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The New-Generation Hydroxyethyl Starch Solutions: The Holy Grail of Fluid Therapy or Just Another Starch?

2010; Elsevier BV; Volume: 24; Issue: 3 Linguagem: Inglês

10.1053/j.jvca.2010.02.021

1532-8422

Glenn S. Murphy, Steven B. Greenberg,

Cardiovascular Health and Disease Prevention

THE OPTIMIZATION OF fluid status in the cardiac surgical patient is a primary management objective of anesthesiologists and critical care clinicians in the perioperative period. Appropriate volume restoration will maximize cardiac output, systemic perfusion pressures, and microcirculatory flow. Recent evidence suggests that intraoperative goal-directed fluid administration may reduce postoperative morbidity and hospital length of stay.1Bundgaard-Nielsen M. Holte K. Secher N.H. et al.Monitoring of perioperative fluid administration by individualized goal-directed therapy.Acta Anaesthesiol Scand. 2007; 51: 331-340Crossref PubMed Scopus (225) Google Scholar However, achieving the goal of "optimal fluid status" in a cardiac surgical patient population may present a challenge for clinicians. Patients often arrive to the operating room with intravascular volume depletion because of aggressive diuresis or critical illness in the preoperative period. Significant and underappreciated blood loss may occur in the operating room. Furthermore, activation of the inflammatory response system during cardiopulmonary bypass (CPB) produces endothelial injury and increased vascular permeability, resulting in a fluid shift from the intravascular to the interstitial compartment. A mean weight gain of 4 kg has been reported on the first postoperative day after cardiac surgery, which was attributed to a 2-L positive fluid balance administered in the operating room and intensive care unit.2Perko M.J. Jarnvig I.L. Højgaard-Rasmussen N. et al.Electric impedance for evaluation of body fluid balance in cardiac surgical patients.J Cardiothorac Vasc Anesth. 2001; 15: 44-48Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Perioperative fluid management is further complicated by the fact that the "ideal" volume therapy for the cardiac surgical patient is unknown. An "ideal" plasma expander should restore and maintain intravascular volume, attenuate hypotension related to hypovolemia, improve microcirculatory flow, minimize alterations in metabolic status, and produce minimal effects on the inflammatory and coagulation systems. In addition, intravascular volume-replacement regimens should not adversely affect postoperative organ system function (eg, renal dysfunction) and should have low acquisition costs. Unfortunately, no plasma expander therapy fulfills all of these criteria. All crystalloids and colloids have unique and complex pharmacochemical characteristics that result in alterations in physiologic functions. At the present time, there are few studies showing clinically relevant outcome advantages of any crystalloid or colloid solution. Not surprisingly, several recent reviews have concluded that there is no clear evidence to recommend one fluid therapy over another.3Holte K. Kehlet H. Fluid therapy and surgical outcomes in elective surgery: A need for reassessment in fast-track surgery.J Am Coll Surg. 2006; 202: 971-989Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 4Brandstrup B. Fluid therapy for the surgical patient.Best Pract Res Clin Anaesthesiol. 2006; 20: 265-283Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar Despite several decades of research and the publication of hundreds of laboratory and clinical investigations, the relative merits of crystalloids or colloids as plasma-replacement agents continue to be actively debated. In the absence of outcome data clearly supporting any particular fluid regimen, the choice of crystalloid or colloid is determined primarily by clinician preference or institutional protocol. Availability and cost considerations also may influence the use of colloids. Hydroxyethyl starch solutions (HES) are used more commonly in the European Union than in the United States.5Boldt J. Volume therapy in cardiac surgery: Are Americans different from Europeans?.J Cardiothorac Vasc Anesth. 2006; 20: 98-105Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar The availability of second- and third-generation HES solutions and lower acquisition costs in Europe likely contribute to these differences in clinical practices. The primary advantages of crystalloid solutions are low costs and an acceptable safety profile in healthy and critically ill patients. However, intravascular retention of crystalloids is poor. In postoperative patients, the infusion of 1,000 mL of 0.9% normal saline resulted in only 180 mL of plasma volume expansion.6Lamke L.O. Liljedahl S.O. Plasma volume changes after infusion of various plasma expanders.Resuscitation. 