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Balanced hydroxyethyl starch solutions: the Holy Grail for clinicians?


Emmanuel Futier
Department of Anaesthesiology and Critical Care Medicine
Estaing Hospital
University Hospital of Clermont-Ferrand
Clermont Ferrand

The administration of intravenous fluids remains one of the most common interventions in medicine. Fluids should be seen as medications with indications, contraindications and side effects. Important differences in interstitial architecture result from using colloids instead of crystalloids for volume replacement. While crystalloids are physiologically distributed within the whole extracellular compartment (80% leave the vascular space), colloids have been designed to remain within the vascular space. Alongside crystalloid solutions, colloids are frequently considered as a class of interchangeable solutions. However, differences in physical properties exist among solutions.

Are hydroxyethyl starches all the same?
Hydroxyethyl starches (HES) are derivatives of amylopectin, a highly branched compound of starch that structurally resembles glycogen, with the anhydroxyethyl glucose residues substituted by hydroxyethyl groups in order to improve the stability of the molecule. In vivo, all HES preparations undergo enzymatic degradation by alpha-amylase.1,2 Physiochemical properties of HES are characterised by:3

The concentration mainly influences the initial volume effect.

Molecular weight
HES are polydisperse systems containing particles with a wide range of molecular mass. In polydisperse systems, the determination of particle mass or relative molecular mass produces an average, which depends on the method used: weight average molecular weight (Mw) and number average molecular weight (Mn). The Mw determines the viscosity and Mn indicates the oncotic pressure. The ratio Mw:Mn gives an index of the degree of polydispersity in the system. The osmotic effectiveness of an HES preparation depends on the number of particles, and not the molecular size. High Mw HES have been found to be associated with a greater degree of accumulation in interstitial spaces and the reticulo-endothelial system,4,5 and are associated with the development of osmotic nephrosis-like lesions in both proximal and distal tubules.3 The degree of plasma and tissue accumulation is dependent on the structure, the HES type and its physicochemical properties. Clearance and residual concentrations of HES are closely related to molar substitution (MS) and the C2:C6 ratio, whereas the oncotic pressure depends on the number of active particles available.

Molar substitution
HES have a varying number of hydroxyethyl residues attached to the anhydrous glucose particles, which influence the solubility of the starch polymer. The degree of substitution refers to the modification of the original substance by the addition of hydroxyethyl groups. The higher the degree of MS, the greater the resistance to degradation, and consequently, the longer its intravascular persistence. MS is the average number of hydroxyethyl residues per glucose subunit: for example, MS = 0.6 indicates that there are six hydroxyethyl residues on average per 10 glucose subunits (hexastarch).

C2:C6 ratio
The ratio refers to the site where substitution has occurred on the initial glucose molecule. Hydroxyethyl groups at the position C2 atom inhibit the access of alpha-amylase to the substrate more effectively than at the C6 position.3 Hence, HES preparations with high C2:C6 ratio are expected to be degraded more slowly.

Although HES has become an established approach to correct hypovolaemia,6 it is incorrect to conclude that all HES have similar properties and are bioequivalent,3 and there is a widespread ignorance of the content and clinical properties of different HES.7 Clinical studies have shown differences between the older (first and second generations, ie, hetastarch, hexastarch and pentastarch) and newer (tetrastarch) HES generations, especially regarding coagulation, tissue storage and renal function.5,8–11 Recent published data have shown adverse effects on renal function and on coagulation12,13 emphasising that the first and second generations should not be extrapolated to newer HES products.14–16 In addition, beside the effects of HES on macrocirculation (maintenance and restoration of intravascular volume), the effects of the third-generation HES 130/0.4 on microcirculation was found to be superior regarding tissue oxygenation when compared with crystalloids and other HES solutions.17–19 However, questions regarding the renal safety of HES remain an issue for clinicians, especially when high doses of colloids are required.20,21 In this context, the use of balanced (or plasma-adapted), rather than an unbalanced carrier solution for HES preparation, could be beneficial.

Advantages of balanced HES preparations
Apart from the substance-specific beneficial effects of HES, there is increasing interest in the type of solvent used,22 with two types of solution available in current practice: 0.9% saline and ‘balanced’ solutions that aim to mimic the biochemical composition of plasma. In contrast to conventional HES solutions, which consist of saline with abnormally high concentrations of sodium and chloride (see Table 1), balanced preparations contain inorganic ions (calcium, potassium or magnesium) or buffer components such as bicarbonate or lactate, and have a smaller sodium concentration.23,24 It has been suggested that large administration of 0.9% saline or colloids dissolved in saline may expose patients to disturbance of acid-base physiology and dilutional-hyperchloraemic acidosis,23,25 whereas balanced solutions may avoid this effect. While the clinical relevance of dilutional-hyperchloraemic acidosis is not fully elucidated,26 there is a trend in current evidence to suggest that it may have adverse consequences which may be circumvented by the use of balanced solutions.22,27

Some reports suggest that balanced solutions may be more beneficial in terms of blood coagulation and platelet function.28 In an animal model of sepsis, Kellum29 found that fluid resuscitation using a balanced HES resulted in significantly less negative base excess (BE) and improved survival rate than resuscitation using 0.9% saline.29 Experimental data also found that dilutional-hyperchloraemic acidosis was associated with a reduction in renal blood flow and a negative effect on glomerular filtration rate.30

Few studies have compared balanced and unbalanced solutions. When used in a plasma-adapted volume replacement strategy in patients undergoing major abdominal surgery, high doses of balanced crystalloids plus balanced HES (2500ml over 24 hours) had better effects regarding BE and electrolyte concentration when compared with a total unbalanced strategy.31 In a recent study, Boldt et al32 also found that, in high-risk surgical patients, a total balanced volume replacement strategy resulted in moderate but significant effects on acid-base status, inflammation, endothelial activation and renal integrity when compared with a total unbalanced regimen. Acid-base disorders represent a common phenomenon in both surgical and ICU patients, and BE is an important surrogate in identifying patients with malperfused tissues.33 Whether additional acid-base disorders induced by volume replacement in patients with pre-existing metabolic acidosis and reduced buffering capacity may be harmless remains to be evaluated.

Most fluids used for correcting hypovolaemia are not adapted to the electrolyte composition of the plasma and do not meet the criteria of an ‘ideal’ volume replacement strategy. When discussing intravenous fluids, a logical approach is to select fluids that are designed to treat specific problems. Crystalloids should be vested (= limited) to replacement of deficits, whereas currently available evidence suggests that plasma losses from the circulation should be replaced with colloids, especially in the surgical context. Among the available synthetic colloids, the development of new HES molecules towards faster and more complete elimination (which is more complete and faster with the new generations) and the third-generation HES (tetrastarch) appear to offer the best compromise between efficacy and safety. Although there is only limited data concerning the clinical relevance of dilutional-hyperchloraemic acidosis, large volumes of 0.9% saline and unbalanced HES preparations expose patients to acid-base disorders, mainly due to an excessive chloride load. Results from the experimental and clinical studies have shown that HES preparations dissolved in a balanced solution could avoid additional complications in patients’ homeostasis. Clinicians always have to remember primum nil nocere. The question of whether modulation of the acid-base status by a balanced volume replacement strategy would beneficially influence organ function, morbidity or even mortality must be evaluated in large, controlled studies in the future.

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