Secondary Logo

Journal Logo

Cardiovascular Anesthesiology: Review Article

Safety of Modern Starches Used During Surgery

Van Der Linden, Philippe MD, PhD*; James, Michael MB ChB, PhD, FRCA, FCA(SA); Mythen, Michael MD FRCA‡§‖; Weiskopf, Richard B. MD

Author Information
doi: 10.1213/ANE.0b013e31827175da

The relative merits of colloids or noncolloidal salt solutions when used for blood volume augmentation remain controversial and appear to be context sensitive. Various starch preparations have been used for this and similar purposes in many clinical circumstances for several decades.1–3 Our understanding of the pharmacokinetic and pharmacodynamic properties of hydroxyethyl starches (HES) has evolved4 so that we now appreciate that both properties vary depending on the starch source and on their chemical composition: degree of substitution, molecular location of substitution, average molecular weight, and molecular weight distribution.5 Consequently, the manufacture of HES has progressed from hetastarches (molar substitution ratio, 0.7), to pentastarches (molar substitution ratio, 0.5), and then to tetrastarches (molar substitution ratio, 0.4 or 0.42). In addition, it is reasonable to consider that different clinical conditions could result in differing effectiveness and safety for these preparations.

The presence of an intact tight glycocalyx/vascular endothelial junction in health provides for the retention of colloids, whereas its impairment in various disorders permits the extravasation of colloids, thus simultaneously increasing the volume of colloid required for resuscitation to that approaching salt solutions6,7 and offering the possibility of adverse effects because of its extravascular presence. The induction of hypervolemia in healthy individuals has also been reported to allow extravasation of colloids.8

Recently, there has been concern regarding possible adverse outcomes when using starch preparations in the intensive care setting, especially in septic patients.9 Prospective, randomized clinical trials10,11 and retrospective analyses9 have suggested that the use of some HES preparations in sepsis adversely affects renal and coagulation function more than does other IV fluids. However, preliminary results from another prospective, randomized study (Crystalloids Morbidity Associated in Severe Sepsis [CRYSTMAS])12 indicated that a lesser volume of a 6% tetrastarch was required than 0.9% sodium chloride (NaCl) to produce hemodynamic stability, without having a difference between the 2 in renal or coagulation function or mortality in patients with severe sepsis. Two large prospective trials have addressed this issue as well: one evaluating a potato-derived 6% 130/0.42 tetrastarch (6S)13 recently reported that 90-day mortality in septic shock is increased in comparison with crystalloid administration. The other, evaluating a maize-derived 130/0.4 tetrastarch, remains in progress (Crystalloid Versus Hydroxyethyl Starch Trial [CHEST]).14

HES is used widely for intravascular volume maintenance or augmentation during surgery. The effectiveness and safety of HES is likely to differ when used in relatively healthy people rather than in septic patients because endotoxic shock or sepsis disrupts vascular integrity in experimental animals15 and patients,16 causing altered distribution of large molecules.17 A recent meta-analysis assessed a 130/0.4 tetrastarch in acutely ill and perioperative patients.18 However, we were unaware of any formal analysis of the data relating to safety emanating from prospective randomized clinical trials using modern tetrastarch products solely in the acute surgical setting, that excluded publications that have been withdrawn. Consequently, we undertook to assess the safety (but not effectiveness) of tetrastarches when used during surgery.


We used a formal search strategy to assess the safety of tetrastarches when used during surgery. We decided a priori to include in our evaluation data only from randomized trials and to focus on the clinical outcomes of renal function, coagulation function, and mortality. For coagulation, our primary measure was that of blood loss. For a secondary measure, we assessed the frequently used surrogate for blood loss: red cell transfusion (volume and fraction of patients receiving red cell transfusion). We decided a priori to extract laboratory assessments of coagulation function, but not to use those as a clinical outcome owing to the uncertain and controversial relationship in the surgical setting between the laboratory and the clinical findings and the greater importance of the latter. For renal assessment, we evaluated the need for renal replacement therapy (RRT) and because of its low incidence and the well-established relationship of renal function to serum creatinine, change or absolute values of the latter as well. Data for urine output were also sought but deemed to be of uncertain clinical importance and, thus, of lesser value than RRT or creatinine, because of the data being influenced by numerous factors other than specific renal impairment. We searched for volunteer trials and clinical trials in adults or children undergoing general and/or regional anesthesia for elective and emergency surgery, and for trauma and burns, where patients received a tetrastarch: either a waxy maize-derived HES 130/0.4 or a potato-derived HES 130/0.42 compared with another intervention such as another colloid, a crystalloid, a blood product, a vasoactive drug, or no other treatment. We searched in all languages. All clinical outcomes were included to avoid missing data of interest that might not have been included in the title, abstract, or key words. We searched MEDLINE, CENTRAL (Cochrane Central Register of Controlled Trials), and EMBASE from January 1, 1997, to December 1, 2011, using the search terms and strategies indicated in Appendix 1. We included all phase 1 to phase 4 trials and randomized clinical trials in patients or volunteers. Volunteer studies were included only if the HES and comparator were given to the volunteer and excluded if the volunteer only supplied a blood sample for ex vivo manipulation and testing. We included studies in which the trial population underwent surgery, trauma, or burns, even when the fluid was given shortly beforehand (e.g., coload for regional anesthesia) or shortly afterward. We excluded trials where the population was not surgical (e.g., cirrhosis, sepsis, stroke) and assessed only primary reports of data and not reviews or meta-analyses.

Appendix 1
Appendix 1

To maximize sensitivity, the search did not attempt to remove duplicate data, except where exactly the same trial or publication appeared on more than one database. Hence, we included data that appeared in a peer-reviewed journal as a conference abstract even when a similar (but not identical) reference appeared later in fully published form. Duplicate data were removed later, when all retrieved publications were examined and evaluated. We did not contact authors to attempt to include any data that they may have gathered, but did not publish, and consequently had not been peer reviewed. We included as well trials that were already known to any of us if they met our inclusion criteria, but had not been found by the electronic searches (Appendix 2).

Appendix 2
Appendix 2

The group met in person on 3 occasions and discussed by telephone and electronic communication the potential value of performing this work to plan the effort, strategy, and organization; to evaluate the results; and to write the article. All of us reviewed the data and contributed to the writing of the article.


Differences in proportions (and odds ratios [ORs], and 95% confidence intervals [CIs]) between those patients receiving a tetrastarch and those receiving a comparator for mortality, for transfusion of allogeneic red cells, and need for RRT were assessed by Fisher exact test (Instat 3 for Macintosh, V3.0b; GraphPad Software, Inc., La Jolla, CA).


