1

(sic)Report of the Committee for the investigation into the allegation of scientific fraud

by Dr. Joachim Boldt and his coworkers September 2011

Introduction: The committee on the investigation of the scientific work by Dr. Boldt was established in November 2010 at the Klinikum Ludwigshafen after allegations against Dr. Boldt became public. The committee consists of the following members: Prof. Dr.E.Martin, Head, Department of Anesthesiology, University of Heidelberg ,chairman Prof. Dr.A.Grau, Medical Director, Klinikum Ludwigshafen a.Rh. Prof. Dr.S.Hagl, former Head of the Department of Cardiac Surgery, University of Heidelberg Prof. Dr.R.Jakobs, Deputy Medical Director, Klinikum Ludwigshafen a.Rh. Prof. Dr.H-G.Sonntag, former Dean of the Faculty of Medicine, University of Heidelberg Prof. Dr.K.Wiedemann, former Head , Dept. of Anesthesiology, Thorax-Klinik, Heidelberg The aim of the committee is to evaluate the scientific work performed by and under the responsibility of Dr. Boldt at the Klinikum Ludwigshafen a.Rh. and to investigate the allegations of potential scientific fraud in this work. The following report summarizes the committee´s work since the end of 2010. It is based on

1. detailed analysis of original research data, whenever retrievable, and either attributable to individual studies or to individual publications

2. scrutiny of hospital records of any patient identified as a participant in any research project

3. interviews with staff members of the Klinikum Ludwigshafen 4. analysis of publications as listed below, in the light of findings from 1.-3.

The committee took into consideration

1. the history of any research project to which a given publication could be related 2. the connection between a given research project and the papers published by Dr.Boldt

and coworkers, regarding respective topics, respective data collections and respective time frames

3. whether the study described in a given publication was performed at all, or to what extent, regarding patients recruited, parameters measured, data collection points chosen, and procedures carried out.

The results of the evaluation of an individual publication are arranged as follows :

1. References: The history of the research project to which a given publication could be related to and, if applicable, the connections between a given research project and other papers published by Dr. Boldt and coworkers are described

2. Sources: In the case extensive material was retrieved regarding an individual project it is described in appropriate detail here.

2

3. Comments: Findings from references and sources are compared to the material presented in the different sections of the publication under scrutiny. The committee refrained from commenting on the discussion section in most publications. It was felt to be illogical to evaluate contentions referring to the methods or results published, because original data either was not available at all, was incomplete or were presented in manipulated versions in the respective publications.

4. Committee evaluation: Based on the foregoing steps, the scientific value of the publication is commented on and a recommendation for future use of its contents is given.

Remarks: Although the committee intended to mainly consider publications with Dr. Boldt as a first author, papers with coworkers as a first author also were evaluated as mandated by requests from external authorities or concern about issues of patient safety. This report does not focus on the votes of ethics committees in charge of the projects of Dr.Boldt and his coworkers. This issue has been conclusively dealt with in the Editors-in Chief Statement Regarding Published Clinical Trials Conducted without IRB Approval by Joachim Boldt as of March 4, 2011 (www.bja.uk/.../editors-in-chief ) All materials mentioned in any evaluation are available in anonymized form upon request. In the following text, each publication is analyzed individually. In several cases more than one publication originates from a single study. Identical or similar text sections may be found in these evaluations of different manuscripts. It is intended to render the individual evaluation understandable without referring to other parts of the report. Heidelberg ,September 4,2011 on behalf of the committee

Prof.Dr.E.Martin Chairman List of publications evaluated

3

1. Boldt J,Haisch G,Suttner S,Kumle B,Schellhase F (sic!) Are lactated Ringer´s solution and normal saline equal with regard to coagulation? Anesth Analg 94(2002)378-84 2. Boldt J,Haisch G,Suttner S,Kumle B,Schellhaass A Effects of a new modified,balanced hydroxyethyl starch preparation (Hextend®)on measures of coagulation. Br J Anaesth 89(2002)722-8 3. Boldt J, Brenner T, Lang J, Kumle B, Isgro F Kidney-specific proteins in elderly patients undergoing cardiac surgery with cardiopulmonary bypass Anesth Analg 97(2003) 1582–9 4. Boldt J, Brenner T, Lehmann A, Lang J, Kumle B, Werling C Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: comparison of a new starch preparation with gelatin. Intensive Care Med 29 (2003)763–769 5. Boldt J,Brenner T, Lehmann A,Suttner SW, Kumle B, Isgro F Is kidney function altered by the duration of cardiopulmonary bypass? Ann Thorac Surg 75 (2003) 906 –12 6. Boldt J, Schölhorn T, Mayer J, Piper S, Suttner S The value of an albumin-based intravascular volume replacement strategy in elderly patients undergoing major abdominal surgery Anesth Analg 103(2006)191–9 7. Mayer J, Boldt J , Röhm KD, Scheuermann K,Suttner SW Desflurane anesthesia after sevoflurane inhaled induction reduces severity of emergence agitation in children undergoing minor ear-nose-throat surgery compared with sevoflurane induction and maintenance Anesth Analg 102(2006)400-4 8. Boldt J, Wolf M, Mengistu A A new plasma-adapted hydroxyethylstarch preparation: In vitro coagulation studies using thrombelastography and whole blood aggregometry Anesth Analg 104(2007)425–30 9.

4

Boldt J,Brosch C,Ducke M,Papsdorf M,Lehmann A Influence of volume therapy with a modern hydroxyethyl starch preparation on kidney function in cardiac surgery patients with compromised renal function: A comparison with human albumin. Crit Care Med 35(2007) 2740-46. 10. Mayer J,Boldt J,Schöllhorn T,Röhm KD,Mengistu AM,Suttner S Semi-invasive monitoring of cardiac output by a new device using arterial pressure wave-form analysis:a comparison with intermittent pulmonary artery thermodilution in patients undergoing cardiac surgery Br J Anaesth 98 (2007)176-82 11. Mayer J, Boldt J, Schellhaaß A, Hiller B, Suttner SW Bispectral index-guided general anesthesia in combination with thoracic epidural analgesia reduces recovery time in fast-track colon surgery Anesth Analg 104(2007)1145-9 12. Boldt J, Brosch Ch, Röhm K, Lehmann A, Mengistu A, Suttner S Is albumin administration in hypoalbuminemic elderly cardiac surgery patients of benefit with regard to inflammation, endothelial activation, and long-term kidney function? Anesth Analg 107 (2008) 1496-1503 13. Boldt J, Brosch Ch, Röhm K, Papsdorf M, Mengistu A Comparison of the effects of gelatin and a modern hydroxethyl starch solution on renal function and inflammatory response in elderly cardiac surgery patients. Br J Anaesth 100 (2008) 457-64 14. Mayer J,Boldt J,Wolf MW ,Lang J,Suttner S Cardiac output derived from arterial pressure waveform analysis in patients undergoing cardiac surgery:validity of a second generation device. Anesth Analg 106(2008)867-72 15. Mayer J,Boldt J,Triem JG,Schellhaaß A,Mengistu AM,Suttner S Individual titration of propofol plasma target improves anaesthetic stability in patients undergoing major abdominal surgery:a comparison with manually controlled infusion. Eur J Anaesthesiol 25(2008)741-47 16. Boldt J, Suttner S, Brosch C, Lehmann A, Mengistu A Influence on coagulation of a potato-derived hydroxethylstarch (HES 130/0.42) and a maize-derived hydroxethylstarch (HES 130/0.4) in patients undergoing cardiac surgery Br J Anaesth 102 (2009)191–7 17.

5

Mayer J,Boldt J,Beschmann R,Stephan A,Suttner S Uncalibrated arterial pressure waveform analysis for less-invasive cardiac output determination in obese patients undergoing cardiac surgery Br J Anaesth 103(2009)185-90 Evaluations

1. Boldt J, Haisch G, Suttner S, Kumle B, Schellhase F (sic) Are lactated Ringer´s solution and normal saline equal with regard to coagulation? Anesth Analg 94 (2002) 378-84. References: The data published in the present paper derive from a study on “ Influence of different volume replacement substances on blood coagulation.”(„Einfluß unterschiedlicher Volumenersatzmittel auf die Gerinnung“). The original research design (institutional code ANA-01105) comprised treatment group I: normal saline (NS),; group II: Ringer´s lactate (RL),; and group III: balanced hydroxyethyl starch preparation (Hextend®) 6%,550/0,7. Upon submission to the Landesärztekammer Rheinland-Pfalz (LÄK-RLP; the State Medical Association of Rheinland-Pfalz) the project received the file code 837.165.01 (2949). The ethics committee of LÄK-RLP requested an explanation as to why the colloid Hextend would not be tested against another, approved colloid preparation and called for a patients´ insurance because of lack of approval for Hextend in Germany. In response to LÄK´s suggestion a new group III, with HES 130/0,4 as a volume replacement fluid, was added to the study design, while the Hextend® group was renamed No. IV. Mutual correspondence terminated, however, on Oct 16, 2001. The material of the study was published in two unequal parts. The first part (see below) was submitted to Anesth Analg in Sept. 2001 and published under the above title. That publication dealt with the group I: NS (normal saline), renamed SS (saline solution), and group II: RL (Ringer´s lactate). A paper dealing with goup II: RL (Ringer´s lactate), group III: HES 130/0,4, and group IV: HES 550/0,7 Hextend® was submitted to Br J Anaesth before May 2002 and published as Boldt J, Haisch G, Suttner S, Kumle B, Schellhaass A. Effects of a new modified, balanced hydroxyethyl starch preparation (Hextend®)on measures of coagulation Br J Anaesth 89 (2002) 722-8. The complete study material in the form of a so-called „inaugural dissertation“(subsequently “dissertation”)was submitted in 2003 to the Faculty of Medicine at Giessen University, Germany, by Alexander Schellhaaß, the last named author in both publications, as a thesis for the degree of medical doctor (Dr. med.). Such work in general is planned and performed under the responsibility of a senior researcher, in this case of Dr. Boldt. Original research data concerning the study and the two publications could not be found. Comments: Methods section: Approval of the ethics committee of LÄK-RLP was not obtained.

