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Shadow of Doubt

Shafer, Steven L. MD

doi: 10.1213/ANE.0b013e31820ad3b7
Editorials: Editorials

Published ahead of print February 4, 2011 Supplemental Digital Content is available in the text.

From the Department of Anesthesiology, Columbia University, New York, New York.

The author declares no conflicts of interest.

Reprints will not be available from the author.

Address correspondence to Steven L. Shafer, MD, Department of Anesthesiology, Columbia University, 630 West 168th St., P&S Box 46, New York, NY 10032. Address e-mail to sshafer@columbia.edu.

Accepted December 9, 2010

Published ahead of print February 4, 2011

In December 2009, Anesthesia & Analgesia published a manuscript by Professor Joachim Boldt describing the effect of 2 different bypass pump priming solutions, albumin or a modern hydroxyethyl starch colloidal solution, on markers of postoperative inflammation and organ function.1 Shortly after this paper was published, 3 readers contacted the Journal to question the small standard deviations of the interleukin IL-6 concentrations reported by Professor Boldt. I verified their concerns with several experts in IL-6 biology, who also thought that the standard deviations were inconsistent with typical IL-6 data. For reference, Figure 1A shows the IL-6 concentrations in Professor Boldt's paper. Figure 1B shows the IL-6 concentrations in a similar study that looked at the effect on IL-6 of different coatings in the bypass circuit.2 As seen in Figure 1B, the standard deviation of the IL-6 assay is expected to be approximately of the same magnitude as the observation itself (i.e., the coefficient of variation is nearly 100%). Professor Boldt's standard deviations are very small in comparison. I was also dismayed when I scrutinized the base excess values reported for patients in the 2 groups in the retracted paper, which appear as Figure 2. It seems farfetched that after cardiopulmonary bypass there would be a base excess of 0, with almost no variability, simply because of a difference in the colloidal solution used to prime the bypass pump.

Figure 1

Figure 1

Figure 2

Figure 2

Research oversight in Germany is quite different than in the United States, as explained in editorials by Professor Förstermann3 and Hoffart et al.4 in this issue of Anesthesia & Analgesia. It took several months to determine who was responsible for ethical conduct of research at Klinikum Ludwigshafen, the hospital where the research was conducted. In May, I brought my concerns to Landesärztekammer Rheinland-Pfalz (“LÄK-RLP”), the State Medical Association of Rheinland-Pfalz. LÄK-RLP investigated the matter, and communicated their findings to me on October 25, 2010. LÄK-RLP identified multiple misrepresentations in the article, outlined in Table 1. Based on these findings, the article was retracted.5

Table 1

Table 1

As explained in the editorial by Hoffart et al.,4 LÄK-RLP does not have the authority to investigate the study site itself. After retraction of the article, Klinikum Ludwigshafen, where the study was allegedly performed, convened an investigating committee to determine the integrity of the research. I received their report on November 25, 2010. Notable findings by the investigating committee include the following:

  1. There are no original patient data or laboratory data to support the findings in the study.
  2. According to the head of the perfusionist team, no albumin has been used as a priming solution since 1999.
  3. According to the pharmacy, no albumin has been delivered to the cardiac operating rooms for many years.
  4. All laboratory measurements, including IL-6, IL-10, intercellular adhesion molecule, neutrophil gelatinase- associated lipocalin, and α-glutathione-S-transferase, would have been performed in the clinical laboratory at the Klinikum Ludwigshafen. These assays have only been performed on patients receiving hydroxyethyl starch priming solutions. The laboratory could identify no assays from patients receiving albumin priming solutions.
  5. Professor Boldt has admitted forging the signatures of the coauthors on the copyright transfer form submitted to Anesthesia & Analgesia.
  6. The coauthors denied participation in the fabrication.
  7. There is no convincing evidence that this study was performed at all.

In other words, the study is fabricated.

In my editorial on the fabrications of Scott Reuben, I likened the growth of human knowledge to the weaving of a tapestry, and the sudden loss of 21 articles to the ripping of a thread.6 The retraction of a single article by Professor Boldt is very different. We don't have the sudden loss of 21 articles, and a clear statement from an institution about the scale of the misconduct. We just have a single fabricated study. However, even one fabricated study casts a large shadow over Professor Boldt's entire body of work.

