主要内容：德国胶体研究大腕 Boldt 09 年 A&A 上胶体体外循环预充论文中，细胞因子和血气数据令人难以置信，受到多名读者来信质疑（而几名心血管麻醉医生审稿人及编辑并没有提出疑问）。后发现，其研究没有得到医院研究委员会 (Institutional Review Board, IRB ）通过，也没有病人同意书，甚至整个实验可能根本就没有做。
Anesthesia Journal Retracts Fluid Paper Over Ethics Concerns, Possible Fraud
Editor: Implications may dwarf Reuben case
Adam Marcus
Joachim Boldt, MD, PhD, a leading German anesthesiologist with more than 200 papers to his name, has been accused of “very serious misrepresentations” in a paper he published late last year in the journal Anesthesia & Analgesia.
In a retraction notice published online Oct. 28, Steven L. Shafer, editor-in-chief of the journal, wrote that Dr. Boldt and his co-authors did not obtain approval from an institutional review board or informed consent from patients in their December 2009 article, “Cardiopulmonary bypass priming using a high dose of a balanced hydroxyethyl starch versus an albumin-based priming system.”
In addition, the journal said, it has reason to suspect that data in the paper were fabricated, a possibility that is being investigated by German authorities. Indeed, the notice stated, “it is possible that the study was never performed at all.”
Hydroxyethyl starch (HES) is a colloidal solution—particles suspended in liquid—that anesthesiologists administer to patients during surgery to keep their blood volume high, in order to maintain adequate delivery of nutrients to cells. Intraoperative fluid management remains an unsettled topic for anesthesiologists, who have taken to calling the controversy the “Great Fluid Debate.”
Renowned Colloid Expert
Dr. Boldt, head of anesthesia at the Klinikum Ludwigshafen, a private hospital in Rheinland, has spent much of his career studying the safety and efficacy of colloids. “Given the number of publications by Prof. Boldt and his co-investigators in this field, the finding of misconduct in a recent publication implies that clinicians should question whether modern colloids have fully addressed the safety concerns that limited the use of first-generation hydroxyethyl starch solutions,” Dr. Shafer told Anesthesiology News.
Dr. Boldt has disclosed receiving funding for his research from makers of hetastarch products including B. Braun, Baxter and Fresenius Kabi. He also has received funding from Plasmaselect and Bernburg, as well as Edwards Lifesciences, which makes devices that allow clinicians to monitor fluids in surgery patients.
Efforts to reach Dr. Boldt were not immediately successful.
The paper in question reported on a study of 50 patients undergoing cardiopulmonary bypass (CP. Some were given hydroxyethyl starch and others received albumin.
According to the authors, “high-volume priming of the CPB circuit with a modern balanced HES solution resulted in reduced inflammation, less endothelial damage, and fewer alterations in renal tubular integrity compared with an albumin-based priming. Coagulation including platelet function was better preserved with high-dose balanced HES CPB priming compared with albumin-based CPB priming.”
However, as Dr. Shafer explained in the retraction notice, the data in the paper simply looked too good to be true: “Shortly following publication the Journal received several letters from concerned readers that the variability in the cytokine assay was too low to be believed. Upon reviewing the results, we concurred with that assessment. We also believed that the variability in blood gas results reported in the paper was too low to be believable.”
Dr. Shafer said Dr. Boldt initially promised to help resolve the issue. However, the researcher soon stopped cooperating, and Dr. Shafer has been dealing with the medical board, LÄK, in Rheinland.
Earlier this week, nine months after he first raised questions about the paper, Dr. Shafer said he heard from the board. Again, from the retraction letter:
“On October 25th I received notification from LÄK about their findings. Professor Boldt’s manuscript describes IRB [institutional review board] review, written informed consent, prospective randomization, and a follow-up questionnaire. LÄK determined that there was no IRB approval, no informed consent, no randomization process, and no follow-up questionnaire as described in the study. These are very serious misrepresentations in Professor Boldt’s manuscript. As a result, the entire manuscript is compromised, and is hereby retracted.”
According to Dr. Shafer's letter, LÄK has asked for but not received research data from Dr. Boldt's group that might help him refute allegations of fraud stemming from the retracted article. "LÄK has not reached a conclusion that the data were fabricated. This is still an open question, and LÄK is continuing its investigation," he wrote.
Even without fabricated data, the ethical lapses certainly are severe enough to get the paper pulled. But, the retraction letter continued, the issues might be far worse:
“Professor Boldt has published more than 200 manuscripts in the peer reviewed medical literature. A shadow has been cast over that body of work based on a determination that the report published in Anesthesia & Analgesia is fraudulent. In the coming months and years we will work with LÄK to determine the veracity of all reports by Professor Boldt published in Anesthesia & Analgesia.”
The paper was cited five times, according to Thomson Scientific's Web of Knowledge, including an editorial that accompanied it in Anesthesia & Analgesia, and another by Dr. Boldt in the Journal of Cardiothoracic and Vascular Anesthesia.
Dr. Shafer said his journal has published in the neighborhood of 40 articles by Dr. Boldt. He has notified other journals—including Anesthesiology, Critical Care and Critical Care Medicine, about the issues with the German scientist’s research and warned them to review his manuscripts. If more than a handful of those require retracting, Dr. Boldt might eclipse the notorious Scott Reuben, MD, as the most significant fraudster yet detected in anesthesiology.
Reuben Fraud Still Taking Toll
Dr. Reuben, a Massachusetts pain specialist, was found to have fabricated data and committed other fraud that led to the retraction of at least 21 papers, many in Anesthesia & Analgesia, in early 2009. Dr. Reuben, who blamed his actions on mental illness, is now serving a six-month prison sentence for health care fraud.
Although Dr. Reuben is in prison, his impact on the journals that published his research has not ended. Dr. Shafer said he spends several hours each week analyzing articles by the disgraced researcher that have not been retracted and handling other fallout from the case.
Dealing with Dr. Boldt's body of publications "could take years," Dr. Shafer said. Dr. Boldt, “has published far more than Reuben. The data that Reuben fabricated supported the safety and efficacy of selective COX-2 inhibitors, drugs with a benign safety profile. Older colloidal solutions are known to interfere with coagulation and renal function and may contribute towards inflammation. Newer colloidal solutions appear to have addressed these limitations. However, some of that research was performed by Prof. Boldt. The safety and efficacy of modern solutions is potentially compromised by the finding of misrepresentations in his research.”
That helps explain the penultimate paragraph of Dr. Shafer’s retraction letter:
“I apologize to our readership, and to the patients cared for by our readership, for the publication of a fraudulent report in Anesthesia & Analgesia. We will examine our editorial policies, the quality of our peer review, and look for ways to detect fraudulent
research in the peer review process.”
Dr. Shafer said the 2009 paper was reviewed by several cardiovascular anesthesiologists, none of whom caught the bogus data. Nor did he suspect anything when he reviewed the report—including the part about perioperative blood gases, which he now views as “obviously unbelievable.”
That, he added, points to the difficulties reviewers and editors face in catching fraud before a manuscript is published. “Things are only obvious once they’re obvious,” he said.
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