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The Next Generation of Colloids: Ready for “Prime Time”?

Nussmeier, Nancy A. MD*; Searles, Bruce E. BS, CCP

doi: 10.1213/ANE.0b013e3181bef685
Editorial: Editorials

From the *Department of Anesthesiology, College of Medicine, and †Department of Cardiovascular Perfusion, College of Health Professions, SUNY Upstate Medical University, Syracuse, New York.

Accepted for publication August 27, 2009.

Address correspondence and reprint requests to Nancy A. Nussmeier, MD, Department of Anesthesiology, SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY 13210. Address e-mail to

In August 2003, the United States (US) Food and Drug Administration (FDA) added the following warning statement to the labeling of 6% hydroxethyl starch (HES) in saline (HESPAN® B. Braun Medical, Irvine, CA): “not recommended for use as a cardiac bypass pump prime, while the patient is on cardiopulmonary bypass (CPB), or in the immediate period after the pump has been discontinued because of the risk of increasing coagulation abnormalities and bleeding in patients whose coagulation status is already impaired.”1 The FDA has not added a similar warning statement to the labeling for Hextend® (BioTime, Berkeley, CA), a newer form of 6% HES product having a smaller average molecular mass formulated in a physiologically “balanced” solution of electrolytes and lactate. More recently, the FDA approved another product, 6% HES 130/0.4 in 0.9% saline (Voluven®, Fresenius Kabi, Halden, Norway), which is classified as a low molecular weight and low molar substitution HES preparation.* As yet, there are no FDA warning statements regarding CPB priming with Voluven. Other more rapidly degradable HES formulations are undergoing clinical trials. Certainly, the introduction of these modern synthetic colloid solutions has renewed interest regarding their expanded use.

In this issue of Anesthesia & Analgesia, Boldt et al.2 present the results of a small clinical trial of patients undergoing coronary artery bypass graft (CABG) surgery with different CPB circuit priming solutions. Several limitations to this study must be acknowledged in interpreting the results. First, the title implies that the comparison is between CPB priming with a “balanced” 6% HES 130/0.42 preparation containing Na+ 140 mmol/L, Cl 118 mmol/L, K+ 4 mmol/L, Ca2+ 2.5 mmol/L, Mg++ 1 mmol/L, acetate 24 mmol/L, and malate2− 5 mmol/L (Tetraspan®, B. Braun, Melsungen, Germany; termed HES in this study) versus an albumin-based solution. However, the comparison was actually between 1500 mL of balanced HES and a saline-based solution (1000 mL of 0.9% saline) that included 500 mL of 5% albumin. Furthermore, the intravascular volume replacement strategy used perioperatively in this study confounds any differences in the measured outcomes between the groups, in that the HES group received additional HES and a balanced electrolyte solution (Sterofundin Iso®, B. Braun) in a 1:2 ratio, whereas the “albumin” group received additional albumin and 0.9% saline solution in a 1:2 ratio. Based on a prior review published by the same authors, this may not be a fair comparison insofar as unwanted electrolyte disturbances and/or acid-base derangements have been noted in studies in animal models and humans when large volumes of saline solution were administered.3 Furthermore, it is not standard practice in the US or Europe to prime CPB circuits with 0.9% saline.4,5 Also, the albumin group received larger transfusion volumes of both red blood cells and fresh frozen plasma. Therefore, it is difficult to determine whether any differences in the findings between study groups are attributable to the use of CPB priming with HES versus albumin or, rather, the decreased osmolarity, ionic imbalance (caused by the use of saline), or greater number of transfusions in the albumin group.

Because this study by Boldt et al.2 is a small clinical trial with significant lack of blinding, it would be reasonable to consider it to be exploratory. However, its publication does provide an opportunity for cardiac anesthesiologists, surgeons, and perfusionists to reconsider the role of nonprotein synthetic colloids for priming the CPB circuit. Specifically, we find ourselves asking if this newer class of balanced low molecular weight, low molar substitution, rapidly degradable HES-based synthetic colloids is safe, efficacious, or better compared with the alternatives in current use as pump prime solutions.

