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Systematic analysis of hydroxyethyl starch (HES) reviews: proliferation of low-quality reviews overwhelms the results of well-performed meta-analyses

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Abstract

Purpose

Hydroxyethyl starch (HES) is a synthetic colloid used widely for resuscitation despite the availability of safer, less costly fluids. Numerous HES reviews have been published that may have influenced clinicians’ practice. We have therefore examined the relationship between the methodological quality of published HES reviews, authors’ potential conflicts of interest (pCOI) and the recommendations made.

Methods

Systematic analysis of reviews on HES use.

Results

Between 1975 and 2010, 165 reviews were published containing recommendations for or against HES use. From the 1990s onwards, favorable reviews increased from two to eight per year and HES’s share of the artificial colloid market tripled from 20 to 60 %. Only 7 % (12/165) of these reviews of HES use contained meta-analyses; these 7 % had higher Overview Quality Assessment Questionnaire (OQAQ) scores [median (range) 6.5 (3–7)] than reviews without meta-analysis [2 (1–4); p < 0.001]. The rates of recommending against HES use are 83 % (10/12) in meta-analyses and 20 % (31/153) in reviews without meta-analysis (p < 0.0001). Fourteen authors published the majority (70/124) of positive reviews, and ten of these 14 had or have since developed a pCOI with various manufacturers of HES.

Conclusions

Low-quality HES reviews reached different conclusions than high-quality meta-analyses from independent entities, such as Cochrane Reviews. The majority of these low-quality positive HES reviews were written by a small group of authors, most of whom had or have since established ties to industry. The proliferation of positive HES reviews has been associated with increased utilization of an expensive therapy despite the lack of evidence for meaningful clinical benefit and increased risks. Clinicians need to be more informed that marketing efforts are potentially influencing scientific literature.

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Acknowledgments

The authors thank B. Kabisch, PhD, M. Muecke, and D. Schwarzkopf for their support in data analysis and J. Maltagliati for editing assistance. No compensation was received for these contributions. Funds for this project were provided by the Intramural Research Program of the U.S. National Institutes of Health. C. Natanson and J. Sun are U.S. government employees, and both did the work on this paper as part of their official U.S. government-funded research duties. However, the opinions expressed do not necessarily represent those of the U.S. National Institutes of Health.

Conflicts of interest

C. Hartog, H. Skupin, J. Sun, and C. Natanson declare that they have no conflict of interest. K. Reinhart has in the past received an unrestricted grant for the conduct of the VISEP study and speaker’s and consultancy fees from B. Braun, Melsungen, Germany. B.Braun, Melsungen also contributed to the German Sepsis Society to fund an endowed professorship for clinical sepsis research at the University Hospital of Jena.

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich-Schiller-University, Erlanger Allee 101, 07747, Jena, Germany

    Christiane S. Hartog, Helga Skupin & Konrad Reinhart

  2. Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA

    Charles Natanson & Junfeng Sun

Authors
  1. Christiane S. Hartog
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  2. Helga Skupin
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  3. Charles Natanson
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  4. Junfeng Sun
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  5. Konrad Reinhart
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Corresponding author

Correspondence to Konrad Reinhart.

Additional information

C. Hartog and H. Skupin contributed equally to this work.

Electronic supplementary material

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Supplementary material 1 (DOCX 67.6 kb)

Appendices

Appendix 1

Electronic search strategy

Keywords: hetastarch OR hydroxyethyl starch OR hydroxyethylstarch OR pentastarch OR haes-steril OR Hextend OR Elohes OR Elohaes OR Expafusin OR Voluven OR hemohes OR hespan OR pentafraction OR pentaspan OR plasmasteril OR plasma expander OR hydroxyethylstarke OR hydroxyathylstarke OR hydroxyethyl starke OR HAES OR hydroxyethylamidon OR (colloid and crystalloid) AND fluid therapy OR fluid OR intensive care OR emergency OR burn OR organ transplantation OR donor resuscitation OR fluid resuscitation OR volume or hemodilution OR head injury OR stroke OR brain injury OR cerebral injury OR intracranial bleeding OR intravascular therapy OR plasma substitutes OR plasma expanders OR remplissage OR volumentherapy OR volumenersatz or plasmaersatz) AND review OR meta-analysis OR systematic review OR narrative review OR overview OR metaanalysis OR pooled analysis.

Appendix 2

The OQAQ is a validated instrument which has been used before in the setting of critical care [40] and anesthesia [41]. The OQAQ quality features according to Oxman et al. [27] and Delaney et al. [40] are as follows:

  1. 1

    Were the search methods used to find evidence on the primary question(s) stated? (2) Was the search for evidence reasonably comprehensive?

  2. 2

    Was the search for evidence reasonably comprehensive?

  3. 3

    Were the criteria used for deciding which studies to include in the overview reported?

  4. 4

    Was bias in the selection of studies avoided?

  5. 5

    Were the criteria used for assessing the validity of the included studies reported?

  6. 6

    Was the validity of all the studies referred to in the text assessed using appropriate criteria?

  7. 7

    Were the methods used to combine the findings of the relevant studies (to reach a conclusion) reported?

  8. 8

    Were the findings of the relevant studies combined appropriately relative to the primary question of the overview?

  9. 9

    Were the conclusions made by the author(s) supported by the data and/or analysis reported in the overview?

  10. 10

    How would you rate the overall quality of this overview?

Possible answers to questions 1–9 are: 1 = no; 2 = partially or cannot tell; 3 = yes. Answer to question 10 is: if the methods that were used are reported incompletely relative to a specific item, that item should be scored as “partially.” Similarly, if there is no information provided regarding what was done relative to a particular question, this question should be scored as “cannot tell,” unless there is information in the overview to suggest either that the criterion was or was not met.

For question 2, for a search to be considered comprehensive the methods used to perform the search should include searching for unpublished material as well as multiple medical databases (EMBASE as well as MEDLINE). If only published material was searched for, the search should be assessed as “partially” For question 4, for bias to have been avoided in the selection of studies, the report should indicate that explicit criteria were used to define studies eligible for inclusion. For question 6, to determine whether the validity was assessed using appropriate criteria, all of the studies in the text must have had their validity assessed and explicit criteria which were appropriate for the type of research question that was being addressed must have been used. For question 8, if no attempt has been made to combine findings, and no statement is made regarding the inappropriateness of combining findings, check “no.” If a summary (general) estimate is given anywhere in the abstract, the discussion, or the summary section of the paper, and it is not reported how that estimate was derived, check off “no,” even if there is a statement regarding the limitations of combining the findings of the studies reviewed. If in doubt, check off “can’t tell.” For an overview to be scored as “yes” on question 9, data (not just citations) must be reported that support the main conclusions regarding the primary question(s) that the overview addresses. The score for question 10, the overall scientific quality, should be based on your answers to the first nine questions. The following guidelines can be used to assist with deriving a summary score: if the “cannot tell” option is used one or more times on preceding questions, a review is likely to have minor flaws at best, and it is difficult to rule out major flows (i.e., a score ≤4). If the “no” option is used on questions 2, 4, 6, or 8, the review is likely to have major flaws (i.e., a score of ≤3, depending on the number and degree of the flaws).

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Hartog, C.S., Skupin, H., Natanson, C. et al. Systematic analysis of hydroxyethyl starch (HES) reviews: proliferation of low-quality reviews overwhelms the results of well-performed meta-analyses. Intensive Care Med 38, 1258–1271 (2012). https://doi.org/10.1007/s00134-012-2614-0

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