6

A form containing declaration of consent was retrieved, but it referred to the original design of three experimental procedures. Evidence of its actual use in recruitment of patients could not be found. Most importantly, no version covering all four experimental groups was found. The randomization as reported, is of dubious value, because in the dissertation there are four experimental groups. However,there groups I/II and groups III/IV also are subjected to pair-wise testing. In the published paper it is maintained, that “a patient-controlled analgesia regimen was used in all patients.” This corresponds to the statement in the later dissertation,that postoperative pain treatment was provided by patient-controlled analgesia. However, the comment made in the present paper that “Epidural anesthesia was not used”. is at variance with the information in the paper Br J Anaesth 89 (2002) 722-8 that “Epidural anaesthesia was used in all patients,” at least with regard to the group of Ringer`s lactate (RL), since this group has been dealt with in both publications. Results section: Table1 is of poor quality. There are erroneous numbers for sex (n=20 instead of n=21), and ASA ratings (n=20); one subject ASA I is missing in group SS (according to the material in the dissertation). Discussion section: The contention (p.383) that “In our study we found no group differences in standard coagulation variables etc.“ is supported by Figs.1-4, but it was never formally tested by intergroup statistics. Committee evaluation: The article was retracted by the publisher for lack of an ethics committee vote. The original research design was misrepresented in the paper by omitting two of four experimental groups. The data of the study group RL (Ringer´s lactate) were also used in the publication Br J Anaesth 89 (2002) 722-8. The substantial differences regarding the descriptions of postoperative pain treatment in this latter group in the two publications and in the later dissertation give rise to serious concern.The statistical tests are of dubious value. Due to the complete lack of original research data the Committee however cannot judge the validity of the scientific statements put forward in the publication. 2. Boldt J, Haisch G, Suttner S, Kumle B, Schellhaass A Effects of a new modified, balanced hydroxyethyl starch preparation (Hextend®) on measures of coagulation Br J Anaesth 89 (2002) 722-8 References The data published in the present paper derive from a study on “Influence of different volume replacement substances on blood coagulation.”(„Einfluß unterschiedlicher Volumenersatzmittel auf die Gerinnung“). The original research design (institutional code ANA-01105) comprised treatment group I: normal saline (NS), group II:Ringer´s lactate(RL), and group III: balanced hydroxyethyl starch preparation (Hextend®)6%,550/0,7. Upon submission to the Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz) the project received the file code 837.165.01 (2949). The ethics committee of LÄK-RLP requested an explanation as to why the colloid Hextend would not be tested against another, approved colloid preparation, and called for a patients’ insurance because of lack of approval for Hextend in Germany.

7

In response to the LÄK´s suggestion, a new group III with HES 130/0,4 as a volume replacement fluid was added to the study design, while the Hextend® group was renamed No. IV. Mutual correspondence terminated, however, on Oct. 16, 2001. The material of the study in a first of two unequal parts (see below) comprising former groups I: NS (normal saline), renamed SS (saline solution), and II: RL(Ringer´s lactate) was accepted for publication in Anesth Analg in September 2001 and published as Boldt J., Haisch G., Suttner S., Kumle B. ,Schellhase F. (sic) Are lactated Ringer´s solution and normal saline equal with regard to coagulation? Anesth Analg 94 (2002) 378-84 Material concerning the former groups II: RL (Ringer´s lactate), III: HES 130/0,4 , and IV: HES 550/0,7 Hextend®, was submitted to Br J Anaesth before May 2002 and published as above. The complete study material as a so-called “Inaugural dissertation”(subsequently “dissertation”)was submitted in 2003 to the Faculty of Medicine at Giessen University, Germany, by Alexander Schellhaaß, the last named author in both publications, as a thesis for the degree of medical doctor (Dr.med.). Such work is planned and performed in general under the responsibility of a senior researcher, in this case of Dr.Boldt. Original research data concerning the study and the two publications could not be found. Comments: Methods section: A vote of the ethics committee of LÄK-RLP was not obtained. A form containing declaration of consent was retrieved, but it referred to the original design of three experimental procedures. Most importantly, no version covering all four experimental groups was found. Evidence of its actual use in the recruitment of patients, especially in a version covering four experimental groups, also could not be found. Randomization, if performed at all, is of dubious value, because in the dissertation there are four experimental groups. However, groups I/II and III/IV therein also are subjected to pair-wise testing. Randomization is futile, if performed, since the three groups were purposely picked from the four groups described later in the dissertation. In the group allocation, Hextend®, RL, and HES 130/0.4, the group SS (saline solution or NS,normal saline) is missing. The data for the present group RL (Ringer´s lactate) have also been used in the publication Anesth Analg 94 (2002) 378-84. In the present paper it is maintained that “Epidural anaesthesia was used in all patients.” This is at variance with the statement in the later dissertation, that postoperative pain treatment was provided by patient-controlled analgesia. It is also at variance with the information in the paper Anesth Analg 94(2002)378-84, where it is said that “Epidural anesthesia was not used” and ”…a patient-controlled analgesia pain regimen was used in all patients.” This contradiction refers at least to the group Ringer`s lactate (RL), since this group has been dealt with in both publications. The use of epinephrine as a vasopressor is not mentioned in the later dissertation; but there instead dopamin is mentioned, as it is also maintained in Anesth Analg 94 (2002) 378-84. Results section: Legends Nos.1 and 2 are interchanged with regard to figure panels. According to the dissertation, intergroup comparisons (Figs 1-3) were only made between HES 130/0.4 and Hextend® groups; but it is unclear whether the RL group was included in the test. The validity is doubtful, because the choice of groups from the data collected for the later dissertation was arbitrary.

8

Committee evaluation: The article was retracted by the publisher for lack of an ethics committee vote. The original research design was misrepresented in the paper by deleting one of four groups. The data for the study group RL (Ringer´s lactate) was also used in the publication Anesth Analg 94(2002)378-84. The substantial differences regarding the descriptions of postoperative pain treatment in this latter group in the two publications and in the later dissertation give rise to serious concern.The statistical tests are of dubious value. Due to the complete lack of original research data the Committee however cannot judge the validity of the scientific statements put forward in the publication. 3. Boldt J, Brenner T, Lang J, Kumle B, Isgro F Kidney-specific proteins in elderly patients undergoing cardiac surgery with cardiopulmonary bypass Anesth Analg 97 (2003) 1582–9 References: A file “Plasmaexpander-Studie HES 130/0.4 vs. Gelafundin 4% (plasma volume expander study HES 130/0.4 vs. gelatin 4%),”, by the second author, Thorsten Brenner (“Brenner file”) was retrieved. It comprised data collected from October 2001 to February 2002 which was stored on four 3.5“ diskettes. In addition, T. Brenner supplied a comprehensive personal data file (“Brenner personal”). A laboratory file concerning parameters of early renal dysfunction was also located. Projects attributable to this study received the institutional codes 02101, 02102, and 02103. Sources: The study protocol contained in the Brenner file enumerates the parameters of fractional sodium excretion, β-NAG, π-GST, α-GST and α-1-microglobulin, corresponding to the parameters covered in the publication(s). In the laboratory file there are handwritten sheets containing test results for the parameters urine sodium and urine creatinine contents, β-NAG, π-GST, and α-GST of 47 participants, with 22 allotted to the HES 130/0.4 group and 25 to the gelatin 4% group. , . Data for α-1 microglobulin for HES n=22 and Gelatin n=25 patients were found in the file “Brenner personal.” The director of the hematological laboratory, where analyses for this parameter are customarily performed, testified to a batch of 183 analyses carried out and with the expenses charged to Dr. Boldt´s account in April 2002. The Brenner files contain data on hemodynamics, gas exchange, routine lab tests, fluid balance, and time frames of the surgical procedures relating to the groups HES 130/0.4 with n = 46 participants and „Gelafundin 4%“(gelatin) with n = 44 participants, and a sum total of n=90 patients. The results of the above laboratory tests for early markers of renal dysfunction in the retrieved files can be unambiguously ascribed to individual patients among the ninety participants recruited. Thus the present publication clearly is based on the data of the group „Gelafundin 4%“(gelatin) with n = 44 participants, contained in the retrieved files. Material from these files has also been used in the publications Boldt J, Brenner T, Lehmann A, Lang J, Kumle B, Werling C. Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: Comparison of a new starch preparation with gelatin Intensive Care Med 29 (2003) 763–769 and

