The Pros and Cons of Hydroxyethyl Starch Solutions

The optimal type of fluid for intravascular volume resuscitation in critically ill patients remains a matter of debate. With their higher molecular weight, colloids remain in the intravascular space longer, and, therefore, provide more rapid hemodynamic stabilization than crystalloids, which extravasate to a greater degree so that more fluids are required to achieve the same end points. However, colloids are more expensive than crystalloids, in particular albumin, so that other colloids have been developed, including gelatins, dextrans, and hydroxyethyl starch (HES) solutions. Hydroxyethyl starch solutions have evolved since they were first developed in the Unite States in the 1970s. The first HES solutions included HES molecules of relatively high molecular weight and high degree of substitution, in an attempt to prolong their vascular persistence. These solutions were associated with an increased risk of bleeding (1,2) and renal failure (3–5). Prolonged persistence in the body also raised concern (6), and there are numerous reports of delayed itching in the dermatologic literature (7). Lower molecular weight HES solutions and solutions with lesser degrees of substitution have since been developed that may have an improved pharmacological profile, with fewer negative effects on coagulation and renal function, and more rapid tissue clearance (8,9). Importantly, in addition to their effects as intravascular volume expanders, HES solutions may have other properties. As early as the 1980s, Zikria et al. (10,11) reported that HES solutions could reduce microvascular permeability, leading to the concept that they could “plug” the leaks created in the endothelium during various disease processes, including sepsis and burns (12). In this issue of Anesthesia & Analgesia, Feng et al. (13) show that, in a model of cecal ligation and perforation, rats that received HES or gelatin solutions had reduced pulmonary capillary leakage compared with those that received normal saline. In addition, HES administration was associated with reduced expression of various proinflammatory mediators, including tumor necrosis factor and interleukin-1, while gelatin administration was not. In their present study, these authors have extended their previous data in rats, which showed that HES significantly reduced lipopolysaccharide-induced increases in lung capillary permeability, and inhibited lung neutrophil accumulation, cytokine-induced neutrophil chemoattractant protein, and nuclear factor-κ B activation (14). Their results also agree with experimental studies from other groups demonstrating the antiinflammatory effects of HES solutions (15–19). Hydroxyethyl starch has been shown to restore macrophage integrity and prevent the increase in interleukin-6 in mice after trauma-hemorrhage (15), to alter the interaction of neutrophils with activated endothelium (16,17), to decrease the neutrophil respiratory burst induced by Escherichia coli (18), and to attenuate hypoxia-induced increases in vascular leakage and acute inflammation (19). Boldt et al. (20), in patients undergoing major abdominal surgery, reported that the administration of HES was associated with reduced markers of inflammation and endothelial activation compared with crystalloid. The Feng et al. data (13) thus seem consistent with previous studies, but interpretation remains difficult. An important question is whether the observed effects are due to the solution itself or, rather, due to the effectiveness of the fluid resuscitation. In in vivo studies it is difficult to separate the specific effects of the individual fluids on the vessels from the general effects of fluid resuscitation. These difficulties are well illustrated by Marx et al. (21) in their study in a porcine model, where the early administration of HES solution restored tissue oxygenation better than Ringer’s lactate solution; however, there were no differences in the albumin escape rate, suggesting that the changes observed were due more to hemodynamic than to specific antiinflammatory effects. Prolonged tissue hypoperfusion with regional tissue hypoxia can increase the inflammatory response. Even in the absence of inflammation, prolonged severe hypoxia results in increased endothelial permeability, believed to be a key factor in the development of organ failure (22); thus, the longer a shock state persists, the greater the likelihood that the patient will develop organ failure. In patients with severe sepsis, we (23) recently showed that the duration of vasopressor requirement was directly related to the risk of subsequent organ failure. Intravascular fluid resuscitation has been shown to reduce the inflammatory response. For example, improved resuscitation after hemorrhage is associated with reduced pulmonary dysfunction and lung inflammation (24,25), and preemptive intravascular volume administration prevents lipopolysaccharide-induced microcirculatory changes (26). In other septic models, intravascular fluid resuscitation attenuated the release of cytokines or platelet activating factor (27,28). Logically, therefore, rapid reversal of acute circulatory failure should result in a shorter and less intense inflammatory reaction, with fewer permeability alterations and less edema formation. In the study by Feng et al. (13), the effects of HES were compared with those of an identical amount of gelatin, a colloid with a molecular weight only half that of albumin. Hence, the intravascular volume effects may have been greater in the HES group than in the other group. Arterial blood pressure was similar in the various groups, but this provides only a rough estimate of hemodynamic stability. Even measurements of cardiac output would not be entirely reassuring. Indeed, macrohemodynamic variables can be restored while the microhemodynamic status remains altered (29). Studies in rats, like that by Feng et al. (13), cannot explore these differences reliably, and one would like to see similar experiments in larger animals, or even in humans, and with a more effective colloid (such as albumin) for comparison. In summary, the intensity of the intravascular fluid resuscitation may be more important than the type of fluid itself, and HES solutions have very effective vascular effects. In the meantime, if the evidence is strong enough to support the antiinflammatory effects of HES, the question then becomes, Do these antiinflammatory properties give HES solutions a definitive advantage over other fluids? Perhaps not. First, a reduced inflammatory response does not necessarily translate into clinical benefit. Decreased capillary leak may be globally beneficial, but decreased neutrophil activation may have unwanted, as well as wanted, consequences. Second, assuming that the antiinflammatory effects are beneficial, other fluids may have similar advantages. Albumin, for example, has been shown to have antiinflammatory and antioxidant effects (30–33). Hydroxyethyl starch solutions may have other drawbacks, including the risk of altered hemostasis and the persistence of HES molecules in the body. In addition, there is new concern about the increased risks of renal failure associated with HES administration. A recent multicenter German study, the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis study, indicates that HES administration in patients with severe sepsis may be associated with an increased risk of acute renal failure. (Data presented at the 27th International Symposium of Intensive Care and Emergency Medicine, Brussels, March 2006.) So, where does this leave us in the big fluid debate? The present results are interesting and add another little piece to the big puzzle, but much more work is needed before we will be able to see the full picture and to better determine where each fluid fits. Although we use these fluids every day, we still know surprisingly little about them.