1976; 5: 93-102Abstract Full Text PDF PubMed Scopus (168) Google Scholar Evidence also suggests that infusions of large volumes (>3 L) of normal saline may produce hyperchloremic metabolic acidosis and postoperative hypercoagulability.7Ng K.F. Lam C.C. Chan L.C. In vivo effect of haemodilution with saline on coagulation: A randomized controlled trial.Br J Anaesth. 2002; 88: 475-480Crossref PubMed Scopus (150) Google Scholar, 8McFarlane C. Lee A. A comparison of plasmalyte 148 and 0.9% saline for intra-operative fluid replacement.Anaesthesia. 1994; 49: 779-781Crossref PubMed Scopus (183) Google Scholar The volume-expanding efficacy of colloids is significantly greater than crystalloids.6Lamke L.O. Liljedahl S.O. Plasma volume changes after infusion of various plasma expanders.Resuscitation. 1976; 5: 93-102Abstract Full Text PDF PubMed Scopus (168) Google Scholar A variety of colloid solutions (dextran, gelatin, albumin, and HES) have been studied in the setting of cardiac surgery, either as priming solutions or as volume therapy in the pre- or post-CPB period. Although dextrans may attenuate the inflammatory response to CPB,9Schuerholz T. Marx G. Dextran-70 to modulate inflammatory response after cardiopulmonary bypass: Potential for a novel approach?.Crit Care. 2007; 11: 163Crossref PubMed Scopus (4) Google Scholar they rarely are used clinically because of the risk of inducing life-threatening anaphylactic reactions. Gelatins appear to have minimal effects on the coagulation system but also are associated with a higher incidence of allergic reactions. Albumin is used as a CPB priming solution and plasma volume expander in some cardiac surgical centers. The high cost of albumin and a small, potential risk of viral transmission have resulted in the limited use of this agent in most countries. HES is a nonprotein plasma expander that has been studied extensively since its introduction into clinical practice in the 1970s. Until recently, only first-generation HES solutions (HESPAN [6% HES 450/0.7 in 0.9% saline]; Braun Medical, Irvine, CA, and Hextend [6% HES 670/0.75 in a balanced solution]; BioTime, Berkeley, CA) were available in the United States. Recently, a new third-generation HES was approved by the Food and Drug Administration (FDA) (Voluven [6% HES 130/0.4 in 0.9% saline, Hospira Inc, Lake Forest, IL]). Clinical studies have shown that first-generation HES products accumulate in various tissues, with pruritus as the main clinical manifestation of tissue storage.10Barron M.E. Wilkes M.W. Navickis R.J. A systematic review of the comparative safety of colloids.Arch Surg. 2004; 139: 552-563Crossref PubMed Scopus (169) Google Scholar First-generation HES solutions may also adversely affect renal function. Intraoperative use of HES (670/0.75) was independently associated with reductions in the glomerular filtration rate throughout the first 5 postoperative days after cardiac surgery.11Winkelmayer W.C. Glynn R.J. Levin R. et al.Hydroxyethyl starch and change in renal function in patients undergoing coronary artery bypass graft surgery.Kidney Int. 2003; 64: 1046-1049Crossref PubMed Scopus (70) Google Scholar Another side effect of great concern to cardiac anesthesiologists and surgeons is the impact of HES solutions on postoperative hemostasis. First-generation preparations have been reported to consistently decrease plasma concentrations of coagulation factor VIII and von Willebrand factor, even when administered in doses below the recommended 24-hour limit of 20 mL/kg.12Claes Y. van Hemelrijck J. van Gerven M. et al.Influence of hydroxyethyl starch on coagulation in patients during the perioperative period.Anesth Analg. 1992; 75: 24-30Crossref PubMed Scopus (69) Google Scholar, 13Conroy J.M. Fishman R.L. Reeves S.T. et al.The effects of desmopressin and 6% hydroxyethyl starch on factor VIIIC.Anesth Analg. 1996; 83: 804-807PubMed Google Scholar These HES products also impair platelet function, likely via an extracellular coating mechanism.14Franz A. Bräunlich P. Gamsjäger T. et al.The effects of hydroxyethyl starches of varying molecular weights on platelet function.Anesth Analg. 2001; 92: 1402-1407Crossref PubMed Scopus (196) Google Scholar In the cardiac surgical setting, the use of hetastarch (first-generation HES) has been shown to increase the risk of postoperative bleeding.15Wilkes M.M. Navickis R.J. Sibbald W.J. Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: A meta-analysis of postoperative bleeding.Ann Thorac Surg. 2001; 72: 527-533Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar Because of these concerns, the FDA has stated that HESPAN use is not recommended during or after CPB because of an increased risk of coagulation abnormalities and bleeding. Similar FDA warnings have not been extended to the administration of Hextend or Voluven in cardiac surgical patients. Two recent developments in HES therapy have greatly improved the safety profile of HES products: (1) the introduction of third-generation, rapidly degradable starches (low molecular weight [MW] and molar substitution [MS]) and (2) the reformulation of HES preparations in balanced plasma-adapted solutions (in contrast to conventional HES dissolved in 0.9% normal saline). It is important to understand the differences between the various HES preparations because the unique physiochemical properties of each agent influence the incidence of side effects. Each generation of HES can be identified on the basis of the following characteristics:1Concentration: concentration impacts initial volume expansion efficacy; 6% solutions are isooncotic (volume expansion 100%), whereas 10% solutions are hyperoncotic.2Molecular weight: HES preparations are described according to mean MW (expressed as kilodaltons [kD]) as high MW (≥400 kD), medium MW (200-400 kD), or low MW (<200 kD).3Molar substitution: molar substitution reflects the average number of hydroxyethyl residues per glucose subunit, which significantly impacts the rate of breakdown of the starch polymer by amylase. HES products are characterized by the level of MS; hetastarch (MS = 0.7), hexastarch (MS = 0.6), pentastarch (MS = 0.5), and tetrastarch (MS = 0.4).4C2/C6 ratio: starches with high C2/C6 ratios are degraded more slowly.5Carrier solution: HES can be diluted in either normal saline with high concentrations of sodium (154 mmol/L) and chloride (154 mmol/L) or in a balanced solution closer in composition to plasma. First-generation HES is characterized by a high MW and degree of MS (HESPAN-6% HES 450/0.7). Third-generation starches are primarily distinguished from other HES solutions by reductions in both MW and MS (130/0.4). These physiochemical modifications of the amylopectin polymer result in an HES with a shorter half-life and an improved side-effect profile.16Westphal M. James M.F. Kozek-Langenecker S. et al.Hydroxyethyl starches: Different products—Different effects.Anesthesiology. 2009; 111: 187-202Crossref PubMed Scopus (303) Google Scholar In addition, the dilution of more rapidly degradable starches in balanced plasma-adapted solutions appears to further reduce the incidence of several of the adverse effects associated with first-generation products.17Boldt J. Saline versus balanced hydroxyethyl starch: Does it matter?.Curr Opin Anaesthesiol. 2008; 21: 679-683Crossref PubMed Scopus (19) Google Scholar The laboratory investigation by Boldt et al in this issue of the Journal examines the effect of one of the new plasma-adapted third-generation HES products (6% HES 130/0.42) on the coagulation system. Several recent clinical trials have examined the effect of perioperative administration of unbalanced (dissolved in normal saline) low-MW tetrastarches (130/0.4 and 130/0.42) on blood loss, transfusion requirements, and/or coagulation parameters after cardiac surgery. These investigations compared patients receiving third-generation solutions with subjects administered other colloids, including albumin, gelatin, and older-generation starches (200/0.5). Albumin has been shown to have a minimal effect or no effect on the coagulation system in a variety of different clinical settings. In a study of pediatric patients undergoing CPB, no significant differences in calculated blood loss were observed between patients randomized to receive either 4% albumin or 6% HES 130/0.4.18Hanart C. Khalife M. De Ville A. et al.Perioperative volume replacement in children undergoing cardiac surgery: Albumin versus hydroxyethyl starch 130/0.4.Crit Care Med. 2009; 37: 696-701Crossref PubMed Scopus (73) Google Scholar Although postoperative outcomes were not different between groups, a higher percentage of children in the albumin group required an allogeneic blood transfusion (78% v 57%).18Hanart C. Khalife M. De Ville A. et al.Perioperative volume replacement in children undergoing cardiac surgery: Albumin versus hydroxyethyl starch 130/0.4.Crit Care Med. 2009; 37: 696-701Crossref PubMed Scopus (73) Google Scholar A meta-analysis comparing albumin versus HES use in CPB surgery concluded that high-MW HES was associated with increased postoperative bleeding.15Wilkes M.M. Navickis R.J. Sibbald W.J. Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: A meta-analysis of postoperative bleeding.Ann Thorac Surg. 2001; 72: 527-533Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar In contrast, medium-MW HES (200/0.5) solutions (8 studies, 299 patients) were not associated with increased blood loss after CPB.15Wilkes M.M. Navickis R.J. Sibbald W.J. Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: A meta-analysis of postoperative bleeding.Ann Thorac Surg. 2001; 72: 527-533Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar It is important to note that studies investigating low-MW HES (which appears to impair coagulation to a lesser degree than medium-MW HES) were not included in this meta-analysis. Schramko et al19Schramko A.A. Suojaranta-Yinen R.T. Kuitunen A.H. et al.Rapidly degradable hydroxyethyl starch solutions impair blood coagulation after cardiac surgery: A prospective randomized trial.Anesth Analg. 2009; 108: 30-36Crossref PubMed Scopus (84) Google Scholar assessed the effects of a short-term postoperative infusion of either HES 200/0.5, HES 130/0.4, or 4% human albumin on blood coagulation in primary elective cardiac surgical patients. Blood loss and transfusion requirements were similar in all groups. However, when compared with the albumin group, transient prolongation of clot formation times and decreases in clot firmness were observed in both HES groups. New HES 130/0.4 preparations in saline also have been compared with gelatin in cardiac surgical patients. Haisch et al20Haisch G. Boldt J. Krebs C. et al.Influence of a new hydroxyethylstarch preparation (HES 130/0.4) on coagulation in cardiac surgical patients.J Cardiothorac Vasc Anesth. 2001; 15: 316-321Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar randomized elective cardiac surgical patients to receive perioperative HES 130/0.4 or 4% gelatin. Postoperative blood loss, blood product use, and standard coagulation variables were similar between groups. Another trial compared the intraoperative and postoperative use of HES 130/0.4 or 3% modified fluid gelatin in patients undergoing primary elective cardiac surgery.21Van der Linden P.J. De Hert S.G. Deraedt D. et al.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: 629-634Crossref PubMed Scopus (89) Google Scholar No differences in blood loss or transfusion requirements were observed between the HES 130/0.4 and gelatin groups when doses were limited to 50 mL/kg.21Van der Linden P.J. De Hert S.G. Deraedt D. et al.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: 629-634Crossref PubMed Scopus (89) Google Scholar Further studies have attempted to show a reduced coagulation effect with low-MW tetrastarches (HES 130/0.4 third generation) when compared with medium-MW pentastarches (HES 200/0.5 second generation). Gallandat Huet et al22Gallandat Huet R.C. Siemons A.W. van Rooyen-Butijn W.T. et al.A novel hydroxylethyl starch (Voluven) for effective perioperative plasma volume substitution in cardiac surgery.Can J Anesth. 2000; 47: 1207-1215Crossref PubMed Google Scholar compared the perioperative administration of these 2 different HES preparations in patients undergoing primary coronary artery bypass graft surgery. A decrease in postoperative bleeding, a reduction in transfusion requirements, and higher von Willebrand factor levels were observed in subjects randomized to receive HES 130/0.4. Another trial showed that the perioperative use of higher doses of HES 130/0.4 (up to 50 mL/kg) was not associated with increased blood loss or blood product use when compared with lower doses of HES 200/0.5 (up to 33 mL/kg).23Kasper S.M. Meinert P. Kampe S. et al.Large-dose hydroxyethyl starch 130/0.4 does not increase blood loss and transfusion requirements in coronary artery bypass surgery compared with hydroxyethyl starch 200/0.5 at recommended doses.Anesthesiology. 2003; 99: 42-47Crossref PubMed Scopus (109) Google Scholar Lastly, in 2008, investigators analyzed pooled data from all studies in major surgery (449 patients in 7 trials) comparing the coagulation effects of HES 200/0.5 and HES 130/0.4.24Kozek-Langenecker S.A. Jungheinrich C. Sauermann W. et al.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: 382-390Crossref PubMed Scopus (134) Google Scholar Statistically significant decreases in blood loss and transfusions were observed in subjects receiving HES 130/0.4 solutions. HES 130/0.4 use also was associated with fewer disturbances in measures of coagulation. These data support the concept of a reduced coagulation effect of new-generation HES preparations. The investigation by Boldt et al in this issue of the Journal provides important data about the effect of a new plasma-adapted low-MW tetrastarch on coagulation. As discussed previously, many studies have shown that tetrastarch use is associated with fewer adverse effects on the coagulation system and reduced postoperative bleeding when compared with other volume-replacement strategies. Similar beneficial effects are observed when balanced HES solutions are compared with unbalanced (normal saline) solutions.25Roche A.M. James M.F. Bennett-Guerrero E. et al.A head-to-head comparison of the in vitro coagulation effects of saline-based and balanced electrolyte crystalloid and colloid intravenous fluids.Anesth Analg. 