9

Boldt J., Brenner T., Lehmann A., Suttner S.W., Kumle B., Isgro F. Is kidney function altered by the duration of cardiopulmonary bypass? Ann Thorac Surg 75 (2003) 906 –12. All the material obtained from measurements in patients and from laboratory analyses was collected by Thorsten Brenner, the second author in all three publications, for later use in his „Inaugural dissertation“(subsequently“dissertation”) to obtain the degree of medical doctor (Dr. med.). Such work is in general performed under the responsibility of a senior researcher, in this case Dr. Boldt. The material, as presented in the paper under discussion and in Ann Thorac Surg 75(2003) 906 –12, provides the main content of the second author´s dissertation,which was submitted to the Faculty of Clinical Medicine at Mannheim, University of Heidelberg in 2004. Comments: Methods section: A vote of the ethics committee of Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz) was not obtained. -Informed consent: In the retrieved study protocol it is outlined, that the patients must be informed according to the rules of the Declaration of Helsinki, with the clarification given in brackets “(yellow information sheet)”. This explanatory remark refers to the yellow–coloured form for patient information and documentation of informed consent widely used preoperatively in routine anaesthesia practice in Germany. This form neither is intended for use in scientific matters, nor in any way does it satisfy the requirements of GMP and the proper conduct of research on patients. Thus, from the beginning of the project it was never intended to adhere to this rule and to obtain consent based on proper information in a controllable way. Inspection of 23 randomly sampled patient files did not yield any entry in the yellow information and consent sheets regarding participation in the study. -Priming of CPB: Inspection of perfusion protocols from 23 randomly sampled patient files taken from the complete study revealed that in almost all cases gelatin or HES was used in the priming fluid proper or in supplemental fillings of the circuit according to the allotted groups. This finding may support the respective contention in the paper. Results section: There are substantial differences between the sample sizes as published (Table 1) and the corresponding ones in the retrieved files. While the groups 70 yr comprise 40 participants each in the publication, with a total sum of 80 participants, the data files mention only 44 patients having received gelatin 4% for volume replacement. The subgroup gelatin 4% with age >70 yrs comprises only 18 participants, and the subgroup gelatin 4% with age 70 yrs, but only for 2 of the 8 patients

10

recruited and those presented in the published paper, and in the data obtained from or ascribed to the respective cohorts. Committee evaluation: The article was retracted by the publisher for lack of an ethics committee vote. From the outset of the study it was agreed to obtain informed consent from the participants in a way which openly violated the rules of GMP and thus also the rights of patients. The retrieved data files are proof that a certain number of patients was recruited for a study performed as outlined in the “Methods” section of the present paper. The Excel sheets of individual patients give evidence of data from blood, urine, hemodynamics, catecholamine administration and fluid balance having been collected as described in the “Methods” section. Due to the striking differences between patient sample sizes in the files and those actually published, comparison between the data in the publication and those calculable from the retrieved data sheets is not feasible. These differences in sample size suggest that the authors of the paper arbitrarily adjusted the number of patients they claimed to have included. The committee recommends neither to draw any scientific conclusions from nor to base any therapeutic decisions upon the content of this publication. 4. Boldt J, Brenner T, Lehmann A, Lang J, Kumle B, Werling C Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: Comparison of a new starch preparation with gelatin Intensive Care Med 29 (2003) 763–769 References: A file “Plasmaexpander-Studie HES 130/0.4 vs. Gelafundin 4% (plasma volume expander study HES 130/0.4 vs. gelatin 4%)”, by the author Thorsten Brenner (“Brenner file ”), was retrieved comprising data collected from October 2001 to February 2002 and stored on four 3.5“ diskettes .A comprehensive personal data file was also supplied by T. Brenner (“Brenner personal”). A laboratory file concerning parameters of early renal dysfunction was also found. Projects attributable to this study received the institutional codes 02101, 02102, and 02103. Sources: The study protocol available in the Brenner file enumerates the parameters fractional sodium excretion, β-NAG, π-GST, α-GST and α-1-microglobulin, corresponding to the parameters covered in the publication(s). The laboratory file contains handwritten sheets with test results for the parameters urine sodium and urine creatinine contents,β-NAG, π-GST, and α-GST of 47 participants, including 22 allotted to the HES 130/0.4 group and 25 to the gelatin 4% group.. Data for α-1 microglobulin for HES n=22 and Gelatin n=25 patients were found in the file “Brenner personal.” The director of the hematological laboratory, where analyses for this parameter are customarily performed, testified to a batch of 183 analyses carried out and with the expenses charged to Dr. Boldt´s account in April 2002. The Brenner file contains data on hemodynamics, gas exchange, routine lab tests, fluid balance and time frames of the surgical procedures relating to the groups HES 130/0.4 with n = 46 participants and „Gelafundin 4%“(gelatin) with n = 44 participants, with a total of n=90 patients. The results of the laboratory tests for early markers of renal dysfunction in the

11

retrieved files can be unambiguously ascribed to individual patients among the 90 participants recruited. Thus the present publication is clearly attributable to the data of the groups HES 130/0.4 with n = 46, and „Gelafundin 4%“(gelatin) with n = 44 participants and a sum total of n = 90, found in the retrieved files. Material from these files has also been used in the publication Boldt J, Brenner T, Lang J, Kumle B, Isgro F Kidney-specific proteins in elderly patients undergoing cardiac surgery with cardiopulmonary bypass Anesth Analg 97(2003) 1582–9 and Boldt J, Brenner T, Lehmann A, Suttner SW, Kumle B, Isgro F Is kidney function altered by the duration of cardiopulmonary bypass? Ann Thorac Surg 75(2003)906 –12. All the material obtained from measurements in patients and from laboratory analyses was collected by Thorsten Brenner, the second author in all three publications, , for later use in his “Inaugural dissertation”(subsequently “dissertation”) to obtain the degree of medical doctor (Dr. med.). Such work is generally performed under the supervision of a senior researcher, in this case Dr. Boldt. The material as presented in the publications in Anesth Analg 97(2003) 1582–9 and in Ann Thorac Surg 75(2003) 906 –12, constitutes the main content of the second author´ dissertation submitted to the Faculty of Clinical Medicine at Mannheim, University of Heidelberg, in 2004. Comments: Methods section: A vote of the ethics committee of Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz) was not obtained -Informed consent: In the retrieved study protocol it is said that the patients must be informed according to the rules of the Declaration of Helsinki, with the clarification given in brackets “(yellow information sheet)”. This explanatory remark refers to the yellow–coloured form for patient information and documentation of informed consent widely used preoperatively in routine anaesthesia practice in Germany. This form neither is intended for use in scientific matters nor in any way does it satisfy the requirements of GMP and the proper conduct of research in patients. Thus, from the outset of the project it was never intended to observe this rule and to obtain in a controllable way consent of patients based on proper information. . . Inspection of randomly sampled patient files did not yield any entry in the yellow information and consent sheets regarding participation in the study. -Priming of CPB: Inspection of perfusion protocols from 23 randomly sampled patient files revealed that in almost all cases gelatin or HES was used in the priming fluid proper or in supplemental fillings of the circuit according to the allotted groups. . This finding may support the respective conclusions of the paper. Results section: In the publication it is maintained that patients > 70 yrs were divided into two study groups, gelatin 4% and HES 130/0.4, with sample sizes of n=20 each. In the retrieved files the respective sample sizes are n =15. Furthermore, according to the files, group HES > 70 yrs contains 4 patients aged less than 70 years. The data sources in both retrieved files give the impression of being self-contained.