The search yielded 213 publications of which 59 were determined to meet the a priori inclusion criteria in the acute surgical environment (excluding abstracts and duplicate publications). These studies included 4529 unique patients who had been randomly allocated to be treated with a tetrastarch (n = 2139) or a comparator (n = 2390). Brand names of various HES products are listed in Appendix 3.

Appendix 3
Appendix 3


Twenty-one studies reported mortality for 1918 randomly allocated patients. There were 11 deaths reported in the 956 patients given a tetrastarch (1.15% [ 95% CI, 0.57%–2.05%] and 22 deaths in the 982 patients given a comparator (2.24% [1.41%–3.37%]. The OR for mortality for HES administration versus all comparators was 0.51 ([0.24–1.05]; P = 0.079; Fig. 1).

Figure 1
Figure 1:
Mortality from all publications reporting such data. Bars are 95% confidence intervals.


Of all reports meeting the a priori criteria, 50 publications randomly allocated patients to receive a tetrastarch or a comparator that included data regarding blood loss, red cell transfusion, or laboratory studies of coagulation (Fig. 2). For analysis of effects of tetrastarch on coagulation and blood loss, studies of trauma were analyzed separately due to trauma-induced changes of coagulation.19 Trials performed in a pure surgical context were evaluated according to their primary outcome measure (see the subsequent paragraphs). Among the 48 surgical studies analyzed, there were 38 randomized clinical trials with data for blood loss, containing 1602 patients randomly allocated to receive a tetrastarch and 1678 allocated to be given another HES, other colloid, or a crystalloid solution (for the purposes of this review, we considered MP4OX, a hemoglobin-based oxygen carrier [HBOC], as a colloid, in as much as it was used in that manner and not for its oxygen-carrying property). There was no suggestion that patients given a tetrastarch had increased blood loss relative to those given other fluids (Fig. 3). Another 3 publications reported information regarding transfusion, but not blood loss, that included 96 patients randomly allocated to receive a tetrastarch and 125 to receive a comparator. In these 3 studies, use of a tetrastarch was not associated with an increase in blood use when compared with albumin or Ringer’s lactate solution but was associated with a decrease in the number of patients transfused when compared with HES 200/0.5.

Figure 2
Figure 2:
Flow chart of reviewed and analyzed publications related to coagulation.
Figure 3
Figure 3:
Ratio of blood loss for patients given a tetrastarch to the blood loss for patients given comparators. The bars are the mean values (95% confidence intervals) of the mean or median group data reported in all publications providing blood loss data for groups of 5 or more trials. n = number of publications providing data; N = number of patients in those trials who were given a tetrastarch; HSA = human serum albumin. Other comparators with <5 trials in a group were MP4OX (a hemoglobin-based oxygen carrier): 2 trials of 385 patients, average blood loss ratio = 0.924; fresh frozen plasma 1 trial, N = 21; blood loss ratio = 1.14; dextran 70 trial, N = 20, blood loss ratio = 0.975. No statistical analyses were performed.

Nine prospective randomized studies compared a saline-based 6% tetrastarch from waxy-maize origin (130/0.4) with other fluids using blood loss as the primary objective (Table 1). All but 1 concerned cardiac surgery, including 2 evaluating pediatric patients and 1 off-pump coronary artery bypass grafting. The other study assessed patients undergoing urological cancer surgery. Only 1 study claimed to be double blind, but the authors did not describe the blinding process.20 None reported an increase in intra- and/or postoperative bleeding. All studies described the transfusion trigger that was applied to patients. The volume of packed red blood cells transfused and the incidence of allogeneic transfusion were comparable between patients randomized to the tetrastarch and those to the control fluid in all reports, except in 1 pediatric study where a significantly smaller fraction of children was exposed to transfusion in the tetrastarch group than that in the 4% albumin group.21

Table 1
Table 1:
Studies Using Blood Loss as the Primary Objective

Twenty prospective randomized studies compared 6% tetrastarches with other fluids using ex vivo coagulation variables as the primary outcome measure. Among these studies, 13 presented data on perioperative blood loss and 9 on perioperative blood transfusion (Table 2). Only 1 trial was double blinded.22 These 13 studies were performed in several surgical contexts: minor surgery, cardiac surgery with and without bypass, and major orthopedic and abdominal procedures. Only 1 study concerned pediatric patients.23 Among these studies, 8 used viscoelastic tests (thromboelastograph, TEG®, Haemonetics, Braintree, MA; or rotational thromboelastometer, ROTEM®, Tem Innovations GmbH, Munich, Germany); 2 used laboratory coagulation variables, 1 flow cytometry, 1 a combination of viscoelastic tests and laboratory coagulation variables, and 1 a combination of viscoelastic tests and flow cytometry. Whatever the coagulation tests assessed, none of these 13 studies reported a higher blood loss associated with the use of tetrastarches. Two studies22,24 reported that tetrastarch was associated with less perioperative blood loss than with pentastarch. None of the studies reported a difference in packed red blood cell volume transfused between patients treated with the tetrastarch and those treated with the other colloids. One study performed in patients undergoing spine surgery25 reported a lower incidence of allogeneic blood exposure in patients receiving the tetrastarch compared with those receiving a balanced hetastarch solution. Seven studies26–32 compared a waxy maize-derived 130/0.4 tetrastarch with pentastarches, hexastarch, hetastarch, modified fluid gelatin, human albumin, and isotonic saline. Of these studies, 5 used viscoelastic tests, 1 laboratory coagulation tests, and 1 flow cytometry. Because none of them reported any results on blood loss and allogeneic blood exposure, the ex vivo coagulation results of effects of these various studied fluids could not be interpreted from a clinical perspective.

Table 2
Table 2:
Studies Using Ex Vivo Coagulation Variables as the Primary Objective and Reporting Blood Loss Data