As Editor-in-Chief of Anesthesia & Analgesia, I am committed to publishing a journal of unimpeachable integrity. That does not mean that everything in the Journal is unimpeachable. Only sacred scripture has that characteristic. Every scientific paper may be inaccurate because of experimental error, incorrect analysis, biased reporting, or outright fraud. My commitment to “unimpeachable integrity” means that credible allegations of misconduct are not ignored or swept under the rug, but are pursued, relentlessly, and sometimes at considerable personal cost.

This commitment to the readership of Anesthesia & Analgesia requires that every article by Professor Boldt in the Journal be scrutinized. He has published 41 papers in the Journal, including 7 articles in 2008 and 2009.1,712 Fortunately, LÄK-RLP and Klinikum Ludwigshafen have agreed to shoulder the unwelcome task of scrutinizing his past work, just as Baystate took responsibility for assessing Scott Reuben's published papers. Since publishing the retraction, I have received credible reports alleging fraud in papers published by Professor Boldt dating back more than a decade. These concerns have been forwarded to LÄK-RLP and Klinikum Ludwigshafen. For my part, I have reached out to the editors of anesthesiology and critical care journals where Professor Boldt has published papers, and will coordinate efforts between the journal editors and the investigating committees at Klinikum Ludwigshafen to work through the backlog of papers. By the time you read this editorial, the initial findings of LÄK and Klinikum Ludwigshafen will have been publicly disclosed. Unglaublich!

Anesthesia & Analgesia has experienced its share of fraud. Not a single case, including this one, has involved a study directly sponsored by a drug or device company. Sponsored studies are very closely audited, with each case report form checked against patient and laboratory data. The IRB process is audited as well, and compliance is verified. To help us work though the backlog of papers by Professor Boldt, I invite companies who directly sponsored studies by Professor Boldt to audit their records and case report forms, provide a rigorous analysis of the whether there is any possibility of fabrication, and submit their process and their results as “Special Articles” to Anesthesia & Analgesia. Drug and device companies are well positioned to shed a bright light on Professor Boldt's published research, perhaps displacing some shadows. Also, the process by which companies can perform highly detailed source-level audits offers an example for those engaged in investigator initiated trials of how to audit research in real time and maintain records of source-level documentation.

What are clinicians to make of this? In the case of the Scott Reuben retractions, we turned to our Editorial Board to provide a rapid assessment of the consequences of research fraud on our understanding of multimodal postoperative analgesia.13 We followed that example in this case. I want to thank Professors Reinhart and Takala for providing, on very short notice, a similar assessment of what we have lost in our understanding of the safety and efficacy of colloidal solutions.14

Carl Sagan referred to science as a candle in the dark.15 The light from the candle penetrates the darkness of ignorance, bringing knowledge and hope. When we find fraud, “darkness gathers. The demons begin to stir.”16

The candlelight of science published in Anesthesia & Analgesia has been dimmed by the shadow cast by this fabrication. It will take years to dispel. We are committed to the task.

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REFERENCES

1. Boldt J, Suttner S, Brosch C, Lehmann A, Röhm K, Mengistu A. Cardiopulmonary bypass priming using a high dose of a balanced hydroxyethyl starch versus an albumin-based priming strategy. Anesth Analg 2009;109:1752–62
2. Sohn N, Marcoux J, Mycyk T, Krahn J, Meng QH. The impact of different biocompatible coated cardiopulmonary bypass circuits on inflammatory response and oxidative stress. Perfusion 2009;24:231–7
3. Förstermann U. Research oversight in Germany: safeguards and shortcomings. Anesth Analg 2011;112:504–6
4. Hoffart J, Teichmann A, Wessler I. Biomedical research in Germany: the role of ethics committee and state medical association. Anesth Analg 2011;112:501–3
5. Shafer SL. Notice of retraction. Anesth Analg 2010;111:1567
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12. Röhm KD, Mengistu A, Boldt J, Mayer J, Beck G, Piper SN. Renal integrity in sevoflurane sedation in the intensive care unit with the anesthetic-conserving device: a comparison with intravenous propofol sedation. Anesth Analg 2009;108: 1848–54
13. White PF, Kehlet H, Liu S. Perioperative analgesia: what do we still know? Anesth Analg 2009;108:1364–7
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15. Sagan C. The Demon-Haunted World: Science as a Candle in the Dark.New York: Ballantine Books, 1996
16. Sagan C. Science and hope. In: Sagan C. The Demon-Haunted World: Science as a Candle in the Dark.New York: Ballantine Books, 1996:27
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