12

In the publication, values for urine sodium, urine creatinine(-clearance), β-NAG, π-GST, α-GST and α-1-microglobulin for 20 patients in each study group are presented in Figs 1, 2 and 3. According to the retrieved laboratory files, data on these parameters were obtained for all of the 15 participants attributable to the groups gelatin 4% > 70 yrs and HES 130/0.4 > 70 yrs. The laboratory technician performing these analyses throughout Dr. Boldt´s scientific interest in these parameters, confirms that for the present project there were no measurements of said parameters beyond those concerning the subjects enumerated in the hand-written sheets retrieved. There is no satisfactory explanation for the differences in the numbers of subjects recruited and those enumerated in the published paper and in the data obtained from or ascribed to the respective cohorts. Committee evaluation: The article by the publisher was withdrawn for lack of an ethics committee vote. From the outset of the study the failure to obtain informed consent from the participants in an open way violated the rules of GMP and thus the rights of patients. The retrieved data files are proof of a certain number of patients having been recruited to a study performed as outlined in the “Methods” section of the present paper. The Excel sheets of individual patients give evidence of data from blood, urine, hemodynamics, catecholamine administration, and fluid balance having been collected as described in the “Methods” section. Due to the striking differences between patient sample sizes in the files and those published, comparison between the data in the publication and those calculable from the retrieved data sheets is not feasible. The differences in sample sizes are suggestive of the authors in the paper arbitrarily having adjusted the numbers of patients they claimed to have included. The committee recommends neither to draw any scientific conclusions from nor to base any therapeutic decisions upon the content of this publication. 5. Boldt J., Brenner T., Lehmann A., Suttner S.W., Kumle B., Isgro F. Is kidney function altered by the duration of cardiopulmonary bypass? Ann Thorac Surg 75 (2003) 906 –12 References: A file “Plasmaexpander-Studie HES 130/0.4 vs. Gelafundin 4% (plasma volume expander study HES 130/0.4 vs. gelatin 4%), “ by the second author, Thorsten Brenner (“Brenner file ”), was retrieved, containing data collected from October 2001 to February 2002 and stored on four 3.5“ diskettes A comprehensive personal data file was also supplied by T. Brenner (“Brenner personal”). A laboratory file concerning parameters of early renal dysfunction was also located. Projects attributable to this study received the institutional codes 02101, 02102, and 02103. Sources: The study protocol contained in the Brenner file enumerates the parameters of fractional sodium excretion, β-NAG, π-GST, α-GST and α-1-microglobulin, corresponding to the parameters covered in the publication(s). The laboratory file contains handwritten sheets with test results for the parameters urine sodium and urine creatinine contents, β-NAG, π-GST, and α-GST of 47 participants,

13

including 22 allotted to the HES 130/0.4 group and 25 to the gelatin 4% group. Data regarding α-1-microglobulin for HES n=22 and gelatin n=25 patients were found in the file “Brenner personal.” The director of the hematological laboratory, where analyses for this parameter are customarily performed, testified to a batch of 183 carried out analyses with the expenses charged to Dr. Boldt´s account in April 2002. The Brenner files contain data on hemodynamics, gas exchange, routine lab tests, fluid balance, and time frames of the surgical procedures for the group HES 130/0.4 with n = 46 participants and the group „Gelafundin 4%“(gelatin) with n = 44 participants, with a total of n=90 patients. The results of the laboratory tests for early markers of renal dysfunction in the retrieved files can unambiguously be assigned to individual patients among the 90 participants.Thus, the present publication clearly is based on the data of the groups „Gelafundin 4%“(gelatin) with n = 44 participants, and HES 130/0.4 with n = 46 participants, total sum n= 90, as documented in the retrieved files. Material from these files has also been used in the publications Boldt J, Brenner T, Lang J, Kumle B, Isgro F Kidney-specific proteins in elderly patients undergoing cardiac surgery with cardiopulmonary bypass Anesth Analg 97(2003) 1582–9 and in Boldt J, Brenner T, Lehmann A, Lang J, Kumle B, Werling C Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: Comparison of a new starch preparation with gelatin Intensive Care Med 29 (2003)763–769. All the material obtained from measurements in patients and from laboratory analyses was collected by the second author in all three publications, Thorsten Brenner,for later use in his “Inaugural dissertation,” to obtain the degree of medical doctor (Dr.med.). Such work is generally performed under the supervision of a senior researcher, in the this case Dr. Boldt. The material as presented in the publication under discussion and the paper in Anesth Analg 97(2003) 1582–9 constitutes the main content of Thorsten Brenner’s dissertation submitted to the Faculty of Clinical Medicine at Mannheim, University of Heidelberg, in 2004. Comments: Methods section: A vote of the ethics committee of Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz) was not obtained. -Informed consent: In the retrieved study protocol it is said that the patients must be informed according to the rules of the Declaration of Helsinki, with the clarification given in brackets: “(yellow information sheet)”. This explanatory remark refers to the yellow–coloured form for patient information and documentation of informed consent widely used preoperatively in routine anaesthesia practice in Germany. This form is neither intended for use in scientific issues nor in any way does it satisfy the requirements of GMP and of the proper conduct of research in patients. Thus, from the outset of the project it was never intended to observe this rules and to obtain in a controllable way consent of patients based on proper information. Inspection of 23 randomly sampled patient files did not yield any entry in the yellow information and consent sheets regarding participation in the study. -Group selection: In the paper it is claimed that 50 consecutive patients undergoing CPB with bypass times < 70 min. and 50 consecutive patients on CPB with bypass times > 90 min. were “prospectively“studied, and selected to receive for volume replacement and priming either

14

HES 130/0.4 or gelatin 4%. However, this contention is illogical, because it is impossible to base prospectively group selection on criteria like bypass time, given that the operation would be performed only in the future. Rather, one can assume on the basis of the data files that from the total of 90 patients studied, only the data of those who met the above selection criteria were retrospectively selected for publication in the present paper. -Priming of CPB: Inspection of perfusion protocols from 23 randomly sampled patient files revealed that in almost all cases gelatin or HES was used in the priming fluid proper or in supplemental fillings of the circuit in accordance with the allotment to a group. ,. This finding may support the respective contention in the paper. Results section: In the publication, from all the patients selected to receive either HES 130/0.4 or gelatin 4% for volume replacement two cohorts were set according to total bypass time of >90 min or 90 min and n=42 patients to the group with bypass time < 70 min,. According to the publication, in the 50 cases with CPB > 90 min gelatin was given to n= 26 and HES to n=24 patients, whereas according to the retrieved files in the 31 cases with CPB > 90 min gelatin was given to n = 16 and HES to n = 15 patients. According to the publication, in the 50 cases with CPB < 70 min gelatin was given to n= 28 and HES to n= 22 patients, whereas according to the retrieved files in the 42 cases with CPB < 70 min, gelatin was given to n=20 patients and HES was given to 22 patients. The data sources in both retrieved files give the impression of being self-contained. There is no satisfactory explanation for the differences in the numbers of subjects recruited in the files and those enumerated in the published paper. In the published paper values for urine sodium, urine creatinine(-clearance), β-NAG, π-GST, α-GST and α-1-microglobulin for the 50 patients in each study group are presented in Figs 1, 2 and 3. However, in the retrieved laboratory files data on these parameters could be found only for 11 out of 42 participants attributable to the group CPB < 70 min.. The data on these parameters for all of the 31 participants from the group CPB > 90 min have been located. The laboratory technician, who performed these analyses throughout Dr. Boldt´s interest in these parameters, confirms that for this project there were no measurements of said parameters other than those involving the subjects enumerated in the retrieved hand-written sheets. There is no satisfactory explanation for the gross differences between the number of data sets for the parameters urine sodium and urine creatinine contents, β-NAG, π-GST, α-GST and α-1-microglobulin in the laboratory files and the numbers of subjects appearing in the published paper . Committee evaluation: This paper is not mentioned in the “Editors-in –Chief Statement Regarding Published Clinical Trials Conducted without IRB Approval by Joachim Boldt,” March 4, 2011.The Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz) however officially informed the present committee,that no vote by its ethics committee had been issued. From the outset of the study it was accepted to obtain informed consent from the participants in a way openly violating the rules of GMP and thus the rights of patients. The retrieved data files are proof that patients were recruited for the study using patient data and laboratory analyses as described in the „Methods“ section of the present paper. The design of the selection of study groups in the present publication is neither supported by logic nor by the retrieved data files. This fact leads to a suspicion of fraudulent intentions.

15

The Excel sheets of individual patients document the data from blood, urine, hemodynamics, catecholamine administration, and fluid balance collected as described in the “Methods” section. Due to the striking differences between patient sample sizes in the files and those published, a comparison between the data in the publication and those calculable from the retrieved data sheets is not feasible. The differences in sample sizes suggest that the authors arbitrarily adjusted the number of patients claimed to be included in this paper. The committee recommends neither to draw any scientific conclusions from nor to base any therapeutic decisions upon the content of this publication. 6. Boldt J, Schölhorn T, Mayer J, Piper S, Suttner S The value of an albumin-based intravascular volume replacement strategy in elderly patients undergoing major abdominal surgery Anesth Analg 103 (2006) 191–9 References: For this project a file was retrieved that contained a study protocol “Vergleich von HA 5% und HES bei abdominalchirurgischen Operationen“ (Comparison of HA (human albumin5% ) and HES (hydroxyethyl starch) in abdominal surgical operations) a handwritten patients´ list, and fragmentary collections of patient data, including anaesthesia record printouts, printouts of coagulation analyses by TEG in the ROTEM ® Whole Blood Hemostasis Analyzer, blood gas analyses, docket sheets for primary data as haemodynamics, blood glucose and fluid balance. There were also laboratory printouts for α-1-microglobulin and handwritten laboratory lists for urine sodium, urine creatinine, α-GST and β-NAG. Comments: Methods section: A vote of the ethics committee of Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz) was not obtained. The study protocol corresponds to the procedures outlined in the „Methods“ section regarding patient allocation to the two study groups, human albumin (HA) and HES 130/0.4, and the selection of data sampling time points, t0 :preoperatively, t1:after surgery or admission to ICU, t2:4 hrs stay on ICU (5 hrs in the paper), t3:24 hrs/1st post-op day. Raw data concerning the perioperative course in 15 patients could be attributed to the study group H A by the anaesthesia record printouts, and partially by attached batch stickers for human albumin. Results section: Laboratory results for analysis of inflammation markers IL-6, sELAM, and sICAM, as published in the paper could not be retrieved. Available are laboratory sheets for results of analyses of α-GST, β-NAG, urine creatinine and urine sodium for 17 patients attributable to the group HA, because the identification numbers (ID) correspond to the individual patient files marked HA (human albumin). Laboratory sheets of urine α-1-microglobulin levels from 4/28/05 may also be attributed to the present project, because the manuscript was submitted for the first time to Anesthesia & Analgesia on 11/11/2005 and assigned No. 05-1500 (e-mail Dr. Shafer 6.1.2011). They are also attributable to the 17 patients in the group HA because the ID numbers correspond to the individual patient files marked HA.