Fifteen prospective randomized studies compared 130/0.4 tetrastarch with other fluids to maintain protocol-defined hemodynamic stability. Thirteen studies reported data for perioperative blood loss and 11 for allogeneic blood transfusion (Table 3). Nine trials were double blinded. Surgical procedures included cardiac surgery (with and without cardiopulmonary bypass), major abdominal surgery, and orthopedic surgery. One was performed in children younger than 2 years. In 11 studies, the volume of tetrastarch required to maintain hemodynamic stability was not different than the volume of the control fluid. One study33 compared the tetrastarch with 20% human albumin, reporting a significantly higher volume of starch required to optimize invasive hemodynamic variables, including cardiac filling pressure and cardiac output. Two studies34,35 compared the tetrastarch solution with an HBOC, MP4OX, given at a dose of 250 to 500 mL to prevent or to treat hypotension induced by spinal anesthesia. Among these 13 studies, 11 did not report a difference in perioperative blood loss between the groups of patients treated with the tetrastarch and the groups with the control fluid. In the 2 other studies, the use of tetrastarch was associated with significantly less perioperative blood loss when compared with a pentastarch36 or a 20% human albumin solution.33 None of the 11 studies presenting data for the volume of packed red blood cells transfused reported a difference between the tetrastarch and the control fluid groups. However, 1 study performed in major orthopedic surgery37 reported a significantly lower total volume of erythrocytes transfused including allogeneic, autologous, and salvaged red cells in patients treated with the 130/0.4 tetrastarch compared with a hetastarch. Among the 7 studies that presented data on the incidence of allogeneic blood transfusion, 5 reported no difference between the patients treated with the tetrastarch and those treated with the control fluid, whereas 2 reported a higher incidence of allogeneic blood exposure in patients treated with a pentastarch38 or the HBOC35 when compared with those treated with the tetrastarch. In a trial in major abdominal surgery,39 a significantly lower number of patients randomized to the tetrastarch group were exposed to allogeneic blood products, although perioperative blood losses were not reported. Another study compared 130/0.4 tetrastarch with 5% albumin solution in patients undergoing living donor liver transplantation40 and did not report blood loss, but the use of packed red blood cells and fresh frozen plasma was not different between the 2 groups.

Table 3
Table 3:
Studies Using Hemodynamic Stability as the Primary Objective and Reporting Blood Loss Data

Two single-blind randomized studies compared the effects of a waxy maize-derived 130/0.4 tetrastarch with either a mixture of colloids or hexastarch and modified fluid gelatin on renal function while presenting data on blood loss and allogeneic blood transfusion41,42(Table 4). Neither reported a significant difference in perioperative blood loss between the studied colloids.

Table 4
Table 4:
Studies Evaluating Renal Function as the Primary Objective and Reporting Blood Loss Data

Finally, 2 single-blind randomized studies compared the effects of a waxy maize-derived 130/0.4 tetrastarch with Ringer’s lactate solution and 20% albumin on tissue inflammatory response and organ perfusion in patients undergoing cardiac surgery43 or hepatectomy44 (Table 5). In the cardiac study, 1500 mL of either HES 130/0.4 or Ringer’s lactate solution was given for cardiopulmonary priming. There were no significant differences in any of the measured variables, including postoperative blood drainage, between the 2 groups, except plasma potassium concentration, which was higher, and plasma chloride concentration, which was lower in the tetrastarch group. In the hepatectomy trial, patients randomized to the colloids required less postoperative fluid volume than those randomized to the crystalloid. Intraoperative blood loss did not differ among the 3 groups. Postoperative blood loss was not reported, but the authors stated that the use of blood products was not different among groups. Hepatic enzymes increased in all groups but were not different among groups. Postoperative inflammatory reaction assessed by C-reactive protein appeared to be less pronounced in the tetrastarch group.

Table 5
Table 5:
Studies Evaluating Systemic Inflammation or Organ Perfusion as the Primary Objective and Reporting Blood Loss Data

In summary, 38 studies have evaluated the effects of tetrastarch on blood loss in patients undergoing various surgical procedures, mainly cardiac, major abdominal, or orthopedic surgery. Among these studies, 1602 patients received a tetrastarch solution and 1678 another colloid or crystalloid solution. Among these 38 trials, 36 evaluated the waxy maize-derived 130/0.4 tetrastarch, 1 evaluated the potato-derived 130/0.42 tetrastarch,23 and 1 evaluated both tetrastarches.45 The studies varied markedly in their protocol, design, and objectives. Overall, no study demonstrated an increase in perioperative blood loss, allogeneic blood volume transfused, or exposure to allogeneic blood products in patients receiving tetrastarches compared with those receiving other colloids or crystalloids. The ratio of blood loss in the tetrastarch group to other groups varied from 0.75 to 1.01, with a mean and 95% CIs that were < 1.0 for comparison with other HES or human serum albumin, and inclusive of 1.0 for gelatin and crystalloid (Fig. 3). Twenty trials reported on red cell transfusion in 2151 patients. Three hundred eight-six of 995 patients given a tetrastarch received allogeneic red cell transfusion compared with 479 of 1027 given a comparator (OR, 0.73 [0.61–0.87]; P = 0.0004; Fig. 4).

Figure 4
Figure 4:
Fraction of patients transfused with allogeneic red cells comparing those given a tetrastarch versus all other comparators. Twenty trials reported allogeneic red cell transfusion (2151 patients); 2 reported no difference without actual data; 18 studies provided data for 2022 patients. Bars are 95% confidence intervals.

Coagulation, Trauma

Two studies reported data on blood loss or transfusion requirements in trauma patients.46,47 The first study was a single-center randomized single-blind trial that evaluated the effects of repetitive doses of up to 70 mL/kg of HES 130/0.4 compared with pentastarch plus albumin in intensive care unit patients with severe head injury.47 Blood drainage and estimated other blood loss were not different between the 2 groups of patients. Intracranial bleeding complications were not different between groups (5/16 in the tetrastarch group and 5/15 in the pentastarch + albumin group) and were not accompanied by coagulation disorders. The second study was a single-center randomized double-blind trial comparing HES 130/0.4 with isotonic saline in severely injured patients requiring more than 3 L of fluid resuscitation in which blunt and penetrating trauma were analyzed separately.46 In the penetrating trauma patients, the volume of erythrocytes transfused was not different between groups (HES 130/0.4, 1553 ± 1562 mL; NaCl 0.9%: 1796 ± 1361 mL). In the blunt trauma patients, the volume of erythrocytes transfused was significantly higher in the tetrastarch group than that in the saline group (HES 130/0.4, 2943 ± 1628 mL; NaCl 0.9%: 1473 ± 1071 mL; P = 0.005), as was the volume of transfused fresh frozen plasma and platelet concentrates. These may have been related to a clinically and statistically significant greater severity of injury in the HES group.


Of the reports meeting the a priori criteria, 41 publications included data regarding renal outcomes of acute renal failure, need for RRT, serum creatinine, creatinine clearance, blood urea nitrogen (BUN), or urine output (Fig. 5). Twenty-six were in major noncardiac surgery, 10 in cardiac surgery, 2 in trauma, 1 in volunteers, and 1 in stroke. Three studies were in children (1 cardiac, 2 noncardiac). The volunteer and stroke studies were excluded from subsequent analysis as they were not in a surgical environment, but neither suggested any renal harm. One additional report examining large infusions of a tetrastarch compared with a pentastarch plus albumin, for up to 28 days in an intensive care unit after head trauma, was not included because there was no specific indication that the patients had undergone surgery.47 However, there was no suggestion of adverse mortality (no deaths in 16 patients in the tetrastarch group and 2 deaths in 15 patients in the pentastarch group) or adverse renal effects (renal failure: 0 with tetrastarch, 2 with pentastarch, and no differences between groups in serum creatinine or creatinine clearance). This resulted in 38 publications with 3127 randomly allocated patients, of which 1532 were given a tetrastarch and 1595 were given a comparator fluid (Fig. 5).

