When the VISEP study was published in 2008,¹ proponents of colloid based resuscitation (myself included) argued that, since the study was conducted using old generation pentastarches, the data were not generalizable to all hydroxyl-ethyl fluids.² Indeed there was an emerging body of evidence supporting the safety of newer, lower molecular weight starches; particularly those composed of balanced salt solutions. Since the mind boggling revelations about the potential scale of academic misconduct by Joachim Boldt,⁷ with a large number of his publications now expunged, we have all become somewhat anxious about the true safety of HES compounds. The answer is now here, following the publication of the 6S study from Scandanavia.⁶
       Colloid fluids have one purpose – to reduce the volume of fluid required to achieve hemodynamic goals. There is something of a transatlantic controversy – the majority of European clinicians have traditionally been colloids believers; the majority of North Americans are not. Colloids are more expensive than crystalloids, have known allergic and bleeding potential and the onus of proof is always on the intervention. Presumably, if colloids are effective, they restore the circulation rapidly, prevent organ failure, prevent fluid related morbidity (pulmonary edema, wound complications, ileus etc.), reduce the length of hospital stay and reduce mortality. If these results are not achieved then colloids are, essentially, intravenous “snake oils”. Previous literature, suggest the opposite – that HES products, in particular, are associated with allergy, renal dysfunction and bleeding. There is essentially no supportive evidence in the ICU, and evidence to support colloids in the operating room is more strongly associated with the use of devices such as esophageal Doppler to achieve resuscitation goals. ⁴ Nevertheless, there is an emerging consensus that fluid over-resuscitation is associated with medley complications, and that measures that restrict overall fluid volume, particularly from 8 to 72 hours following injury or surgery, may be associated with improved outcomes.^3-5 Often fluid studies are single centred, compare one colloid against another, or use weak or surrogate endpoints. What we needed was a multicentre, international study, that looked at hard long term endpoints.

The Scandanavian group randomized 800 critically ill patients to a Ringer’s acetate solution that either contained 130/0.4 HES or did not.⁶ The patients were followed on an intention to treat basis for 90 days. Patients were enrolled if they met the criteria for severe sepsis within the previous 24 hours. Patients were given fluid by bedside clinicians in accordance with their clinical judgement (i.e. there was no fluid resuscitation protocol), and were blinded to the nature of the fluid administered. The quantity of study fluid was limited to the maximum daily dose of colloid (50ml/kg); open label Ringer’s acetate was administered if this volume was exceeded, and patients could receive saline, blood products and albumin.
This impressively simple study was conducted in 4 countries, with 50% of patients being cared for in academic medical centres and 50% in community hospitals. The study was powered to demonstrate a 10% reduction in mortality among 800 randomized patients at 90 days. What the authors demonstrated, however, was the opposite.
At 90 days following randomization, 201 of 398 patients (51%) assigned to HES 130/0.4 had died, as compared with 172 of 400 patients (43%) assigned to Ringer’s acetate (absolute risk increase of 8%, number needed to treat 12; P=0.03). In the 90-day period, 87 patients (22%) assigned to HES were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer’s acetate (absolute risk increase of 6% NNT 16; P=0.04). The risk of bleeding did not reach statistical significance – although post hoc analysis following randomization suggests that the HES group had a greater incidence of bleeding.
Interestingly, the volume of fluid administered to each group was not different: there was not colloid-effect, no fluid sparing. This was consistent with the findings of the VISEP trial.² Although a significant proportion of both groups received blood products or albumin, there was no statistical significance between the groups. In fact, the only difference between the groups was whether or not HES was administered; patients that received HES 130/0.4 were more likely to die or have kidney injury.

At this point in time the weight of evidence is now stacked up against the use of HES solutions in critical illness; the use of these agents in septic shock cannot be justified.

References

    1.    Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N et al. Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis. N Engl J Med 2008;358(2):125-139.

2.    Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N et al. Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis. N Engl J Med 2008;358(2):125-139.

3.    Kehlet H, Bundgaard-Nielsen M. Goal-directed Perioperative Fluid Management: Why, When, and How? Anesthesiology 2009;110(3).

4.    Lubarsky DA, Proctor KG, Cobas M. Goals Neither Validated Nor Met in Goal-directed Colloid versus Crystalloid Therapy. Anesthesiology 2009;111(4).

5.    Nisanevich V, Felsenstein I, Almogy G, Weissman C, Einav S, Matot I. Effect of Intraoperative Fluid Management on Outcome after Intraabdominal Surgery. Anesthesiology 2005;103(1).

6.    Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, +àneman A et al. Hydroxyethyl Starch 130/0.42 versus Ringer’s Acetate in Severe Sepsis. N Engl J Med 2012;367(2):124-134.

7.    Shafer SL. Shadow of Doubt. Anesthesia & Analgesia 2011;112(3):498-500.

This article is copyrighted by Patrick Neligan 2012 please do not reproduce without permission