16

In the headline of Table 1 of the present publication the sample sizes are n=25 each for HA and HES 130/0.4, but adding the surgical procedures yields n=22 for the HA group and n=21 for the HES group. In Table 3 of the publication, “Infused Volumes and Urine-Blood Output,” under the heading “Crystalloids (ml)” for the group HA a sum of 5070±1030 ml is given, while the volumes infused intraoperatively are 5050±1350 ml and postoperatively 2720±510 ml. For the group HES 130/0.4, a sum total of 4550±880 ml is given, while the volumes infused intraoperatively are 4250±980 ml and postoperatively 2600±360ml.. The small sums total suggest misrepresentation. Committee Evaluation: The article was retracted by the publisher for lack of an ethics committee vote. The data collections retrieved are proof that patients were recruited into the group: human albumin 5%, and for the collection of data on hemodynamics, catecholamine administration, and fluid balance, as well as for parameters of early renal dysfunction. The actual number of patients recruited into both groups could not be determined. A comparison of data retrieved to those published is not possible. In the paper there are inconsistencies regarding demographics and crystalloid administration. Due to the incompleteness of the preserved data collection, the committee cannot establish the validity of the scientific statements put forward in the publication. 7. Mayer J, Boldt J, Röhm K D, Scheuermann K, Suttner SW Desflurane anesthesia after sevoflurane inhaled induction reduces severity of emergence agitation in children undergoing minor ear-nose-throat surgery compared with sevoflurane induction and maintenance Anesth Analg 102 (2006) 400-4 References: The evaluation by the Committee rests on the Excel data file JM 5/05 provided by the first author, Dr. J. Mayer, on the results of an interrogation by the committee, and on an interview held with one of the committee members. Methods section: An ethics vote was not applied for and not obtained from Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz). Parents of the children included in the study were not explicitly informed and consent for the their children’s participation in this study was neither asked for nor granted. According to the Excel file JM 5/05, there was a randomization procedure, assumedly carried out by Dr. Boldt. The file contains data of n=19 patients each for the group Sevoflurane/Sevoflurane and the group Sevoflurane/Desflurane. This corresponds to the sample size reported in the publication and therefore the data appears to be complete and plausible. Results section:

17

The results as published reflect correctly and to a full extent, with one minor exception, the data presented in the Excel file. Namely, in the Excel file under headings “Nausea” and “Vomiting” one event is entered. In Table 5 of the publication under “Adverse effects and need for rescue medication there is no corresponding entry under the heading “Nausae, vomiting, shivering”. This discrepancy cannot be explained anymore. Committee evaluation: The article was retracted by the publisher for the lack of an ethics committee vote. After comparison of the data published and those preserved in the Excel file JM/05, the scientific conclusions put forward in the present publication are without any doubt valid. The minor discrepancy mentioned does not impact the essential statements made. The committee concludes, that the material retrieved does fully support the scientific conclusions put forward in the manuscript formerly accepted for publication by the editorial board. The committee however also points out that no informed consent was obtained from the participating minors or their parents as required by GMP. 8. Boldt J, Wolf M, Mengistu A A new plasma-adapted hydroxyethylstarch preparation: In vitro coagulation studies using thrombelastography and whole blood aggregometry Anesth Analg 104 (2007) 425–30 References: A project was filed with the institutional study committee of GfK (Gesellschaft für Klinische Forschung im Klinikum Ludwigshafen) on 01.26.2006 and received the code ANA-05104 G. The third author, Dr. A. Mengistu, was interviewed on 05.19.2011. Methods section: In contrast to the statement made in the paper “after approval by the IRB,” a vote from the ethics committee of Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz) was neither applied for, nor obtained. Results section: Dr. Mengistu, the third author, carried out all the measurements using thrombelastography and whole blood aggregometry as described in the methods section. He cannot , however, provide any data relevant to the present paper because all the test results were handed over to Dr. Boldt and were eventually destroyed when the contents of Dr.Boldt´s hard disk were erased. Scrutiny of the dedicated memory of the ROTEM-device revealed a complete lack of data for the period 2005 to 2010 caused either by a storage gap or by the deletion of data. These data could not be reconstituted. Committee evaluation: The publication by the publisher was retracted due to lack of an ethics committee vote. Because all relevant data is irretrievable, it cannot be established whether the study was carried out as described in the publication. Due to this complete lack of original data the Committee cannot judge the validity of the scientific statements put forward in the publication.

18

9. Boldt J, Brosch C, Ducke M, Papsdorf M, Lehmann A. Influence of volume therapy with a modern hydroxyethyl starch preparation on kidney function in cardiac surgery patients with compromised renal function: A comparison with human albumin Crit Care Med 35 (2007) 2740-46. References: The study design “Einfluss unterschiedlicher Volumenersatzlösungen auf die Nierenfunktion bei kardiochirurgischen Patienten” (Influence of different volume replacement solutions on renal function in cardiac surgery patients) received the institutional code ANA-06105. Criteria for patient inclusion were age ≥80 years and creatinine ≥1.5 mmol/L(sic)(correctly 1,5 mg/dl), separately. The patients for volume replacement were to receive either 6% HES (Mw 130.000, degree of molar substitution 0.4), or 4% gelatin solution, or 5% human albumin solution(HA). Eventually patients were divided into three groups with age > 80 y to receive for volume replacement either HES 130/0.4, or gelatin, or human albumin (publications attributable: Anesth Analg 107 (2008) 1496-1503; Br J Anaesth 100 (2008) 457-64) and into two groups for creatinine > 1,5 mg/dl to receive for volume replacement either HES 130/0.4 or human albumin 5% (publication attributable to the present paper). Laboratory analyses were carried out between December 2006 and February 2007. Comments : Methods section: There was no vote obtained from the competent ethics committee of Landesärztekammer Rheinland -Pfalz („LÄK-RLP“), the State Medical Association of Rheinland-Pfalz, Germany. -Patients: Excel tables were found for patients allotted to the two groups: human albumin, marked HA>1,5(creatinine>1,5), and hydroxyethyl starch, marked HES (Voluven) Crea>1,5, accompanying the laboratory analyses of serum albumin content, of markers of renal function, cystatin C, α-GST, β-NAG and NGAL, and of inflammation markers IL 6, IL-10 and ICAM. The group named HA>1.5 comprised 15 patients, while the group named HES Crea>1,5 included 20 patients. All patients could be identified and their hospital records could be retrieved. The patient allocation into the respective groups in the Excel-tables was marked as completed and it showed an exclusive request for the performance of the said laboratory analyses by encircling and by the instruction “nur die” (only these) in Dr. Boldt´s handwriting. The two groups of patients can be unambiguously attributed to the present publication, because the blood parameter cystatin C as an early marker of renal dysfunction with results shown in Fig.2 in the present study population, was exclusively analyzed in all of Dr. Boldt´s studies. -Informed consent: Forms of declaration of consent were retrieved attributable to 8 patients in the HES-group. They, however, do not comply with the requirements of GCP and with those of a formal clinical study because no mention is made of a randomization process regarding the different volume replacement regimens described in the publication. -Randomization is not verifable. -Pump priming: In the anaesthesia records obtained in form of a comprehensive printout from the departmental semiautomatic recording system the explicit use of human albumin 5% with entered batch codes could be found for each of the 15 patients in the human albumin group. In 6 records mention is made of application into the pump reservoir (“in HLM”, i.e. “into the