Figure 5
Figure 5:
Flow chart of reviewed and analyzed publications related to renal function.

Renal Replacement Therapy

Seven studies reported the need for RRT (Table 6). Seven of 388 (1.8%) patients receiving a tetrastarch had RRT compared with 12 of 402 (3.0%) receiving a comparator (OR, 0.60 [0.23–1.53]; P = 0.35; all were other colloids, except for 1 group of crystalloid in 1 trial).46

Table 6
Table 6:
Studies Reporting Data for RRT


Twenty-one studies reported on serum creatinine concentrations or creatinine clearance after administration of the test fluids (Table 7). One thousand five patients were given a tetrastarch, and 1051 patients were given a comparator for studies in major abdominal surgery,42,48–50 abdominal aortic surgery,41,51 cardiac surgery,43,52–55 pediatric cardiac surgery,21 orthopedic surgery,34,35 major urologic surgery,39 laparoscopic abdominal surgery,56 hepatectomy,44 hepatic transplantation,40 and renal transplantation.57 The period for which creatinine was reported varied up to 14 days after administration. All but 3 studies showed no difference in peak creatinine concentrations or nadir creatinine clearances during the postoperative period. Two studies found a statistically better outcome for a tetrastarch,41,56 and 1 found a lower creatinine with a crystalloid comparator, but no difference in change of creatinine or creatinine clearance.53 Overall, there was no indication that administration of a tetrastarch resulted in creatinine clearance or plasma concentrations that differed from that of any other group (Fig. 6). The ratio of peak serum creatinine in the tetrastarch group to other groups varied from 0.86 to 1.08, with 95% CIs inclusive of 1.0.

Table 7
Table 7:
Studies Reporting Serum Creatinine or Creatinine Clearance Data
Figure 6
Figure 6:
Ratio of peak postoperative serum creatinine concentration for patients given a tetrastarch to the peak postoperative serum creatinine for patients given comparators. The bars are mean values (with 95% confidence intervals) of the mean or median group data reported in all publications providing serum creatinine data. n = number of publications providing data; N = number of patients in those trials who were given a tetrastarch; HSA = human serum albumin. No statistical analyses were performed.

Of special interest is renal function where the risk of renal impairment is increased: after kidney or hepatic transplantation or abdominal aortic surgery. In a trial of 80 patients undergoing renal transplantation, 40 were randomly allocated to receive a tetrastarch and 40 were given 4% succinylated gelatin,57 with volumes of colloid and red cells administered and operative duration that did not differ between the groups. After transplantation, serum creatinine, serum β2 microglobulin, urinary β2 microglobulin, and α1 microgloblulin concentration decreased similarly in the 2 groups, but BUN decreased more rapidly and urinary microalbumin reached a statistically lower concentration in the tetrastarch group than that in the gelatin group. In a trial of 40 patients undergoing hepatic transplantation, 20 patients were randomly allocated to receive either a tetrastarch or a human serum albumin.40 There were no significant differences for serum creatinine or creatinine clearance between the 2 groups. A study of 65 patients (random allocation: 32 given a tetrastarch, 33 given gelatin) with preoperative renal impairment who underwent abdominal aortic surgery found no differences between the 2 groups for postoperative serum creatinine, creatinine clearance, or urine output.51 Another study randomly allocated 21 patients to be given a tetrastarch, 21 patients to be given a pentastarch, and 20 patients to be given gelatin during aortic aneurysm surgery.41 Urinary α1 microglobulin, immunoglobulin G:creatinine ratio, BUN, and creatinine were lower in the tetrastarch group than that in the gelatin group.

Urine Output

Thirty-five trials with 2616 patients compared urine output after random allocation to receive a tetrastarch (1264 patients) or a comparator (1352). No study reported a statistical difference between groups. Although some trials had a relatively small sample size, none of the reported values were of sufficient magnitude to suggest that larger studies would detect a difference that might be clinically meaningful.

In summary, 24 trials evaluated the need for RRT or creatinine clearance or concentration in 1134 patients given a tetrastarch and 1177 given a comparator. There was no evidence that tetrastarch administration induced renal impairment as judged by these variables, including in subpopulations of patients at high risk for postoperative degradation of renal function.


We found that trials randomly allocating patients to receive tetrastarch just before or during surgery, or both, do not appear to indicate that tetrastarch is associated with the adverse clinical outcomes of increased blood loss, increased use of allogeneic red cells, increased incidence of renal impairment or failure, or mortality. The data failed to provide any suggestion of such adverse consequences of tetrastarch administration in the surgical environment. We assessed only trials that randomly allocated patients to receive the tetrastarch or the comparator to minimize bias, but we did evaluate both blinded and unblinded trials. Although an unblinded trial is vulnerable to greater bias compared with a blinded trial, we did not detect any difference in the results of these 2 types of studies.

A previous examination58 reviewed individual data of patients from 7 studies comparing HES 130/0.4 to HES 200/0.5 for perioperative intravascular volume replacement. Although patients randomized to the tetrastarch group received more starch than those randomized to receive pentastarch, they had less perioperative blood loss, were less frequently exposed to allogeneic blood products, and when transfused received a smaller volume of packed red blood cells.

It is worth noting that the duration of follow-up in the trials that we evaluated was relatively short. It is understandable that the follow-up period was limited, as most of the trials were performed before any suspicion was raised of possible long-term adverse effects. Furthermore, many of the trials examined were for regulatory purposes, and their design was driven by regulatory considerations. The relatively limited duration of reporting, in part, may account for the difference between our results of no adverse safety effects and the opposite finding of other reports, such as the recently completed so-called 6S study.13 In that trial, follow-up was for 90 days, but no differences in survival were noted until 60 days after HES administration. In addition to the issue of reporting duration and study design (a randomized clinical trial versus review of previously published studies), other important differences, such as the long-term use of large volumes of HES, likely contributed to the differing results. Patient population is perhaps the most important difference between the studies that we analyzed and the 6S trial. It is likely that the preponderance of patients we included had relatively normal, intact endovascular function and glycocalyces; the opposite is likely to have been the case in the septic shock patients studied in the 6S trial (only 45 of the 798 patients were not in septic shock at the time of enrollment, and there was no suggestion of an adverse outcome in that small subpopulation). The endovascular glycocalyx acts as a selective barrier for exchange of fluid and molecules between plasma as tissue spaces,59–61 and its degradation results in immediate tissue edema.61 Septic shock and hypoxia degrade endovascular integrity and the glycocalyx,16,62 resulting in the extravasation of large molecules and fluid from intravascular to extravascular spaces. Such substantial extravasation of HES, together with an increased need for volume augmentation, would have resulted in the loss of its intravascular colloidal function, creating a need for additional fluid therapy, and unknown consequences for abnormal amounts of extravascular HES, either or both of which could have contributed to the observed increased late mortality in the 6S trial.

