Is the literature inconclusive about the harm of HES? We are not sure
Intravenous hydroxyethyl starch (HES) solutions were introduced for clinical use about 50 years ago without extensive clinical assessment, and this is also the case for the other currently available IV fluid solutions. HES solutions found widespread acceptance because, when compared with crystalloids, their use is associated with a superior volume effect resulting in faster hemodynamic stability with less total volume, and thus a less-positive fluid balance . Experimental data also showed positive effects on the microcirculation and attenuated inflammation. In addition, starch solutions are cheaper than albumin and they have longer shelf lives. Small studies with older HES molecules suggested renal toxicity, impaired coagulation, and long-term retention in the reticuloendothelial system . The nephrotoxicity has been related to their storage in tubular cells (osmotic nephrosis) . The modern tetrastarches were supposed to be devoid of these toxic side effects because of their lower average molecular weight, degree of substitution, and concentration. Recent trials have challenged this assumption, however.
The 6S trial in 800 patients with severe sepsis and high illness severity (control group mortality 43 %) showed increased 90-day mortality, increased need for renal replacement therapy (RRT), and increased requirement for blood products in the HES group . This trial compared a more recently developed potato-based isotonic tetrastarch molecule dissolved in a balanced carrier fluid versus a buffered crystalloid solution in the control group. In contrast to traditional expectations of a need for more crystalloid, there was no significant difference in the cumulative volume of resuscitation fluid used, in hemodynamic parameters in the first 24 h, or in fluid balance over the first three study days.
In the CHEST trial, 7000 ICU patients who were less sick (control group mortality 17 %) but who had a requirement for fluid resuscitation were randomized to a saline-based maize-derived isotonic tetrastarch or 0.9 % saline, prepared in indistinguishable bags . This study did not show a difference in 90-day mortality, but reported an increased need for renal replacement therapy, somewhat higher creatinine levels, and increased need for blood products in the HES group. However, the CHEST results were not entirely internally consistent with a hazard attributable to HES. First, the trial showed a greater volume effect of HES than saline. Indeed, the HES patients had higher mean central venous pressures (perhaps reflecting greater intravascular persistence) and a significantly lower incidence of new cardiovascular failure. This occurred in the presence of a substantially lower amount of study fluid, and together with the higher urine output, this in turn resulted in a less positive fluid balance in the HES group. Second, fewer patients in the HES group experienced mild or moderate acute kidney injury (AKI) (by RIFLE criteria) than in the saline group. This observation was confirmed in a Cochrane analysis (based on 8769 patients in 20 studies) and might be related to the better short-term volume effect reversing a prerenal state, whereas more severe forms of AKI could be the result of tissue accumulation of starch leading to injury in susceptible kidneys. It is also possible that a mild diuretic effect was present in those healthier patients, reducing the incidence of oliguria and thus of mild AKI. After deletion of the urine output criteria for AKI, the difference for the milder forms disappeared and the association with more severe forms strengthened .
When considered together, the 6S and CHEST trials appear to suggest that worse survival is only shown in patients with severe sepsis and high illness severity, although this idea was not specifically reported in either study alone [4, 5]. Whether this represents a true dose effect or an increased susceptibility to starch toxicity in severely ill patients is not clear . Mainly on the basis of these two trials, regulatory agencies around the world made it either impossible or very difficult to use HES solutions in critically ill patients, and demanded restrictions and renal follow-up in other settings. The resulting controversy resulted in a proliferation of meta-analyses and heavy debates [8, 9]. This debate has recently intensified with the publication of a report which appears to demonstrate inconsistencies in the adverse event (AE) reporting methodology of the CHEST trial . Specifically, it is unclear whether or not all patients exposed to HES prior to randomization were included in the HES group, or just those who subsequently experienced an AE. Although this controversy will probably not change the principal findings of the study, and thus arguably will not affect the regulators’ positions either, there appears to be a need to clarify precisely which patients did and did not experience an AE.
Limitations of the 6S and CHEST trials included the absence of significant differences in AKI incidence, the lack of predefined indications for the initiation of RRT, the absence of an effect on RRT after adjustment for confounders in CHEST, prolonged administration of study fluids, protocol violations, not respecting dose limitations, and doubts about the appropriateness and effectiveness of fluid resuscitation in patients that were already fluid-resuscitated before inclusion [11, 12]. Unnecessary fluid-induced hypervolemia could have stimulated the release of atrial natriuretic peptide (ANP) that in turn caused shedding of the glycocalyx, potentially explaining the absence of a differential volume effect .
The key question is whether these findings are relevant also to the short-term use of starch solutions, e.g., in the operating room environment, and whether or not they apply to the initial hemodynamic stabilization of acutely hypovolemic patients. Another randomized trial of colloids versus crystalloids in the ICU setting (CRISTAL trial) found no difference in 28-day mortality or need for RRT. There were also fewer days of mechanical ventilation and cardiovascular support with colloids (mainly starches) when compared with crystalloids. In fact, patients treated with colloids in that study had better 90-day survival . As expected, the median volume administered in the first 7 days was significantly higher in the crystalloid group. Faster hemodynamic stabilization with HES had also been previously reported in the CRYSTMAS trial .
Other settings of acute hypovolemia include trauma and surgery, both situations with a lower risk of glycocalyx disruption. In the setting of penetrating trauma a blinded comparison of tetrastarch with 0.9 % saline demonstrated that the colloid group received less fluid, had a more rapid decrease in lactate, and less renal injury. In blunt trauma no difference in fluid requirement was noted but the HES group required more blood products . In high-risk surgical patients, goal-directed therapy including starches for preload optimization has been shown to reduce postoperative complications. Two small, blinded randomized controlled studies (RCTs) in this setting found a volume-sparing effect with tetrastarches compared with crystalloids without adverse renal outcomes, although the event rate for the latter was very low [17, 18].
Most studies comparing starches with other fluids in surgical patients are small, non-blinded, and have low event rates and short follow-up [19, 20]. In contrast to the short-term benefit related to the volume-sparing and improved volume effect with faster hemodynamic stabilization, the potential harm from starches may require more time to manifest: “immediate gratification with delayed costs” . In this regard it is interesting to note that the mortality curves in the 6S trial only started to diverge after 15–20 days. Alternatively the short-term advantages may have long-term benefit that outweighs harm in surgical patients . However the available evidence does not allow a definitive conclusion.
In summary, outside the ICU harm from correcting acute hypovolemia with starches has not been clearly demonstrated, but we still lack adequately designed RCTs. The evidence of benefit is limited to short-term effects on hemodynamics and fluid balance. This knowledge gap could potentially be filled with large blinded randomized trials evaluating long-term outcomes with regard to survival and morbidity, including kidney function. While awaiting these results clinicians should consider fluids as IV drugs that should be used with the same caution and respect as any other medication, taking into account the specific indication for their use, any contraindications, and with careful consideration of the possibility of toxicity.
Compliance with ethical standards
Conflicts of interest
No conflicts of interest.
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