19

heart-lung machine.” This term in German is used for cardio-pulmonary bypass known as CPB)). Upon scrutiny of the anaesthesia records, the committee concluded that from these entries and from the graphic representation in the anaesthesia charts of human albumin administration one could not establish with sufficient certainty whether the said colloid was applied to the patient´s vascular system or to the pump reservoir during CPB running. There is no evidence to prove that human albumin was used as a constituent in the pump priming procedure proper, that is in the preparatory filling of the pump reservoir before connecting the patient to the CPB circuit. In particular, the perfusionists deny such use during the period when the study was performed. -Follow-up questionnaires Follow-up questionnaires directed at the patient´s physician were found for 14 of the 15 patients in the HA group and for 14 of the 16 patients of the HES group,who were eventually discharged (see below). The response rates of 93% and 87.5% respectively are at variance with the overall response rate of 68% claimed in the paper. The physicians addressed were left absolutely unaware of the real intentions of the questionnaire, and the purpose stated in the letter (concern about possible prolongation of hospital stay attributable to preoperatively increased serum creatinine levels) could not be traced as an issue, neither in the retrieved study plan nor in the methods section of the publication. Results section: -Procedures: In the summary and in the discussion mentioned are only CABG patients, but in the Table 1 a wide variety of cardiac surgical procedures is enumerated. Table 1 is of poor quality; in the headline n= 25 for each group are mentioned, but gender sums yield only 20. The mean values for CPB time are missing and they are meaningless for cross-clamp time. -Markers for renal function and inflammation: Original laboratory data were obtained from groups smaller than published (n=25): HES group n=20; human albumin group n=15. The laboratory technician performing these analyses throughout Dr. Boldt´s interest in these parameters, confirms that for the present project there were no measurements of said parameters beyond those concerning the subjects enumerated in the retrieved Excel tables. There is no satisfactory explanation for the differences in the numbers of subjects recruited and those mentioned in the publication. In view of the gross differences in study group sizes between the populations recruited and the ones published, it is debatable whether a meaningful comparison between the retrieved laboratory data and the corresponding published graphs can be made at all. Results of analyses of serum albumin content, inflammation markers (IL-6, IL-10 and ICAM) were not published in the present paper. -Outcome: In the publication it is stated that “Mortality was similar in both groups (one patient died in each group secondary to postoperative myocardial infarction)” (p 2742). The analysis of the retrieved hospital records revealed, however, that none of the 15 patients in the HA group had died, but among the 20 patients in the HES group four patients had died during their hospital stay, none of them from myocardial infarction. The four patients died after surgery between days 27 to 57 and the committee found no evidence that the patients’ death was causally related to the study medication given within the first two days after surgery.. It is also claimed in the paper that no patient suffered acute renal failure and none needed hemodialysis or hemofiltration during the intensive care stay, during the hospital stay, or afterwards. However, according to the hospital files, hemodialysis was required once in the

20

HA group and in two patients in the HES group. One patient in the HA group and 4 patients in the HES group had also required prolonged mechanical ventilation during their ICU stay. There is no satisfactory explanation for these discrepancies between outcome data from the hospital files and those provided in the present publication. The hospital records of the patients who had died were intensively evaluated by several members of the committee. They arrived at the conclusion that the difference in the numbers of fatalities between the two experimental groups are not attributable to procedures or agents applied as required by the study protocol. This conclusion is based to a major extent on the fact, that the fatalities occurred late during the course of observation, between postoperative days 27 and 57, whereas the study medications had been administered during surgery and the first and second postoperative days only. A causal relationship between treatment as required by the study protocol and the fatalities observed could not be established. Committee evaluation: The publication was retracted by the publisher due to lack of an ethics committee vote. In view of the misrepresentation of group sizes and the ambiguous entries in the anaesthesia records regarding the use of human albumin in the pump, we conclude that the study has not been performed as described in the publication. The grave misrepresentation of in-hospital mortality in the HES group and in the numbers of serious adverse events in the publication may suggest fraudulent intentions. It is highly unethical to obtain consent from the participants in a study upon untrue information or when essential information is withheld. Results of such a study cannot be accepted. The committee recommends neither to draw any scientific conclusions from nor to base any therapeutic decisions upon the content of this publication. 10. Mayer J, Boldt J, Schöllhorn T, Röhm K D, Mengistu A M, Suttner S Semi-invasive monitoring of cardiac output by a new device using arterial pressure wave-form analysis: A comparison with intermittent pulmonary artery thermodilution in patients undergoing cardiac surgery Br J Anaesth 98 (2007) 176-82 References: The evaluation of this paper is based on an Excel file „EdwardsDaten/.xls“ provided by Dr. Mayer, the first author, on the results of an interrogation by the committee, and on an interview held with one of the committee members. Comments: Methods section: An ethics vote was not obtained from Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz). The submitted Excel data sheets included 194 pairs of measured values obtained by a novel semi-invasive Edwards method of cardiac output measurement, and by the established pulmonary artery catheter thermodilution method. In the present publication, however, we find 244 pairs of measured and derived parameters. This discrepancy was explained by Dr. Mayer as follows: the Excel file in question constituted a preliminary data collection in the first author´s private computer only up to a certain time. This preliminary collection was extended to 244 data pairs by entering further

21

data as acquired at the department´s premises. The completed data sheets were destroyed during the irrevocable erasure of the hard disk of the departmental computer initiated under Dr. Boldt´s responsibility, but without involvement by the first author. The veracity of this information cannot be fully proven by the Committee, but the first author asserts that this has been the true course of events. Results section: Results from calculations based on the pairs of measured data from the Excel sheets are to a certain degree in accordance with the published results. Committee evaluation: The publication was retracted by the publisher due to lack of an ethics committee vote. Appreciating the explanation offered by Dr. Mayer and considering the submitted data sheets and the degree of accordance of the said calculations with the data published, the Committee concludes that Dr. Mayer´s assertions are plausible and the clinical study was performed as published. Due to the incompleteness of the preserved data, the Committee cannot finally decide on the validity of the scientific statements put forward in the publication. 11. Mayer J, Boldt J, Schellhaaß A, Hiller B, Suttner S W Bispectral index-guided general anesthesia in combination with thoracic epidural analgesia reduces recovery time in fast-track colon surgery Anesth Analg 104 (2007) 1145-9 Reference: The evaluation of this paper is based on the Excel file “BIS/Fastrack-Studie” provided by Dr. J. Mayer, the first author, on the results of questioning by the Committee, and on an interview with one of the committee members. Comments: Methods section: An ethics vote was not obtained from Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz). The sample sizes in the Excel sheets (n=15 for controls and n=16 for the BIS(Bispectral Index) group of patients) considerably differ from those published (n=22 for controls and n=22 for the BIS group). The first author explained this discrepancy by stating that the Excel file in question constituted a preliminary data collection in his private personal computer, into which the data were entered only up to a certain time. Later, the data were added up to the 22 data sets in the two groups as published at the department´s premises. The completed data sheets were destroyed as a result of irrevocable erasure of the hard disk of the departmental computer initiated under Dr. Boldt´s responsibility, but without involvement by the first author. The veracity of this contention cannot be proven by the committee, but Dr. Mayer asserts that this has been the true course of events. Results section: Results from calculations based on the measured data from the Excel sheets correspond to a certain degree with the published results . Committee evaluation:

22

The publication was retracted by the publisher due to lack of an ethics committee vote. Appreciating the explanation offered by Dr. Mayer and considering the submitted data sheets,along with the degree of accordance of the said calculations with the published data, the Committee concludes that Dr. Mayer´s assertions are plausible and that the clinical study was performed as published. Due to the incompleteness of the preserved data collection, the Committee cannot finally establish the validity of the scientific statements put forward in the publication. 12. Boldt J., Brosch Ch., Röhm K., Lehmann A., Mengistu A., Suttner S. Is albumin administration in hypoalbuminemic elderly cardiac surgery patients of benefit with regard to inflammation, endothelial activation, and long-term kidney function? Anesth Analg 107 (2008) 1496-1503 Reference: The study design “Einfluss unterschiedlicher Volumenersatzlösungen auf die Nierenfunktion bei kardiochirurgischen Patienten” (Influence of different volume replacement solutions on renal function in cardiac surgery patients) received the institutional code ANA-06105. Criteria for patient inclusion were age≥ 80 years or creatinine≥1.5 mmol/L(sic)(correctly 1,5 mg/dl). For volume replacement the patients were to receive either 6% HES (Mw 130.000, degree of molar substitution 0.4), or 4% gelatin solution, or 5% human albumin (HA) solution. Eventually patient recruitment with patients aged >80 y was divided into three groups. who were to receive as volume replacement either HES 6% 130/0.4, or gelatin 4%, or human albumin 5%, (publications: present paper and Br J Anaesth 100(2008)457-64), and into two groups with creatinine > 1,5 mg/dl that received for volume replacement either HES 130/0.4, or 5% human albumin (publication: Crit Care Med 35 (2007) 2740-46). Laboratory analyses were carried out in March and April 2007 Comments: Methods section: An ethics vote was not obtained from Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz) . -Patients: Excel tables were found for patients allotted to the three groups: human albumin, designated HA >80 J (yrs); hydroxyethyl starch, designated HES >80 J (yrs); and gelatin, designated Gela > 80 (J) (yrs), were found accompanying the laboratory analyses of serum albumin content, markers of inflammation (IL 6, IL 10, sICAM), and markers of renal impairment (α-GST and NGAL). The group HA> 80 J comprised 11 patients, the group HES > 80 J comprised 12 patients, and the group Gela > 80 comprised 17 patients. All patients could be identified and their hospital records could be retrieved. The patient allocation to the respective groups is marked as completed; the respective Excel sheets contain the handwritten request for the performance of the said numbers of laboratory analyses indicated by the notes “11x”, “12x” and “17x” in Dr. Boldt´s handwriting.. On the Excel sheet „Gela >80“ there is a handwritten calculation for 160 lab kits needed, resulting from a number of 40 patients and 4 sampling times: T0 before (surgery), T2 4 hrs (after surgery), T3 1st (postop) day, and T4 2nd (postop) day. Again, handwriting was done by Dr. Boldt. The material concerning the two experimental groups HA>80J and HES > 80 J may unambiguously be attributed to the present publication because of the predetermined age