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The initial clinical application of extracorporeal circulation for cardiac surgery in the early 1950s was with circuits requiring very large volumes of priming solution. The state of clinical practice at this time was recorded in the field’s first textbook.6 Early CPB circuits were typically primed with 1–5 L of fresh whole blood. Concerns regarding the hazards of blood transfusion along with concerns about the high viscosity of the resultant CPB prime solution led to experiments with hemodilution and asanguineous CPB prime techniques. By the early 1960s, many centers were using crystalloid CPB primes. Drawbacks included rapid extravasation of the prime fluid into the interstitium and acidosis.7 These issues were addressed by the addition of plasma expanders to the CPB prime and the adoption of balanced electrolyte crystalloid solutions as the primary diluents.

Throughout the 1970s, there was little standardization of CPB priming composition. Prime solutions used at that time included unbalanced isotonic solutions (0.9% saline and 5% dextrose in water) and balanced isotonic solutions (lactated Ringer’s solution) as well as balanced hypertonic solutions (5% dextrose in lactated Ringer’s solution). In attempts to attenuate fluid loss and edema formation, colloids such as Dextran® (Hospira Worldwide, Lake Forest, IL), albumin, and plasma protein fractions were evaluated.8 However, the negative effects of Dextran on blood coagulation were clearly undesirable.9 The risk of disease transmission with plasma protein and the steep increase in the cost of albumin led to the use of gelatin solutions manufactured from bovine collagen and hydroxyethylated polymers of starch.10 This practice was abandoned by most centers when the FDA withdrew US marketing approval for the use of gelatin for intravascular volume expansion in 1978 because it was associated with reduced blood clotting, prolonged bleeding time, and increased blood viscosity.11 By the 1990s, widely read textbooks made reference to “the modern priming solution” containing a variety of electrolytes in concentrations similar to plasma.12 Currently, there is nearly universal acceptance regarding the use of a balanced electrolyte solution to prime the extracorporeal circuit (e.g., LR, Normosol® [Hospira Worldwide], or Plasmalyte® [Baxter, Deerfield, IL]).4,5,13

The use of colloids as a component of the CPB prime, however, is less standardized in current clinical practice. One systematic review of this topic concluded that “albumin appears to be, in general, the safest colloid of the four we reviewed [albumin, hydroxyethyl starch products, dextran, and gelatin].”14 Adverse events considered by the authors included mortality, anaphylactoid reactions, pruritus, coagulopathy, renal failure, circulatory dysfunction, hepatic dysfunction, and tissue deposition.14 Another large retrospective review of 19,578 patients undergoing CABG surgery concluded: “Albumin use appears to be associated with a lower incidence of mortality after CABG surgery compared to nonprotein colloid use.”15 Notably, these reviews did not separately consider HES preparations of low (≤130 kD) versus high molecular weight or low (≤0.5) versus high molar substitution.

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Perioperative concerns regarding the use of original HES preparation for CPB priming center around the risk of inducing coagulation abnormalities16 and postoperative renal dysfunction.17 These concerns must be fully addressed in studies of the newer HES synthetic colloids. Commentators have noted that even some recent trials of HES preparations versus alternatives (albumin or crystalloid) show a trend toward greater blood loss, incidence of renal morbidity, or mortality in patients receiving HES.18–21 These commentators argue that the observed safety problems are inherent in the HES molecule, rather than in the properties of unique HES solutions.

However, proponents of the use of third-generation, balanced low molecular weight, low molar substitution, rapidly degradable HES preparations for CPB priming22,23 argue that these modern products may have advantages over first- or second-generation preparations in several respects. The most current HES preparations reportedly have minimal, if any, influence on coagulation24 and are dissolved in plasma-adapted solutions that no longer contain nonphysiological amounts of sodium and chloride and thus do not produce hyperoncotic kidney failure.18,25 Although investigators using modern HES preparations for CPB priming have reported reassuring results regarding both hemostasis2,26–29 and kidney function,2,30–32 these studies are limited by small sample size and single-center study design. Thus, consensus on the safety and efficacy of these newer HES preparations for CPB priming has not yet been achieved.

In summary, modern balanced HES products may well represent a significant advance for use in extracorporeal circuit priming. Widespread adoption of such priming practice cannot be recommended until the results of larger, multicenter, well-controlled clinical studies are available, including clinically relevant biomarkers and outcomes. The study by Boldt et al. in this issue of Anesthesia & Analgesia is another step toward achieving the level of evidence needed for routine use of third-generation HES preparations in CPB priming.

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*US Food and Drug Administration. Available at: Accessed July 15, 2009.
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