Shocking: A “Newer” Hetastarch Product Is Nephrotoxic and Deadly in Severe Sepsis

OVER THE LAST four decades, 6% hydroxyethyl starch (hetastarch) products have been promoted as a less-expensive alternative to 5% human albumin for blood volume expansion. But as we are now learning from a stream of recent published evidence, for selected populations, hetastarch (HES) can come with its own price to pay — in safety.

The 450/0.7 class* of high-molecular weight HES, which includes Hespan and Hextend, actually comprises polymers of varying sizes, mainly removed from the circulation by slow excretion through the kidneys. Special care is advised in the prescribing information for patients with impaired renal clearance¹ to minimize the risk of acute renal failure.

Because HES products also directly lower circulating factorVIII activity and von Willebrand antigen levels, their labeling recommends use “with caution” in open-heart surgeries for several decades before published retrospective case reviews^2,3,4 showed that administration of HES sharply increases the risk of excessive bleeding in relation to albumin use in typically cold, hemodiluted and anti-coagulated patients undergoing cardiopulmonary bypass surgeries. Finally in 2003, a specific warning was added to the U.S. labeling for all 6% HES products.

“Improved” Low-Molecular-Weight HES Products

It was against this backdrop that a new class of lower-molecular-weight (130/0.4*) HES products was introduced in Europe in the late 1990s, including Tetraspan 6% 130/0.4 in Ringer’s acetate (B. Braun Medical) and Voluven 6% 130/0.4 in 0.9% sodium chloride injection (Fresenius Kabi). The U.S. Food and Drug Administration approved Voluven for sale in 2007, and it is currently distributed through Hospira. These “improved” HES products feature more rapid renal excretion than the older 450/0.7 products and lesser effect on coagulation function. Thus, there is reason to expect them to have a better overall adverse event risk profile compared with the older 450/0.7 HES products that still predominate in U.S. hospitals.

For years, there has been controversy over whether HES products could have deleterious effects on renal function in patients without a history of kidney disease. Similar to the instance in which excessive bleeding complications were eventually shown to be a problem specifically in cardiopulmonary bypass surgery, it turns out that the answer depends on which patient populations one looks at.

A large 2007 observational study examining a heterogeneous population of 3,147 patients across 198 European intensive care units determined that administration of HES had no influence on renal function or the subsequent need for renal replacement therapy (RRT).

This finding seemingly contrasted with a 2001 report by French researchers who documented an 83 percent higher risk of acute renal failure in severe sepsis or septic shock patients receiving a 200 kDa HES product than in those receiving a gelatin-based volume expander.⁶

In fact, the long-standing “controversy” over renal toxicity actually reflects an issue of research focus. The matter now appears to have been settled by two recent landmark studies, both published in The New England Journal of Medicine. In a 2008 study, a German team reported that 262 severe sepsis patients randomized to receive a high-molecular-weight (200/0.5) HES product had significantly higher rates of acute renal failure and renal replacement therapy than 275 others who received Ringer’s lactate.⁷

Then this year, a Scandinavian team reported on a clinical trial in which they randomized 804 severe sepsis patients to 130/0.4 HES or Ringer’s acetate, and documented a significantly increased risk of severe bleeding, RRT requirement and death for those receiving HES.⁸ Not in critical care patients generally, but specifically in severe patients, a low-molecular weight HES product chemically similar to Voluven has now been shown to be both nephrotoxic and coagulopathic. Broader Implications of the New HES/Sepsis Findings While HES is generally safe and effective for treatment of hypovolemia, the available evidence convincingly shows that administration of at least two popular types of hetastarch products is independently associated with increased risk of renal and other serious complications in patients with severe sepsis. Adding a new warning to the labeling of these HES products or perhaps specifying the presence of sepsis or septic shock as a contraindication may therefore be in order. But will this suffice to protect other patients from potential harm?

Possibly not. Consider the debilitated, very elderly and/or immunocompromised patient undergoing a major abdominal, urological or extensive trauma surgery who is perioperatively infused with large volumes of HES in lieu of human albumin. A small but meaningful percentage of these at-risk patients will have the misfortune of developing postoperative sepsis, in some cases progressing to severe sepsis or septic shock.

The elimination half-life of conventional 450/0.7 and 130/0.4 HES products is about 46 and 12 to 16 hours, respectively.⁹ In certain surgical subpopulations at increased risk of postoperative sepsis, could there be a corresponding increased risk of nephrotoxicity, bleeding or death associated with residual non-excreted HES? It is a difficult question that might be answerable only with painstaking retrospective analysis of many thousands of discharge records. Such a study might never be done.

In the meantime, it may be worthwhile to consider the recent clinical literature before reflexively substituting “cheaper” HES for the colloid that nature has perfected in its own evolutionary laboratory: human serum albumin.

* “450” and “130” refer to the minimum molecular weight, and “0.4” and “0.7” refer to the degree of molar substitution of hydroxyethyl groups on the glucose units of the starch polymer.