Hydroxyethyl Starch (Voluven) Causes Kidney Failure In Large Trial
Hydroxyethyl starch (HES) was already wearing a scarlet letter as an potentially dangerous volume resuscitation agent for patients in shock, after evidence emerged this year that hydroxyethyl starch kills people with severe sepsis. Now, another huge, convincing trial shows that hydroxyethyl starch (Voluven) damages kidneys and increases the need for dialysis, in a broad spectrum of critically ill patients.
Hydroxyethyl starch has long been known to sometimes cause organ damage, mainly to the kidneys and liver. But diehard proponents of hydroxyethyl starch emphasized that most of the proof of harm in previous studies was from the use of concentrated HES (10%, with molecular weight of more than 200 kD and a "molar substitution ratio" or hydroxyethyl groups on the glucose molecule of more than 0.5), whereas commonly used solutions are lower concentration (6%, molecular weight 130 kD, ratios of 0.38 to 0.45).
ANZICS investigators set out to settle the question with the Crystalloid versus Hydroxyethyl Starch Trial (CHEST), using the supposedly safer lower-concentration hydroxyethyl starch in thousands of patients.
What They Did
Authors enrolled 7,000 critically ill patients in 32 ICUs in Australia and New Zealand who were deemed by the admitting physician to need volume resuscitation, and randomized them to receive 6% hydroxyethyl starch (130/0.4) in 0.9% saline (Voluven brand) or 0.9% saline (in identical bags) for fluid resuscitation in the ICU until death, discharge, or 90 days after randomization. Patients were about 40% surgical/60% nonsurgical, and were sick: 29% had sepsis; two-thirds were mechanically ventilated; half were on vasopressors. This was funded by their government and the makers of Voluven.
After receiving the maximum daily dose of about 3-4 liters of 6% hydroxyethyl starch, patients got normal saline. After they left the ICU, any fluid was permitted. The primary outcome was all-cause mortality at 90 days; acute kidney injury, dialysis need, and multiple other secondary outcomes were measured. They calculated 90% power to identify a 3.5% absolute difference in 90-day mortality or a 1.5% increase in acute renal failure.
What They Found
Patients receiving hydroxyethyl starch had a 21% relative (1.2% absolute) increased risk of needing dialysis or other renal replacement therapy (7.0%) compared to those getting normal saline (5.8%) -- a number-needed-to-harm of 83.
Patients getting hydroxyethyl starch received less total fluid, but more blood products. They had higher bilirubin levels with more pruritis and rash (hydroxyethyl starch accumulates in the liver, damaging it). They had slightly lower need for vasopressors, but no improvement in parameters of tissue perfusion (lactate) or mean arterial pressure.
There was no difference in mortality (17% vs. 18%) or other outcomes. Post hoc analyses showed elevated creatinine and decreased urine output in the hydroxyethyl starch group in the first week of treatment.
What It Means
Products like hetastarch, pentastarch, and Voluven became popular for their perception among surgeons and anesthesiologists as superior volume expanders to normal saline; the FDA approved hydroxyethyl starch for acute blood loss in 2008. But some have wondered whether aggressive marketing boosted Voluven's profile: in 2011 the FDA sent Hospira, Voluven's U.S. marketer, an untitled letter warning them not to over-hype hydroxyethyl starch's volume expansion properties.
Much of the basis for support of hetastarch comes from the more than 350 published papers of early strong hetastarch proponent Dr. Joachim Boldt, a German anesthesiologist. Dr. Boldt has since been disgraced and his body of work is being reviewed and often retracted for alleged data falsification and ethics violations. In fact, Boldt holds the current world record for retractions: 89 at last count, according to Retraction Watch. Dr. Boldt was even under criminal investigation in 2011 for fabricating research results, according to Anesthesiology News. (He wrote the article cited above, and has also received funding from the makers of various hetastarch products, including Voluven.)
In this trial, people getting hydroxyethyl starch required more blood, not less. So what's the reason to use it, again? In truth, I've never actually even seen the stuff ... and from what's been published, I have no desire to ever see it dripping into my patients' IVs.
Despite all the above, millions of units of Voluven continue to be infused globally each year. It's rarely used in the U.S., but a 2009 FDA safety review (not including the recent data) concluded hydroxyethyl starch was safe and appropriately labeled (including its potential to cause anaphylaxis). Hospira markets Voluven in the U.S.
Clinical Takeaway: No starch, please -- not in my shirts, nor in my veins.
John Myburgh, Simon Finfer, Steven A.R. Webb, et al for the CHEST Investigators and the ANZICS Clinical Trials Group. Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care. NEJM 2012; 367: 1901-1911.