2006; 102: 1274-1279Crossref PubMed Scopus (90) Google Scholar, 26Roche A.M. James F.M. Grocott M.P. et al.Coagulation effects of in vitro serial haemodilution with a balanced electrolyte hetastarch solution compared with a saline-based hetastarch solution and lactated Ringer's solution.Anaesthesia. 2002; 57: 950-955Crossref PubMed Scopus (56) Google Scholar, 27Boldt J. Mengistu A. Seyfert U.T. et al.The impact of a medium molecular weight, low molar substitution hydroxyethyl starch dissolved in a physiologically balanced electrolyte solution on blood coagulation and platelet function in vitro.Vox Sang. 2007; 93: 139-144Crossref PubMed Scopus (13) Google Scholar Although it appears intuitively logical that balanced tetrastarches should be superior to unbalanced tetrastarches in terms of coagulation, there is limited evidence to support this hypothesis. Boldt et al diluted the blood from 15 healthy male volunteers by 10%, 30%, or 50% using a plasma-adapted or saline-based 6% HES 130/0.42 preparation. These degrees of dilution would reflect values typically observed during CPB in patients with large, medium, and small initial red cell masses (small, medium, and large degrees of hemodilution with a fixed volume of prime). Rotational thromboelastometry was used to assess changes in coagulation, and a whole-blood platelet function analyzer was used to measure changes in platelet function. At 30% and 50% dilution levels, several measures of coagulation were significantly less impaired in the balanced tetrastarch group compared with the saline-adapted tetrastarch group. Platelet function also was better preserved in the balanced tetrastarch group. The in vitro study design described by Boldt et al, which assessed the impact of HES solutions on whole blood clot formation and appears to be a valid method of measuring the effects of crystalloids and colloids on the coagulation system, has been used in previous investigations.25Roche A.M. James M.F. Bennett-Guerrero E. et al.A head-to-head comparison of the in vitro coagulation effects of saline-based and balanced electrolyte crystalloid and colloid intravenous fluids.Anesth Analg. 2006; 102: 1274-1279Crossref PubMed Scopus (90) Google Scholar, 26Roche A.M. James F.M. Grocott M.P. et al.Coagulation effects of in vitro serial haemodilution with a balanced electrolyte hetastarch solution compared with a saline-based hetastarch solution and lactated Ringer's solution.Anaesthesia. 2002; 57: 950-955Crossref PubMed Scopus (56) Google Scholar, 27Boldt J. Mengistu A. Seyfert U.T. et al.The impact of a medium molecular weight, low molar substitution hydroxyethyl starch dissolved in a physiologically balanced electrolyte solution on blood coagulation and platelet function in vitro.Vox Sang. 2007; 93: 139-144Crossref PubMed Scopus (13) Google Scholar In general, the findings from in vitro coagulation studies (dilution of blood samples from volunteers) have correlated with the observations from clinical trials. HES preparations that impair coagulation to a greater degree in the laboratory setting also are associated with greater blood loss and transfusion requirements in surgical patients. However, it is important to note that the results from studies in the carefully controlled laboratory environment may not be directly applicable to the operating room, particularly in patients undergoing CPB. Surgery and bypass induce dysfunction of platelets and coagulation factors and activate the fibrinolytic system. The effect of new low-MW tetrastarches on the coagulation system in the complex milieu of the cardiac operating room suite is not clearly defined. Before worldwide adoption of new-generation HES preparations for cardiac surgical patients, several considerations involving the present literature must be taken into account. Widespread variation exists among the present studies relating to the use of protocol-driven fluid and blood product administration. The dependence of these studies on goal-directed therapy, or the lack thereof, may strongly affect the amount of colloid and blood products given to patients. Variability in hemodynamic pressure monitoring thresholds for fluid administration and hemoglobin threshold values for the transfusion of red cells may account for some of the observed differences among investigations. Statistically significant blood loss may not translate into clinically significant blood loss. Some studies show a small difference in actual blood loss (200-500 mL) with wide standard deviations.24Kozek-Langenecker S.A. Jungheinrich C. Sauermann W. et al.