Misconduct biased fluid resuscitation studies

There are "serious safety concerns" associated with the use of hydroxyethyl starch for fluid resuscitation in critically ill patients, say the authors of a meta-analysis in JAMA.

Its use increased patients' risk for renal injury and mortality, but only after exclusion of studies by a German investigator, Joachim Boldt, accused of ethical and scientific misconduct, report Ryan Zarychanski (University of Manitoba, Winnipeg, Canada) and co-workers.

"The clinical use of colloidal starch solutions, including hydroxyethyl starch, has increased despite their higher cost relative to crystalloid solutions, lack of evidence of their clinical superiority, and pervasive safety concerns," writes the team.

Colloid use has even been incorporated into clinical guidelines, but many of these are now under review following the retraction of a number of papers by Boldt, including some with evidence of data fabrication.

Zarychanski et al included 38 trials in their meta-analysis, seven of which were published by Boldt. In this analysis, which included data on 10,880 patients, use of hydroxyethyl starch was associated with a nonsignificant 1.20% absolute increase in mortality risk.

But after the researchers excluded the Boldt studies, leaving them with data on 10,290 patients, the mortality risk associated with hydroxyethyl starch use rose to a significant 1.51% absolute increase. There was also a 5.45% absolute increase in renal failure risk and a 3.12% rise in use of renal replacement therapy.

The seven Boldt trials were not retracted, because they predated the period of investigation, and they did not report reduced mortality with hydroxyethyl starch use. However, the findings were neutral, whereas those of the other trials in the analysis found an increased mortality risk with hydroxyethyl starch, and Zarychanski et al found significant heterogeneity between the two groups of trials. Removing the Boldt trials increased the overall strength of evidence grading from low to moderate, they say.

In an editorial accompanying the study, Massimo Antonelli and Claudio Sandroni (both from Università Cattolica del Sacro Cuore, Rome, Italy) highlight the importance of continually reviewing guidelines in the light of new information. "With the inclusion of studies by Boldt et al, the medical community might reasonably have concluded that use of hydroxyethyl starch was not inappropriate," they say.

But they also point out that the study "does not add direct evidence to inform the long-standing controversy about colloids vs crystalloids," because of the wide range of hydroxyethyl starch comparators used in the included trials.

"This observation is not a limitation of the study, but rather of the current literature," they say, adding that large randomized trials will be needed to address the issue.

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