Evidence is mounting that one of the most frequently used interventions in intensive care units (ICUs) does more harm than good. Data from a clinical trial published today show that patients given an antishock drug known as hydroxyethyl starch (HES) were more likely to need renal dialysis or kidney transplantation than those treated with saline solution. HES patients were also more likely to die within 90 days, although that difference was not statistically significant.
HES, a synthetic derivative of regular starch, is a large molecule that binds liquid and is commonly given to patients who have lost a lot of blood. The compound keeps up their blood volume and prevents their circulation from collapsing. A first study indicating that HES could be harmful to patients was published in The Lancet in 2001, but it was largely ignored by regulatory agencies, says Tobias Welte, a pulmonologist at the Hannover Medical School in Germany who has studied the compound. In June of this year, a clinical trial conducted in Denmark, published inThe New England Journal of Medicine, concluded that septic patients treated with HES were significantly more likely to die within 90 days and to need renal replacement therapy than patients treated with an alternative called Ringer's acetate.
That study sparked a row between author Anders Perner of Copenhagen University Hospital, who argued that the results applied to all HES compounds, and German drug company Fresenius Kabi, which felt its own compound, Voluven, was wrongly implicated by the paper. Some researchers called for the drugs to be taken off the market, but regulatory authorities argued that data from a second large clinical trial that was about to finish—and which used Voluven—was crucial.
Results from that trial, which took place in Australia and New Zealand, were published today in The New England Journal of Medicine. The Crystalloid versus Hydroxyethyl Starch Trial (CHEST) includes data from more than 6600 patients treated in ICUs. Of the patients treated with HES, 18% died, versus 17% for those treated with saline solution.
The difference is not significant, but study author John Myburgh from The George Institute for Global Health in Sydney, Australia, says that may be due to the fact that patient groups with a higher mortality were excluded from the trial, making it harder to detect a statistically significant difference. "Perner looked at septic patients. Our population was a general population of adult ICU patients," says Myburgh, who is presenting his paper at the Annual Congress of the European Society of Intensive Care Medicine in Lisbon today. He also points out that renal replacement therapy was more often needed and there were significantly higher rates of adverse events such as bleeding or itching in the HES group. Together, the two studies provide no evidence that HES compounds benefit the patient and instead raise safety concerns, he argues.
Perner agrees that the evidence points in the same direction. "It has never been shown that any of these compounds benefit patients," he says. "At the very least they should carry a label that they are contraindicated in septic patients and that extreme caution should be taken in use with other patients with increased risk of kidney failure or bleeding." That includes most patients who would routinely get HES in an ICU, he says.
But the discussion has wider implications, Myburgh says. "We need to consider more closely what fluid we give to specific patients and how much"—and perhaps the licensing process for fluids needs to be reformed. "These are really intravenous drugs and should be treated as such."