23

limitation corresponding to the age data in Table 1 and the presentation of serum albumin levels unique to this paper. Material concerning the experimental groups HES > 80 J and Gela > 80 can be found in the article Boldt J, Brosch Ch, Röhm K, Papsdorf M, Mengistu A Comparison of the effects of gelatin and a modern hydroxethyl starch solution on renal function and inflammatory response in elderly cardiac surgery patients. Br J Anaesth 100 (2008) 457-64. -Informed consent: Retrieved were completed and signed forms of declaration of consent attributable to 5 patients in the HES> 80 J group. They, however, do not comply with the requirements of GCP and with those of a formal clinical study because no mention is made concerning the randomization process involving different volume replacement regimens described in the publication. -Randomization is not verifiable. -Pump priming: In the anaesthesia records obtained as a comprehensive printout from the departmental semiautomatic recording system explicit use of human albumin 5% with batch codes entered could be found for 9 patients in the human albumin group. In 6 records mention is made of administration into the pump reservoir (“in HLM” i.e.”into the heart-lung machine.”. This term is used in German for CPB, cardio-pulmonary bypass). Upon scrutiny of the anaesthesia records the Committee concluded on the basis of these entries and the graphic representation in the anaesthesia charts of human albumin administration, that it could not be established with sufficient certainty whether the said colloid was applied to the patient´s vascular system or to the reservoir of the bypass circuit during CPB running. There is no evidence to prove that human albumin was used as a constituent in the pump priming procedure proper, that is in the preparatory filling of the pump reservoir before connecting the patient to the CPB circuit. In particular, the perfusionists deny such use during the period when the study was performed. -Follow-up questionnaires: Follow-up questionnaires directed at the patient´s physician were found for 6 of the 10 patients in the HA group and for 5 of the 11 patients of the HES group eventually discharged (see below). The response rates of 60% and 45% respectively are different from the overall response rate of 82% claimed in the paper, but may reflect inadvertent loss of questionnaires. The physicians addressed were left absolutely unaware of the real intentions of the questionnaire. The purpose stated in the letter (concern about possible prolongation of hospital stay attributable to preoperatively increased serum creatinine levels) was not an issue spelled out either in the retrieved study plan or in the methods section of the publication. Results section: -Patients In the publication, the data only from the two experimental groups HA >80 and HES > 80 are listed , while the documents retrieved clearly indicated that a third study group, Gela>80(J), was involved. The sample sizes for the groups published (Table 1) are 25 each, while according to the retrieved data sheets the albumin group only contained 11 and the HES group 12 patients. While in the present publication the sample size for the group HES >80 is given as n=25, the sample size of the same group is given in the publication in Br J Anaesth 100 (2008) 457-64 as n=30. The discrepancy cannot be satisfactorily explained. -albumin serum concentration

24

In the publication there is no proof that the criterion for inclusion in the study, a serum albumin level < 3,5 mg/dL the day before surgery, was ever met in the recruited patients, since no data concerning this parameter are given. Measurement of serum albumin concentration is not a component of the routine preoperative laboratory check for cardiac patients at the Klinikum Ludwigshafen. In the hospital files of the identified participants, as well as in the laboratory files proper, preoperative values for serum albumin levels could not be found for any of the patients. Thus, it is doubtful that the patients in this study constituted a hypoalbuminaemic population as claimed and whether the conclusions, based on this prerequisite, are valid. -Markers of inflammation and renal function: The original laboratory data were obtained from groups smaller than in the publication: human albumin group n=11, HES group n=12. The laboratory technician performing these analyses throughout Dr. Boldt´s interest in these parameters, confirms that for the present project there were no measurements of said parameters done beyond those of the subjects enumerated in the retrieved Excel-tables. There is no satisfactory explanation for the differences between the numbers of subjects recruited and those presented in the publication. Intergroup comparisons as shown in Figs.1, 3, 5 are of doubtful value since comparisons to the third group of the original project, Gela > 80J (gelatin) (see Br. J Anaesth 100(2008)457-64 ), were not performed. Considering the gross differences in group sizes between the populations recruited and the ones presented in the publication, it is debatable whether meaningful comparisons between the retrieved laboratory data and the published respective graphs are at all feasible. -Outcome: According to the retrieved files there was one fatality in each of the two experimental groups. This corresponds to the number of fatalities mentioned in the present paper, but the differences in group sizes between the retrieved and the reported data need to be taken into account. Committee evaluation: The publication was retracted by the publisher due to lack of an ethics committee vote. We conclude that the study has not been performed as described in the publication because of the misrepresentation of group sizes, failure to prove the state of hypoalbuminaemia in the study population as claimed, withholding the results of a third study group, Gelafundin 4%, and the ambiguous entries in the anaesthesia records regarding the use of human albumin in the pump priming.. To obtain consent from participants in a study on the basis of false information or by withholding essential information is highly unethical. Results from such a study cannot be possibly accepted. The committee recommends neither to draw any scientific conclusions from nor to base any therapeutic decisions upon the content of this publication. 13. Boldt J, Brosch Ch, Röhm K, Papsdorf M, Mengistu A Comparison of the effects of gelatin and a modern hydroxethyl starch solution on renal function and inflammatory response in elderly cardiac surgery patients Br J Anaesth 100 (2008) 457-64 Reference:

25

The study design “Einfluss unterschiedlicher Volumenersatzlösungen auf die Nierenfunktion bei kardiochirurgischen Patienten” (Influence of different volume replacement solutions on renal function in cardiac surgery patients) received the institutional code ANA-06105. Criteria for patient inclusion were age ≥80 years or creatinine ≥1.5 mmol/L(sic)(correctly 1,5 mg/dl). The patients for volume replacement were to receive either 6% HES (Mw 130.000, degree of molar substitution 0.4), or 4% gelatin solution, or 5% human albumin solution(HA). Eventually patient recruitment was divided into three groups with patients aged > 80 y, who were to receive for volume replacement either HES 6% 130/0.4, or gelatin 4%, or human albumin 5% (publications: Anesth Analg 107 (2008) 1496-1503; present paper) and into two groups for creatinine > 1,5 mg/dl to receive for volume replacement either HES 130/0.4 or 5% human albumin(publication: Crit Care Med 35 (2007) 2740-46). Laboratory analyses were carried out in March and April 2007. Comments: Methods section: An ethics vote was not obtained from Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz). -Patients: The Excel tables for patients allotted to the three groups: human albumin, designated HA > 80 J (yrs), hydroxyethyl starch, designated HES >80 J(yrs), and gelatin, designated Gela > 80( J )(yrs), were found along with the accompanying laboratory analyses of serum albumin content, markers of inflammation (IL 6, IL 10, sICAM) and markers of renal impairment (α-GST and NGAL). The group HA> 80 J comprised 11 patients,;the group HES > 80 J comprised 12 patients; and the group Gela > 80 comprised 17 patients. All of the patients could be identified and their hospital records could be retrieved. The patient allocation to the respective groups is marked as completed along with an exclusive request for the performance of the said laboratory analyses by the notes “11x”,”12x” and “17x” appearing on the respective Excel sheets in Dr. Boldt´s own handwriting. Also in Dr. Boldt´s own hand on the Excel sheet „Gela >80“ there is a calculation for 160 lab kits needed, derived from a number of 40 patients and 4 sampling points in time: T0 („baseline“ in the publication) before (surgery), T2 4 hrs (after surgery), T3 1st (postop) day, T4 2nd (postop) day. The material concerning the two experimental groups Gela >80J and HES >80 J may unambiguously be attributed to the present publication because of the predetermined age limitation corresponding to the age data in Table 1,and to the analysis of inflammation markers in patients receiving gelatin as a volume replacement solution in cardiac surgery which are unique to this paper. Material concerning the experimental groups HES>80 J and HA>80J can be attributed to the publication Anesth Analg 107 (2008) 1496-1503. Thus material concerning the study group HES > 80 J was used in two different papers. -Informed consent: Retrieved were also completed and signed forms of declaration of informed consent attributable to one patient in the Gela>80 J group and to 5 patients in the HES> 80 J group. Their content, however, does not comply with the requirements of GCP and with those of a formal clinical study, because no mention is made of a randomization process regarding the different volume replacement regimens described in the publication. -Randomization is not verifiable. -Follow-up Questionnaires: Follow-up questionnaires directed at the patient´s physician were found for 10 of the 16 patients in the gelatin group and for 5 of the 11 patients of the HES group eventually discharged. The response rates of 62.5% and 45% respectively are different from the overall response rate of 82% claimed in the paper, but may reflect inadvertent loss of questionnaires.