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: 382-390Crossref PubMed Scopus (134) Google Scholar Blood loss may only be clinically significant if it were to prompt the administration of blood products or result in hemodynamic instability. The type of patient population targeted for HES administration also may affect the overall generalization of its use. The majority of the published clinical studies enrolled patients undergoing primary elective cardiac surgery. The effect of new-generation HES solutions on patients at high risk for postoperative bleeding and other adverse events has not been defined. The timing of the administration of HES in the perioperative period may affect clinical outcomes. One investigation has shown that hypocoagulability may be enhanced if HES 130/0.4 is used in the cardiac surgical intensive care unit.19Schramko A.A. Suojaranta-Yinen R.T. Kuitunen A.H. et al.Rapidly degradable hydroxyethyl starch solutions impair blood coagulation after cardiac surgery: A prospective randomized trial.Anesth Analg. 2009; 108: 30-36Crossref PubMed Scopus (84) Google Scholar CPB induces alterations in the function of numerous physiologic systems; therefore, the impact of new HES preparations on adverse events may potentially be different if infused before, during, or after CPB. The rate of the administration of HES may alter coagulation status. The rapid infusion of second- and third-generation HES solutions has been shown to impair postoperative coagulation;19Schramko A.A. Suojaranta-Yinen R.T. Kuitunen A.H. et al.Rapidly degradable hydroxyethyl starch solutions impair blood coagulation after cardiac surgery: A prospective randomized trial.Anesth Analg. 2009; 108: 30-36Crossref PubMed Scopus (84) Google Scholar these findings suggest that rapid administration rates may negate the beneficial effects of newly developed HES products on the coagulation system. There are little data supporting maximal safe dose limits of any HES product, particularly in relation to the effect on coagulation. Finally, the interpretation of findings from clinical trials is complicated by the fact that there is no universally accepted "gold standard" fluid-replacement regimen. In randomized studies evaluating new HES agents, it is uncertain whether control patients should receive crystalloids, albumin, gelatin, or older-generation HES (no "ideal" comparative fluid agent). It is important for clinicians to consider all of these issues related to study design when evaluating previous and future investigations of HES in the clinical setting. Perhaps it is time for anesthesiologists in the United States to re-evaluate the use of HES in cardiac surgical patients. The data from this laboratory investigation by Boldt et al provide further support for the safety of balanced, third-generation HES solutions. However, further clinical studies are needed to determine the effect of balanced, rapidly degradable HES on blood loss, transfusion requirements, renal function, and other important outcome measures in patients after CPB. In a recent small, randomized pilot study enrolling 50 coronary artery bypass graft surgery patients, the CPB circuit was primed with either 1,500 mL of 6% HES 130/0.42 in a balanced electrolyte solution or 500 mL of 5% albumin plus 1,000 mL of 0.9% normal saline.28Boldt J. Suttner S. Brosch C. et al.Cardiopulmonary bypass priming using a high dose of a balanced hydroxyethyl starch versus an albumin-based priming strategy.Anesth Analg. 2009; 109: 1752-1762Crossref PubMed Scopus (66) Google Scholar Priming of the circuit with the balanced tetrastarch resulted in less impairment of coagulation, reduced release of inflammatory markers, and fewer alterations in renal tubular integrity compared to albumin prime. Although these initial findings are promising, more data from multiple large-scale clinical investigations are required before balanced rapidly degradable HES preparations can be recommended as routine volume-replacement therapy in cardiac surgical patients. Although beneficial effects of new HES preparations on mortality may not be observed in these trials (not yet shown in the "crystalloid v colloid debate"), improvements in other important outcome variables (coagulation, metabolic status, organ function, inflammation, weight gain, microcirculatory flow, and hospital length of stay) may be noted when compared with conventional volume-replacement regimens. The accumulating data from laboratory and clinical investigations suggest that balanced third-generation HES solutions are safe and effective plasma expanders. The development of novel HES agents advances clinicians another step closer in the quest for an "ideal" intravascular replacement agent. It is likely that modern balanced HES solutions will play a greater role in the perioperative management of the cardiac surgical patient in the near future.