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Hydroxyethyl starch, a synthetic colloid used worldwide for acute fluid resuscitation in critically ill patients, appears to significantly raise the risks of mortality and severe renal injury, compared with other resuscitation solutions, according to a systematic review and meta-analysis published in the Feb. 20 issue of JAMA.
The use of hydroxyethyl starch and other colloidal starch solutions has increased "despite their higher cost relative to crystalloid solutions, lack of evidence of their clinical superiority, and pervasive safety concerns," said Dr. Ryan Zarychanski of the section of critical care and the section of hematology and medical oncology, University of Manitoba, Winnipeg, and his associates (JAMA 2013;309:678-88).
Nonetheless, "over the years, hydroxyethyl starch products have appeared in several resuscitation guidelines, including those of the U.S. Hospital Consortium, and have often been advocated as the cornerstone of resuscitation therapy," the researchers noted.
Many of the data supporting the use of hydroxyethyl starch were recently retracted from the literature, however, after an investigation found that leading scientist Dr. Joachim Boldt had used unethical research practices and had fabricated data in at least 88 studies.
"All major systematic reviews and clinical guidelines are now being revised to account for the retracted data and permit sensitivity analyses on the remaining publications by Boldt et al.," Dr. Zarychanski and his colleagues said.
They performed a rigorous systematic review of randomized controlled trials comparing hydroxyethyl starch against crystalloid, albumin, or gelatin IV fluids for acute fluid resuscitation in critically ill adults. The study subjects were treated in emergency or intensive care settings during 1982-2012.
The meta-analysis covered 38 trials, including 7 studies by Dr. Boldt that had not been retracted because they had been published before 1999, the cutoff date for the misconduct investigation.
A total of 35 studies involving 10,880 patients contributed mortality data to the meta-analysis. The overall mortality risk was significantly higher for patients randomly assigned to receive hydroxyethyl starch than for those assigned to other solutions (relative risk, 1.07).
When the data from the seven Dr. Boldt studies were excluded from the meta-analysis, the pooled results from the remaining 28 trials (10,290 patients) showed an even stronger increase in mortality risk (RR, 1.09).
The seven Boldt trials were then excluded from all further analyses.
Ten trials reported on the rate of renal replacement therapy in 9,258 patients. The use of hydroxyethyl starch was associated with a significantly greater risk of renal injury (RR, 1.32), compared with other resuscitation fluids.
The incidence of acute renal failure was reported in five trials involving 8,725 patients. Again, the incidence of this adverse effect was significantly greater in patients randomly assigned to receive hydroxyethyl starch than in those receiving other fluids (RR, 1.27).
Several sensitivity and subgroup analyses all supported the findings from the main analysis. The results indicate that "clinical use of hydroxyethyl starch for acute volume resuscitation is not warranted due to serious safety concerns," Dr. Zarychanski and his associates said.
Although hydroxyethyl starch solutions are effective volume expanders, their effects are not confined to the circulatory system, the investigators explained. The solutions also are deposited in the endothelial cells, kidneys, liver, muscle, skin, and spleen.
"Proponents of starch solutions have argued increased safety with each newly marketed product, but evidence from randomized trials [does] not support these claims," the study authors said.
In addition, their meta-analysis demonstrated that the publication of inaccurate or fraudulent data "can influence how the global medical community interprets a given body of literature, and how exclusion of questionable studies can shift the balance of evidence toward benefit or harm."
Dr. Zarychanski reported no relevant financial disclosures; an associate reported ties to Bristol-Myers Squibb and Abbott Laboratories.