Hydroxyethyl starch 130/0.4, widely used for fluid resuscitation in hypovolemia due to severe sepsis, raises the risk of death within 90 days, compared with Ringer’s acetate, according to a report published online June 27 in the New England Journal of Medicine.
The low-molecular-weight hydroxyethyl starch (HES) is a colloid solution thought to afford more rapid and lasting circulatory stabilization, compared with standard IV fluids such as Ringer’s acetate. HES 130/0.4 has been widely adopted in ICUs around the world, even though data about its effectiveness are limited and several trials have raised concerns about its safety, said Dr. Anders Perner of the department of intensive care, Copenhagen University Hospital, and his associates.
Their Scandinavian Starch for Severe Sepsis/Septic Shock study was an international trial to compare the effects of HES 130/0.4 against Ringer’s acetate on the composite outcome of death or end-stage kidney failure within 90 days of treatment. The study population comprised 800 septic shock patients treated at 13 university-affiliated ICUs and 13 nonacademic general ICUs in Denmark, Norway, Finland, and Iceland between December 2009 and November 2011.
When their physicians decided that volume expansion was required, the study participants were randomly assigned in equal numbers to receive fluid resuscitation with either HES 130/0.4 or Ringer’s acetate in a manner that concealed treatment assignment from patients, clinicians, research staff, and study committee members.
The median cumulative volume of fluid administered was 3,000 mL.
The primary outcome measure (a composite of death or dependence on dialysis), occurred in 51% of patients who received the starch, compared with 43% of those who received Ringer’s solution. When the two outcomes were analyzed separately, this difference was found to be entirely due to an increased risk of death in the starch group, the investigators said (N. Engl. J. Med. 2012 July 27 [doi:10.1056/NEJMoa1204242]).
In multiple further analyses of the data, including logistic regression and per-protocol analyses, these results persisted. The separation of the survival curves indicated that HES 130/0.4 tends to induce death late in the course of hospitalization, Dr. Perner and his colleagues said.
In addition, more patients in the starch group than in the Ringer’s group required renal replacement therapy (61% vs. 44%) or developed bleeding complications (10% vs. 6%).
Previous studies suggested that a high proportion of HES "is taken up and deposited in tissues, where it cannot be metabolized and it acts as a foreign body. Long-term toxic effects of HES deposition have been described in the kidney, liver, and bone marrow.
"Together, all these negative effects of HES may have caused the late deaths observed in our trial" and in previous studies, the researchers noted.
This study also raises the question of whether HES 130/0.4 is actually more potent than crystalloids in patients with severe sepsis. "We did not observe significant differences in trial fluid volumes between the study groups," a result that has been reported in a previous study, they added.
The study findings should be generalizable to other populations because this trial had broad inclusion criteria and very few exclusion criteria. It even included patients who had acute kidney injury at baseline, the authors said.
This study was supported by the Danish Research Council, the Rigshospitalet Research Council, and the Scandinavian Society of Anesthesiology and Intensive Care Medicine. Dr. Perner reported receiving grant support from Fresenius Kabi.