A recent meta-analysis assessed 25 trials of either perioperative or acutely ill patients, attempting to discern the influence of retracted publications, apparently as a prelude to the CHEST.18 Six of the trials were in intensive care units, and 3 of those trials were in severe sepsis encompassing 101 patients of the total 1608 reviewed. We assessed considerably more trials strictly in the surgical setting, with more than 3 times as many patients. Thus, the 2 reviews differ in scope and intent.

It should be further noted that none of the trials we examined, except the 2 trials with an HBOC,34,35 had a substantial number of patients, thus limiting the power of any one individual study. However, examination of the 38 surgical trials that reported blood loss in 1602 patients treated with tetrastarch and compared with 1678 patients given a comparator and 1134 patients given a tetrastarch and compared with 1177 patients given a comparator in 24 trials in whom renal function (RRT or creatinine) was examined did not provide a hint of increased blood loss, decreased renal function, or mortality. In fact, in those trials in which the comparator fluid was either other starches or human serum albumin, the blood loss with the tetrastarches was 0.88 and 0.75 of those comparators, respectively, with 95% CIs that did not cross 1.0. In addition, the 18 trials of 2022 patients reporting data for numbers of patients transfused with allogeneic red cells (not including the 2 trials that reported “no difference” without presenting data) suggest the possibility of a lesser transfusion rate with a tetrastarch than the comparators.

Of further consideration is the reliability of the primary clinical end point we assessed for coagulation function: that of blood loss. The estimation of intraoperative blood loss is subject to interperson variability,63 and those values frequently differ from those estimated from changes in hematocrit.64 While the absolute values reported in the clinical trials we assessed might have inaccuracies, the relative values comparing tetrastarches to other fluids administered should be more reliable, as within a trial the blood losses were estimated in the same manner by the same personnel.

Only 1 study in blunt trauma patients reported a higher exposure to blood product in patients treated with HES 130/0.4 compared with those treated with NaCl 0.9%.46 In blunt trauma patients where there is more diffuse microvascular damage, adverse effects on coagulation may lead to greater blood loss and higher exposure to blood products. However, the authors (and we) could not form a conclusion regarding the influence of HES 130/0.4 on coagulopathy and bleeding in the blunt trauma patients as that particular group had a higher injury severity and the worst coagulation screen on admission, perhaps reflecting a higher incidence or severity of trauma-induced coagulopathy.19

We had decided, before analyzing the reports, not to perform a formal meta-analysis because we judged from our knowledge that the trials were too heterogeneous in design and populations studied. We did not examine the use other HES products (pentastarches and hetastarches) for use in surgery or the use of tetrastarches during other circumstances (e.g., sepsis), and thus our conclusions apply only to tetrastarches when used in the surgical setting.

In summary, we conclude that data in the peer-reviewed literature do not suggest an adverse safety signal when tetrastarches are used intraoperatively or in the immediate postoperative period or both. We did not address the continued postoperative use, as is being performed in the CHEST trial; thus, the data set we have presented here will stand separately from whatever those findings will be. The limitations (such as duration of follow-up) of the underlying data we examined suggest that it may be worthwhile to gather additional data in the postoperative period. On the basis of our inability to detect a hint of an adverse signal, at this time it would seem an inappropriate use of resources to conduct a full-scale randomized controlled trial. Rather, as hypothesis generating, it could be useful to examine existing databases or generate data in registries.


Name: Philippe Van Der Linden, MD, PhD.

Contribution: This author helped design the research, review the articles, review the data, and write the manuscript.

Attestation: Philippe Van Der Linden attests to the integrity of the analysis and approved the final manuscript.

Conflicts of Interest: This author received reimbursement for expenses related to travel to 3 meetings and for his time related to conducting the research described in this publication. This author received fees/travel reimbursement from Fresenius-Kabi Germany, Janssen Cilag, Sangart Inc.

Name: Michael James, MB ChB, PhD, FRCA, FCA(SA).

Contribution: This author helped design the research, review the articles, review the data, and write the manuscript.

Attestation: Michael James attests to the integrity of the analysis and approved the final manuscript.

Conflicts of Interest: This author received reimbursement for expenses related to travel to 3 meetings and for his time related to conducting the research described in this publication. This author received fees/travel reimbursement from Baxter, BBraun, Fresenius-Kabi, Hospira.

Name: Michael Mythen, MD, FRCA.

Contribution: This author helped design the research, review the articles, review the data, and write the manuscript.

Attestation: Michael Mythen attests to the integrity of the analysis and approved the final manuscript.

Conflicts of Interest: This author received reimbursement for expenses related to travel to 3 meetings and for his time related to conducting the research described in this publication. This author received fees/travel reimbursement from AQIX, Baxter, BBraun, Covidien, Fresenius-Kabi, Hospira, LidCo, and Medical Defence Technologies LLC.

Name: Richard B. Weiskopf, MD.

Contribution: This author helped design the research, review the articles, review the data, and write the manuscript.

Attestation: Richard B. Weiskopf attests to the integrity of the analysis and approved the final manuscript. Richard B. Weiskopf is the archival author.

Conflicts of Interest: This author received reimbursement for expenses related to travel to 3 meetings and for his time related to conducting the research described in this publication. This author received fees/travel reimbursement from the US Department of the Army, NIH/NHLBI, US FDA, TerumoBCT, CSL-Behring, OPK Biotech, Sangart, and Covidien; Richard B. Weiskopf was an employee of Novo Nordisk A/S 2005–2007.

This manuscript was handled by: Jerrold H. Levy, MD, FAHA.


The authors thank Dr Frank Bepperling and Dr Martin Holler of Fresenius-Kabi for their careful respect of the rules established by the authors that provided the authors complete freedom and prohibited their input or influence on the process and the manuscript, for which the authors are solely responsible.

The authors are grateful to Dr Edward Burdett for having conducted the literature search and to Dr Christoph Messer and DBM Agentur Für Marketing Und Kommunikation GmbH for having organized the retrieved references and produced extracts of data contained therein.


