To the Editor:
We thank the authors for their important and informative review article “Hydroxyethyl Starches: Different Products—Different Effects ” published in the July 2009 issue of Anesthesiology.1However, there is inaccurate information in the column titled “Maximum Daily Dose, ml/kg” in table 1, which we believe should be corrected. Two references are cited for table 12,3; however, neither provide support for all the maximum daily doses listed. It seems that the main reference provided to support these data is a similar table (also table 1) in the September 2005 issue of Anesthesiology.2This earlier publication does not provide any references for the maximum daily dose column, other than for mentioning that “All statements are given by the manufacturers.”
For example, it is a point of fact that hydroxyethyl starch 670/0.75 in 6% balanced solution (Hextend®, Hospira Inc., Lake Forest, IL) has no maximum daily dose promulgated by the manufacturer in the Food and Drug Administration-approved package insert.*Under “Dosage and Administration,” there is language regarding what might “typically” be administered (“Doses of more than 1,500 ml per day for the typical 70-kg patient (approximately 20 ml per kg of body weight) are usually not required . . .”), but this is in no way a “maximum daily dose” or “safe recommended dose” as some have erroneously argued.
For most of the starches, and certainly for hydroxyethyl starch 670/0.75 (Hextend®) and hydroxyethyl starch 600/0.7 (Hespan®, B. Braun Medical Inc., Irvine, CA), it is impossible to designate any safe maximum dose. No dose-finding randomized trials (or observational studies) have ever been done that demonstrate that 20 ml/kg is “safe” but 21 ml/kg causes a clinically significant worse outcome. Observational studies are very confounded in this setting because patients who receive larger volumes of these starches invariably have more extensive surgery and/or bleeding or may require more blood and blood products. Therefore, in the absence of data from well-designed randomized trials, it is impossible to know whether the larger volume of starch is a cause of bleeding or a marker for more complex surgeries with an expected increased blood loss. Multivariate analysis is an imperfect science and cannot control for this level of confounding. In vitro studies, which assess the impact of dose via increases in percent hemodilution, cannot be used to define a clinical “maximum safe dose.” Finally, it is possible that even if larger doses have theoretical effects on bleeding risk, these effects may be balanced by theoretical benefits of starch related to decreased tissue edema.
In summary, we are not arguing that there is not a provable maximum safe dose for some of these fluids. However, based on existing data, it is impossible at this time to cite a maximum daily dose for some of these fluids, as has been published.1,2
†Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina. email@example.com