26

The physicians addressed were left absolutely unaware of the real intentions of the questionnaire.The alleged purpose stated in the letter, concern about a possible prolongation of hospital stay attributable to preoperatively increased serum creatinine levels, was not an issue either in the retrieved study plan or in the methods section of the publication . -Data collection points: In the present paper five data collection points are defined: t0 („baseline“): after the induction of anaesthesia, t1: at the end of surgery, t2: 5 hrs after surgery, t3 and t4: first and second postoperative day. It is also claimed that samples for estimation of IL-6, IL-10 and ICAM-1 plasma concentrations were drawn at discharge from the hospital. This is gravely inconsistent with the finding in the laboratory sheets of four data collection points defined in Dr. Boldt´s own handwriting (see above). Results section: -Patients: In the paper, only the data from the two experimental groups, gelatin > 80 J and HES > 80, are published, while according to the retrieved documents clearly a third study group, HA>80 (human albumin in patients 80 yrs and beyond), was involved. The sample sizes for the groups included in the present paper (Table 1) are 30 each, while according to the data sheets retrieved, the gelatin group only comprised 17 and the HES group 12 patients. While in the present publication the sample size for the group HES > 80 is given as n=30, the sample size for the same group, HES >80, in the publication in Anesth Analg 107 (2008) 1496-1503 is given as n=25. The discrepancy cannot be explained. In Table 1 the sample sizes in the headline of 30 for each study group are at variance with the sums of surgical procedures, which give 29 for the gelatin 4% group and 31 for the HES group. There is no satisfactory explanation for these discrepancies. -Markers of renal function and of inflammation: The original laboratory data were obtained from groups smaller than the published ones: gelatin group n=17, HES group n=12. The laboratory technician, who performed these analyses throughout Dr. Boldt´s interest in these parameters, confirms that for the present project there were no measurements of said parameters beyond those concerning the subjects enumerated in the retrieved Excel tables. There is no satisfactory explanation for the differences in the numbers of subjects recruited and those listed in the publication. For urine α-GST and urine NGAL in Fig 2 data are shown from 5 time points, with point 2 designated as “end of surgery,” and point 3 designated as “5 h ICU.” This is at variance with the experimental design (see above) and with the retrieved laboratory data sheets, where explicitly only 4 time points are mentioned and data from only 4 sampling points in time are provided. In these documents time point 3 is designated “4 h ICU” and no mention is made of a time point “end of surgery”. According to the testimony of the laboratory technician, no additional analyses for the said parameters were ever run, as for instance for a time point “end of surgery”. There is no satisfactory explanation for the grave discrepancy in data acquisitions as claimed and as proven. For IL-10 (Fig 3 b) and ICAM-1 (Fig 4) data are shown data from 5 time points. There are no data displayed for the time point “end of surgery.” The failure to display data for time point “end of surgery” is at variance with the design put forward in the Methods section. Time point 5 is designated as “Discharge from hospital”. This is at variance with the experimental design (see above) and the retrieved laboratory data sheets, where explicitly only 4 time points are mentioned and the data from only 4 sampling points in time can be found. In these documents time point 3 is designated “4 h ICU” and no mention is made of a time point “discharge from hospital.” As testified by the laboratory technician, additional

27

analyses for the said parameters were never run, as for instance for a time point “discharge from hospital”. There is no satisfactory explanation for the grave differences in data acquisitions as claimed and as proven. It is debatable whether meaningful comparisons between the laboratory data retrieved and the respective graphs published as a result are at all feasible, considering the gross differences in study group sizes between the populations recruited and the ones published, and the differences in the number of time points listed in the publication and those contained in the laboratory sheets. Intergroup comparisons as shown in Figs.1-4, are of doubtful value, since comparisons to the third group of the original project, HA > 80J (human albumin) (see Anesth Analg 107 (2008) 1496-1503) were not performed. higher. -Outcome: According to the retrieved files, there was one fatality in each of the two experimental groups. This is in accordance with the number of fatalities given in the present paper, but differences in group sizes between the retrieved data and the reported data need to be taken into account. Committee evaluation: The publication was retracted by the publisher due to lack of the vote by an ethics committee. In view of the misrepresentation of group sizes, disparities between the number of data collection points in the laboratory sheets and in the paper, as well as within the paper proper, and because of withholding the results of a third study group, human albumin 5%, we conclude that the study has not been performed as described in the publication. To obtain consent from participants in a study on the basis of false information or with essential information withheld is highly unethical. Results from such a study cannot be possibly accepted. It would appear that this paper does not lend itself to Continuous Medical Education (CME). The committee recommends neither to draw any scientific conclusions from nor to Base any therapeutic decisions upon the content of this publication. 14. Mayer J, Boldt J, Wolf MW, Lang J, Suttner S Cardiac output derived from arterial pressure waveform analysis in patients undergoing cardiac surgery: Validity of a second generation device Anesth Analg 106 (2008) 867-72 Reference: The evaluation of this paper is based on an Excel file „EdwardsDaten/.xls“ provided by Dr. Mayer, the first author, on the results of an interrogation by the committee, and on an interview with one of the committee members. Comments: Methods section: An ethics vote was not obtained from Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz). 120 pairs of measured values have been entered into the submitted Excel data sheets ; data were obtained by the novel semi-invasive Edwards method of cardiac output measurement or

28

by the established pulmonary artery catheter thermodilution method. However, the present publication lists 282 pairs of measured and derived parameters. The Excel file contains data from 15 patients recruited, whereas in the publication n=40 patients are enumerated. This discrepancy was explained by Dr. Mayer by the Excel file in question containing a preliminary data collection on his private personal computer only up to a certain time. This collection was then completed at the department´s premises by entering further data as acquired up to the 282 data pairs published. The completed data sheets were destroyed as a result of irrevocable erasure of the hard disk of the departmental computer initiated under Dr. Boldt´s responsibility, but without involvement by the first author. The veracity of this contention by the committee cannot be definitely proven, but the first author asserts that this was the true course of events. Results section: The data collected in the Excel file provided by the first author testify to the recruitment of patients for this a study as published. Results from calculations based on the pairs of measured data from the Excel sheets are to a certain degree in accordance to the results published. Committee evaluation: The publication was retracted by the publisher due to lack of an ethics committee vote. Appreciating the explanation offered by Dr. Mayer and considering the similarity between the data from the submitted sheets and the data published, the committee concludes that Dr. Mayer´s assertions are plausible and the clinical study was performed as published. Due to the incompleteness of the preserved data collection, the Committee cannot firmly establish the validity of the scientific statements put forward in the publication. 15. Mayer J, Boldt J, Triem J G, Schellhaaß A, Mengistu AM, Suttner S Individual titration of propofol plasma target improves anaesthetic stability in patients undergoing major abdominal surgery: A comparison with manually controlled infusion Eur J Anaesthesiol 25(2008)741-47 Reference: The evaluation of this paper is based on an Excel file “OTCI 2-2 xls.” provided by Dr. Mayer, the first author, on the results of an interrogation by the committee, and on an interview with one of the committee members. Methods section: An ethics vote was not obtained from Landesärztekammer Rheinland-Pfalz (LÄK-RLP- the State Medical Association of Rheinland-Pfalz). The sample sizes in the Excel sheets for TCI (Target Controlled Infusion) n= 12 and MCI (Manually Controlled Infusion) n = 9 are substantially different from those in the publication, with n=28 for FM-TCI(Fluid Manager-TCI) and n=28 for MCI (Table 1). This discrepancy was explained by the first author as resulting from the Excel file in question constituting a preliminary data collection on his private personal computer only up to a certain time. This collection was later completed up to the published sample sizes n=28 for groups FM-TCI and MCI respectively by entering further data as acquired at the

29

department´s premises. The completed data sheets were destroyed as a result of irrevocable erasure of the hard disk of the departmental computer initiated under Dr. Boldt´s responsibility, but without involvement by the first author. .The veracity of this contention by the committee cannot be definitely proven , but the first author asserts that this was the true course of events. Results section: The content of the Excel file provided confirms recruitment of patients for a study as delineated in the publication. Committee evaluation: The publication was retracted by the publisher due to lack of an ethics committee vote. Appreciating the explanation offered by Dr. Mayer and considering that the submitted data sheets show a certain degree of accordance between the original data and the data published, the committee concludes that Dr. Mayer´s assertions are plausible and the clinical study was performed as published. Due to the incompleteness of the preserved data collection, the Committee cannot firmly establish the validity of the scientific statements put forward in the publication. 16. Boldt J, Suttner S, Brosch C, Lehmann A, Mengistu A Influence on coagulation of a potato-derived hydroxethylstarch (HES 130/0.42) and a maize-derived hydroxethylstarch (HES 130/0.4) in patients undergoing cardiac surgery Br J Anaesth 102 (2009) 191–7 References: The evaluation is based on