1. Gollub S, Schechter DC, Hirose T, Bailey CP. Use of hydroxyethyl starch solution in extensive surgical operations. Surg Gynecol Obstet. 1969;128:725–8
2. Solanke TF. Clinical trial of 6 per cent hydroxyethyl starch (a new plasma expander). Br Med J. 1968;3:783–5
3. Lee WH Jr, Rubin JW, Huggins MP. Clinical evaluation of priming solutions for pump oxygenator perfusion. Ann Thorac Surg. 1975;19:529–36
4. Tamada T, Okada K, Ishida R, Kamishita K, Irikura T. Studies on hydroxyethyl starch as a plasma expander. II. Influences of molecular weight of hydroxyethyl starch on its physicochemical and biological properties. Chem Pharm Bull. 1971;19:286–91
5. Westphal M, James MF, Kozek-Langenecker S, Stocker R, Guidet B, Van Aken H. Hydroxyethyl starches: different products–different effects. Anesthesiology. 2009;111:187–202
6. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton RSAFE Study Investigators. . A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350:2247–56
7. Chappell D, Jacob M, Hofmann-Kiefer K, Conzen P, Rehm M. A rational approach to perioperative fluid management. Anesthesiology. 2008;109:723–40
8. Rehm M, Haller M, Orth V, Kreimeier U, Jacob M, Dressel H, Mayer S, Brechtelsbauer H, Finsterer U. Changes in blood volume and hematocrit during acute preoperative volume loading with 5% albumin or 6% hetastarch solutions in patients before radical hysterectomy. Anesthesiology. 2001;95:849–56
9. Bayer O, Reinhart K, Sakr Y, Kabisch B, Kohl M, Riedemann NC, Bauer M, Settmacher U, Hekmat K, Hartog CS. Renal effects of synthetic colloids and crystalloids in patients with severe sepsis: a prospective sequential comparison. Crit Care Med. 2011;39:1335–42
10. Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, Brochard L. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet. 2001;357:911–6
11. Brunkhorst FM, Engel 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 KGerman Competence Network Sepsis (SepNet). . Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358:125–39
12. Guidet B, Martinet O, Boulain T, Philippart F, Poussel JF, Maizel J, Forceville X, Feissel M, Hasselmann M, Heininger A, Van Aken H. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: the CRYSTMAS study. Crit Care. 2012;16:R94
13. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, Madsen KR, Møller MH, Elkjær JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Søe-Jensen P, Bestle M, Strand K, Wiis J, White JO, Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB, Thormar K, Kjældgaard AL, Fabritius ML, Mondrup F, Pott FC, Møller TP, Winkel P, Wetterslev J6S Trial Group; Scandinavian Critical Care Trials Group. . Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124–34
14. Myburgh J, Li Q, Heritier S, Dan A, Glass PCrystalloid Versus Hydroxyethyl Starch Trial (CHEST) Management Committee. . Statistical analysis plan for the Crystalloid Versus Hydroxyethyl Starch Trial (CHEST). Crit Care Resusc. 2012;14:44–52
15. Marechal X, Favory R, Joulin O, Montaigne D, Hassoun S, Decoster B, Zerimech F, Neviere R. Endothelial glycocalyx damage during endotoxemia coincides with microcirculatory dysfunction and vascular oxidative stress. Shock. 2008;29:572–6
16. Steppan J, Hofer S, Funke B, Brenner T, Henrich M, Martin E, Weitz J, Hofmann U, Weigand MA. Sepsis and major abdominal surgery lead to flaking of the endothelial glycocalix. J Surg Res. 2011;165:136–41
17. Bansch P, Nelson A, Ohlsson T, Bentzer P. Effect of charge on microvascular permeability in early experimental sepsis in the rat. Microvasc Res. 2011;82:339–45
18. Gattas DJ, Dan A, Myburgh J, Billot L, Lo S, Finfer SCHEST Management Committee. . Fluid resuscitation with 6% hydroxyethyl starch (130/0.4) in acutely ill patients: an updated systematic review and meta-analysis. Anesth Analg. 2012;114:159–69
19. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54:1127–30
20. Vanhoonacker J, Ongenae M, Vanoverschelde H, Donadoni R. Hydroxyethyl starch 130/0.4 versus modified fluid gelatin for cardiopulmonary bypass priming: the effects on postoperative bleeding and volume expansion needs after elective CABG. Acta Anaesthesiol Belg. 2009;60:91–7
21. Hanart C, Khalife M, De Villé A, Otte F, De Hert S, Van der Linden P. Perioperative volume replacement in children undergoing cardiac surgery: albumin versus hydroxyethyl starch 130/0.4. Crit Care Med. 2009;37:696–701
22. Kim JY, Lee JW, Kweon TD, Kwak YL, Kim JH, Bang SO. The effect of 6% hydroxyethyl starch 130/0.4 on hemostasis and hemodynamc efficacy in off-pump coronary artery bypass surgery: a comparison with 6% hydroxyethyl starch 200/0.5. Korean J Anesthesiol. 2007;53:14–21
23. Osthaus WA, Witt L, Johanning K, Boethig D, Winterhalter M, Huber D, Heimbucher C, Suempelmann R. Equal effects of gelatin and hydroxyethyl starch (6% HES 130/0.42) on modified thrombelastography in children. Acta Anaesthesiol Scand. 2009;53:305–10
24. Muralidhar K, Garg R, Mohanty S, Banakal S. Influence of colloid infusion on coagulation during off-pump coronary artery bypass grafting. Indian J Anaesth. 2010;54:147–53
25. Choi SJ, Ahn HJ, Chung SS, Kim MH, Choi DH, Lee SM, Kang JG, Kim JK. Hemostatic and electrolyte effects of hydroxyethyl starches in patients undergoing posterior lumbar interbody fusion using pedicle screws and cages. Spine. 2010;35:829–34
26. Turker G, Yilmazlar T, Mogol EB, Gurbet A, Dizman S, Gunay H. The effects of colloid pre-loading on thromboelastography prior to caesarean delivery: hydroxyethyl starch 130/0.4 versus succinylated gelatine. J Int Med Res. 2011;39:143–9
27. Huang ZL, Wang SJ, Zhou RL, Zhang MZ, Hang YN. Effects of hydroxyethyl starch 130/0.4 and 200/0.5 on coagulation and platelet function. J Shanghai Jiaotong Univ. 2009;29:569–73
28. Mittermayr M, Streif W, Haas T, Fries D, Velik-Salchner C, Klingler A, Oswald E, Bach C, Schnapka-Koepf M, Innerhofer P. Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration. Anesth Analg. 2007;105:905–17
29. 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
