletassociated mechanism of reduced bleeding after HES 130/0.4 infusion. Tests of the platelet response to agonists at the cellular level using flow cytometry, and an overall measure of platelet function using the platelet function analyzer, permitted the detection and characterization of HES-induced antiplatelet effects as a function of degradability.7 Higher platelet numbers, together with better preserved platelet reactivity, may account for the reduced bleeding after HES 130/0.4 infusion. Less impairment of the interaction between thrombin, factor XIII, and fibrinogen in the presence of HES 130/0.412,13 may also have resulted in stronger clot polymerization and reduced bleeding. After infusion of HES 130/0.4, which is rapidly metabolized, plasma concentrations and in vivo Mw are lower compared to less metabolized HES products.17 Total body clearance of HES 130/0.4 is about 5 6 times higher than for HES 200/0.5, and 2331 times higher than for hetastarch15,32; renal excretion of HES 130/0.4 is preserved in mild to severe nonanuric renal impairment.33 The combination of increased
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clearance and optimized in vivo Mw of HES 130/0.4 is thought to be responsible for the reduced effects of HES 130/0.4 on coagulation.15,17 In contrast, hetastarch accumulates in plasma.34 High persisting concentrations of a colloid should be avoided, since they are not expected to exert a relevant therapeutic effect but may have adverse effects. The increased therapeutic safety index of HES 130/0.4 compared to less metabolizable starches has been acknowledged by European Union countries and by an increasing number of overseas regulatory authorities by changing the former maximum daily dose from 33 to 50 mL/kg body weight per day.35 Waxy maize starch HES 130/0.4 (Voluven) has recently been approved by the Food and Drug Administration36 at a maximal daily dose of 50 mL/kg. The efficacy of plasma volume substitution by HES 130/0.4 and HES 200/0.5 has been demonstrated to be comparable in several pivotal trials.17,18,20 The extent and duration of the plasma volume effect of HES 130/0.4 were at least as sustained as after hetastarch administration in volunteers when using the radiolabeling technique.37 Efficacy in volume substitution therapy was also found to be similar between hetastarch and HES 130/0.4 during major orthopedic surgery.30 A different pentastarch product, 10% HES 200/0.5 (Hemohes), was associated with higher rates of acute renal failure and renal replacement therapy than was a modified Ringers solution containing 45 mmol/L of lactate in critically ill patients in the recent multicenter VISEP trial.38 In that trial, high cumulative doses were given up to 21 days (median, 70 mL/kg, range not reported), and the dose limitation for that specific product of 20 mL kg1 d1 was significantly exceeded in 100/262 subjects. Ten percent HES 200/0.5 administered in patients with contraindications against the use of HES (e.g., anuric, renal replacement therapy) may explain this observation. Furthermore, hyperoncotic solutions like HES 200/0.5 (10%) may produce renal dysfunction.39 Studies with tetrastarch 130/0.4 (6%) which, in contrast to HES 200/0.5 (10%) is isooncotic and which does not accumulate in plasma, did not show a deterioration of renal function compared to controls when used in volunteers with moderate to severe nonanuric renal failure,33 in elderly patients undergoing major surgery,40 in cardiac and aortic surgery patients with renal dysfunction41 43, and in intensive care patients.44 Limitations of our pooled analysis have to be considered when extrapolating the results to clinical practice. Heterogeneity in study designs of individual trials is a common problem of both pooled analyses and meta-analyses. Also, our total number of patients in the studies is relatively small. Further, crystalloids, additional colloids (such as albumin and gelatin), carrier solutions, as well as transfusion triggers and blood replacement management were not standardized across individual trials. However, since statistically significant and consistent results were obtained
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despite heterogeneous study designs, the clinical effect size of the investigated variable must be high. From the statistical view, conducting a meta-analysis or pooled analysis is justified in such situations especially if (also unknown) heterogeneity is included in the mathematical model as a cofactor. From the clinical view, heterogeneity in the analyzed trials may better represent varying clinical practice compared to one study design with one homogenous fluid and transfusion management. Another limitation of our pooled analysis is that coagulation tests were done in some studies but not in others, time points of blood withdrawal were not identical, and the performed conventional laboratory tests are not sensitive to the pathomechanism of dilutional coagulopathy. However, the present results obtained at similar time slots confirm previous studies313 showing a clear difference between pentastarch and tetrastarch. Considering the observed differences in conventional laboratory tests as indicators, we believe that the conclusion is justified to identify the lower antihemostatic side effects of tetrastarch as the reason for reduced perioperative blood loss. Nevertheless, further studies directly comparing HES 130/0.4 and HES 200/0.5 have to verify this hypothesis by using point-of-care tests sensitive to platelet function, clot formation, and clot polymerization, as well as to the multifactorial nature of bleeding associated with trauma and major cardiac, orthopedic and urologic surgery. In conclusion our data show that blood loss and transfusion requirements can be significantly reduced in patients undergoing major surgery when using third generation HES 130/0.4 (Voluven) compared to second generation starch HES 200/0.5. Since HES 130/0.4 and HES 200/0.5 were found similar regarding volume efficacy in other studies, HES 130/0.4 should be preferred to less rapidly metabolizable HES solutions in prevention and treatment of perioperative hypovolemia, especially if large volumes are required. ACKNOWLEDGMENTS Dr. Sauermann is head of DATAMAP, a Contract Research Organization providing biometrical services. His institutions received funding for biometrical services related to several clinical studies of Fresenius Kabi, all performed according to GCP. Fresenius Kabi, Bad Homburg, Germany, manufactured both materials (6% HES 130/0.4 and 6% HES 200/0.5) discussed in the manuscript. REFERENCES
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35. Swedish Product Information for Voluven. Available at http://www.lakemedelsverket.se/upload/SPC_PIL(Pdf/humspc/ Voluven%20for%20infusion.pdf. Assessed on June 8, 2007 36. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01765.html. Accessed on May 26, 2008. 37. James MF, Latoo MY, Mythen MG, Mutch M, Michaelis C, Roche AM, Burdett E. Plasma volume changes associated with two hydroxyethyl starch colloids following acute hypovolaemia in volunteers. Anaesthesia 2004;59:738 42 38. Brunkhorst FM, Englel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:12539 39. Bartels C, Hadzik B, Abel M, Roth B. Renal failure associated with unrecognized hyperoncotic states after pediatric heart surgery. Intensive Care Med 1996;22:492 4 40. Boldt J, Brenner T, Lehmann A, Lang J, Kumle B, Werling C. Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: comparison of a new starch preparation with gelatin. Intensive Care Med 2003;29:7639 41. Boldt J, Brosch C, Ducke M, Papsdorf M, Lehmann A. Influence of volume therapy with a modern hydroxyethylstarch preparation on kidney function in cardiac surgery patients with compromised renal function: a comparison with human albumin. Crit Care Med 2007;35:2740 6 42. Mahmood A, Gosling P, Vohra RK. Randomized clinical trial comparing the effects on renal function of hydroxyethyl starch or gelatine during aortic aneurysm surgery. Br J Surg 2007; 94:42733 43. Godet G, Lehot J, Janvier G, Steib A, de Castro V, Coriat P. Safety of HES 130/0.4 (Voluven) in patients with prcoperative renal dysfunction undergoing abdominal aortic surgery: a prospective, randomized, controlled, parallel-group multicentre trial. Eur J Anaesthesiol 2008;19 44. Neff TA, Doelberg M, Jungheinrich C, Sauerland A, Spahn DR, Stocker R. Repetitive large-dose infusion of the novel hydroxyethyl starch 130/0.4 in patients with severe head injury. Anesth Analg 2003;96:14539

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