30. Felfernig M, Franz A, Bräunlich P, Fohringer C, Kozek-Langenecker SA. The effects of hydroxyethyl starch solutions on thromboelastography in preoperative male patients. Acta Anaesthesiol Scand. 2003;47:70–3
31. Bulanov AIu, Shulutko EM, Shcherbakova OV, Liubimova LS, Zhelnova EI. [Thromboelastographic characteristics of different infusion therapy regimens in healthy bone marrow donors]. Anesteziol Reanimatol. 2009;5:23–7
32. Ahn HJ, Yang M, Gwak MS, Koo MS, Bang SR, Kim GS, Lee SK. Coagulation and biochemical effects of balanced salt-based high molecular weight vs saline-based low molecular weight hydroxyethyl starch solutions during the anhepatic period of liver transplantation. Anaesthesia. 2008;63:235–42
33. Kim D.. Seventy-two hour peri-operative volume replacement with 6% HES 130/0.4 vs. 20% albumin in patients undergoing abdominal, cranial, and orthopedic surgery. Anesth Pain Med. 2009;4:235–41
34. van der Linden P, Gazdzik TS, Jahoda D, Heylen RJ, Skowronski JC, Pellar D, Kofranek I, Górecki AZ, Fagrell B, Keipert PE, Hardiman YJ, Levy H6090 Study Investigators. . A double-blind, randomized, multicenter study of MP4OX for treatment of perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia. Anesth Analg. 2011;112:759–73
35. Olofsson CI, Górecki AZ, Dirksen R, Kofranek I, Majewski JA, Mazurkiewicz T, Jahoda D, Fagrell B, Keipert PE, Hardiman YJ, Levy HStudy 6084 Clinical Investigators. . Evaluation of MP4OX for prevention of perioperative hypotension in patients undergoing primary hip arthroplasty with spinal anesthesia: a randomized, double-blind, multicenter study. Anesthesiology. 2011;114:1048–63
36. Gallandat Huet RC, Siemons AW, Baus D, van Rooyen-Butijn WT, Haagenaars JA, van Oeveren W, Bepperling F. A novel hydroxyethyl starch (Voluven) for effective perioperative plasma volume substitution in cardiac surgery. Can J Anaesth. 2000;47:1207–15
37. Gandhi SD, Weiskopf RB, Jungheinrich C, Koorn R, Miller D, Shangraw RE, Prough DS, Baus D, Bepperling F, Warltier DC. Volume replacement therapy during major orthopedic surgery using Voluven (hydroxyethyl starch 130/0.4) or hetastarch. Anesthesiology. 2007;106:1120–7
38. Langeron O, Doelberg M, Ang ET, Bonnet F, Capdevila X, Coriat P. Voluven, a lower substituted novel hydroxyethyl starch (HES 130/0.4), causes fewer effects on coagulation in major orthopedic surgery than HES 200/0.5. Anesth Analg. 2001;92:855–62
39. Heinze H, Hage K, Hackmann F, Schäfer R, Zulkowski R, Klotz KF.. Comparison of HES 130/0.42 and HES 200/0.5 for hemodynamic stabilisation in major urological surgery. Appl Cardiopulm Pathophysiol. 2009;13:11–9
40. Mukhtar A, Aboulfetouh F, Obayah G, Salah M, Emam M, Khater Y, Akram R, Hoballah A, Bahaa M, Elmeteini M, Hamza A. The safety of modern hydroxyethyl starch in living donor liver transplantation: a comparison with human albumin. Anesth Analg. 2009;109:924–30
41. 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;94:427–33
42. Harten J, Crozier JE, McCreath B, Hay A, McMillan DC, McArdle CS, Kinsella J. Effect of intraoperative fluid optimisation on renal function in patients undergoing emergency abdominal surgery: a randomised controlled pilot study (ISRCTN 11799696). Int J Surg. 2008;6:197–204
43. Shahbazi S, Zeighami D, Allahyary E, Alipour A, Esmaeeli M, Ghaneie M. Effect of colloid versus crystalloid administration of cardiopulmonary bypass prime solution on tissue and organ perfusion. Iran Cardiovasc Res J. 2011;5:24–31
44. Yang J, Wang WT, Yan LN, Xu MQ, Yang JY. Alternatives to albumin administration in hepatocellular carcinoma patients undergoing hepatectomy: an open, randomized clinical trial of efficacy and safety. Chin Med J. 2011;124:1458–64
45. Zdolsek HJ, Vegfors M, Lindahl TL, Törnquist T, Bortnik P, Hahn RG. Hydroxyethyl starches and dextran during hip replacement surgery: effects on blood volume and coagulation. Acta Anaesthesiol Scand. 2011;55:677–85
46. James MF, Michell WL, Joubert IA, Nicol AJ, Navsaria PH, Gillespie RS. Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma). Br J Anaesth. 2011;107:693–702
47. 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;96:1453–9
48. Kulla M, Weidhase R, Lampl L.. Hydroxyethyl starch 6% 130/0.42 in acetate-buffered Ringer’s solution as a part of a balanced-volume resuscitation in abdominal surgery. Anästh Intensivmed. 2008;49:7–18
49. Ickx BE, Bepperling F, Melot C, Schulman C, Van der Linden PJ. Plasma substitution effects of a new hydroxyethyl starch HES 130/0.4 compared with HES 200/0.5 during and after extended acute normovolaemic haemodilution. Br J Anaesth. 2003;91:196–202
50. Boldt J, Schöllhorn T, Münchbach J, Pabsdorf M. A total balanced volume replacement strategy using a new balanced hydoxyethyl starch preparation (6% HES 130/0.42) in patients undergoing major abdominal surgery. Eur J Anaesthesiol. 2007;24:267–75
51. Godet G, Lehot JJ, Janvier G, Steib A, De Castro V, Coriat P. Safety of HES 130/0.4 (Voluven®) in patients with preoperative renal dysfunction undergoing abdominal aortic surgery: a prospective, randomized, controlled, parallel-group multicentre trial. Eur J Anaesthesiol. 2008;25:986–94
52. Van der Linden PJ, De Hert SG, Deraedt D, Cromheecke S, De Decker K, De Paep R, Rodrigus I, Daper A, Trenchant A. Hydroxyethyl starch 130/0.4 versus modified fluid gelatin for volume expansion in cardiac surgery patients: the effects on perioperative bleeding and transfusion needs. Anesth Analg. 2005;101:629–34
53. Tiryakioğlu O, Yildiz G, Vural H, Goncu T, Ozyazicioglu A, Yavuz S. Hydroxyethyl starch versus Ringer solution in cardiopulmonary bypass prime solutions (a randomized controlled trial). J Cardiothorac Surg. 2008;3:45
54. Kasper SM, Meinert P, Kampe S, Görg C, Geisen C, Mehlhorn U, Diefenbach C. 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
55. Boldt J, Lehmann A, Römpert R, Haisch G, Isgro F. Volume therapy with a new hydroxyethyl starch solution in cardiac surgical patients before cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2000;14:264–8
56. Jover JL, García JP, Martínez C, Espí A, Gregori E, Almagro J. [Hydroxyethyl starch to protect renal function in laparoscopic surgery]. Rev Esp Anestesiol Reanim. 2009;56:27–30
57. Wu Y, Wu AS, Wang J, Tian M, Jia XY, Rui Y, Yue Y. Effects of the novel 6% hydroxyethyl starch 130/0.4 on renal function of recipients in living-related kidney transplantation. Chin Med J. 2010;123:3079–83
58. Kozek-Langenecker SA, Jungheinrich C, Sauermann W, Van der Linden P. 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. Anesth Analg. 2008;107:382–90
59. van Haaren PM, VanBavel E, Vink H, Spaan JA. Localization of the permeability barrier to solutes in isolated arteries by confocal microscopy. Am J Physiol Heart Circ Physiol. 2003;285:H2848–56
60. van den Berg BM, Nieuwdorp M, Stroes ES, Vink H. Glycocalyx and endothelial (dys) function: from mice to men. Pharmacol Rep. 2006;58 Suppl:75–80
61. van den Berg BM, Vink H, Spaan JA. The endothelial glycocalyx protects against myocardial edema. Circ Res. 2003;92:592–4
62. Ward BJ, Donnelly JL. Hypoxia induced disruption of the cardiac endothelial glycocalyx: implications for capillary permeability. Cardiovasc Res. 1993;27:384–9
63. Meiser A, Casagranda O, Skipka G, Laubenthal H. [Quantification of blood loss. How precise is visual estimation and what does its accuracy depend on?]. Anaesthesist. 2001;50:13–20
64. Brecher ME, Monk T, Goodnough LT. A standardized method for calculating blood loss. Transfusion. 1997;37:1070–4
65. Ellger B, Freyhoff J, van Aken H, Booke M, Marcus MAE. High-dose volume replacement using HES 130/0.4 during major surgery. Nederlands Tijdschrift voor Anesthesiologie. 2006;19:63–8
    66. Chong Sung K, Kum Suk P, Mi Ja Y, Kyoung Ok K. Effects of intravascular volume therapy using hydroxyethyl starch (130/0.4) on post-operative bleeding and transfusion requirements in children undergoing cardiac surgery: a randomized clinical trial. Acta Anaesthesiol Scand. 2006;50:108–11
      67. Boks RH, Wijers MJ, Hofland J, Takkenberg JJ, Bogers AJ. Low molecular starch versus gelatin plasma expander during CPB: does it make a difference? Perfusion. 2007;22:333–7
        68. Ooi JS, Ramzisham AR, Zamrin MD. Is 6% hydroxyethyl starch 130/0.4 safe in coronary artery bypass graft surgery? Asian Cardiovasc Thorac Ann. 2009;17:368–72
          69. Lee JS, Ahn SW, Song JW, Shim JK, Yoo KJ, Kwak YL. Effect of hydroxyethyl starch 130/0.4 on blood loss and coagulation in patients with recent exposure to dual antiplatelet therapy undergoing off-pump coronary artery bypass graft surgery. Circ J. 2011;75:2397–402
            70. Chen G, Yan M, Lu QH, Gong M. Effects of two different hydroxyethyl starch solutions (HES200/0.5 vs. HES130/0.4) on the expression of platelet membrane glycoprotein. Acta Anaesthesiol Scand. 2006;50:1089–94
              71. Schramko AA, Suojaranta-Ylinen RT, Kuitunen AH, Kukkonen SI, Niemi TT. Rapidly degradable hydroxyethyl starch solutions impair blood coagulation after cardiac surgery: a prospective randomized trial. Anesth Analg. 2009;108:30–6
                72. Schramko A, Suojaranta-Ylinen R, Kuitunen A, Raivio P, Kukkonen S, Niemi T. Hydroxyethylstarch and gelatin solutions impair blood coagulation after cardiac surgery: a prospective randomized trial. Br J Anaesth. 2010;104:691–7
                  73. Choi YS, Shim JK, Hong SW, Kim JC, Kwak YL. Comparing the effects of 5% albumin and 6% hydroxyethyl starch 130/0.4 on coagulation and inflammatory response when used as priming solutions for cardiopulmonary bypass. Minerva Anestesiol. 2010;76:584–91
                    74. Jin SL, Yu BW. Effects of acute hypervolemic fluid infusion of hydroxyethyl starch and gelatin on hemostasis and possible mechanisms. Clin Appl Thromb Hemost. 2010;16:91–8
                      75. Liang H, Yang CX, Li H, Wen XJ, Zhou QL, Gu MN. The effects of preloading infusion with hydroxyethyl starch 200/0.5 or 130/0.4 solution on hypercoagulability and excessive platelet activation of patients with colon cancer. Blood Coagul Fibrinolysis. 2010;21:406–13
                        76. Sander O, Reinhart K, Meier-Hellmann A. Equivalence of hydroxyethyl starch HES 130/0. 4 and HES 200/0. 5 for perioperative volume replacement in major gynaecological surgery. Acta Anaesthesiol Scand. 2003;47:1151–8
                          77. Jungheinrich C, Sauermann W, Bepperling F, Vogt NH. Volume efficacy and reduced influence on measures of coagulation using hydroxyethyl starch 130/0.4 (6%) with an optimised in vivo molecular weight in orthopaedic surgery: a randomised, double-blind study. Drugs R D. 2004;5:1–9
                            78. Mehta Y, Dhar A, Meharwal SZS, Trehan N. Comparison of new HES (130/0.4) and HES (200/0.5) in OPCAB surgery. J Anesthesiol Clin Pharmacol. 2007;23:273–8
                              79. Yap WW, Young D, Pathi V. Effects of gelatine and medium molecular weight starch as priming fluid in cardiopulmonary bypass—a randomised controlled trial. Perfusion. 2007;22:57–61
                                80. Standl T, Lochbuehler H, Galli C, Reich A, Dietrich G, Hagemann H. HES 130/0.4 (Voluven) or human albumin in children younger than 2 yr undergoing non-cardiac surgery. A prospective, randomized, open label, multicentre trial. Eur J Anaesthesiol. 2008;25:437–45
                                  81. Fenger-Eriksen C, Hartig Rasmussen C, Kappel Jensen T, Anker-Møller E, Heslop J, Frøkiaer J, Tønnesen E. Renal effects of hypotensive anaesthesia in combination with acute normovolaemic haemodilution with hydroxyethyl starch 130/0.4 or isotonic saline. Acta Anaesthesiol Scand. 2005;49:969–74
                                    82. Kasper SM, Strömich A, Kampe S, Radbruch L. Evaluation of a new hydroxyethyl starch solution (HES 130/0.4) in patients undergoing preoperative autologous blood donation. J Clin Anesth. 2001;13:486–90
                                      © 2013 International Anesthesia Research Society