Mannitol in Head Injury
Cochrane Investigation

Message to CRASH Collaborators about high dose mannitol therapy

Between 2001 and 2004, three reports were published by Dr Julio Cruz and colleagues presenting the results of three clinical trials comparing high dose and conventional dose mannitol in the treatment of head injury. They appeared to show that high dose mannitol was dramatically effective in reducing death and disability after head injury.

Cruz C, Minoja G, Okuchi K. Improving clinical outcomes from acute subdural hematomas with emergency preoperative administration of high doses of mannitol: a randomized trial. Neurosurgery 2001;49(4):864-71.

Cruz C, Minoja G, Okuchi K. Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupilary widening. Neurosurgery 2002;51(3):628-38.

Cruz J, Minoja G, Okuchi K, Facco E. Successful use of the new high-dose mannitol treatment in patients with Glasgow Coma Scores of 3 and bilateral abnormal pupillary widening: a randomized trial. Journal of Neurosurgery 2004;100(3):376-83.

The trials were included in a systematic review of the effectiveness of mannitol in head injury and published in the Cochrane Library in July 2005. The review concluded that "high dose mannitol appears to be preferable to conventional dose mannitol in the acute management of comatose patients with severe head injury."

In May 2006, Dr Jorge Mejia, Colombian National Co-ordinator of the CRASH-2 trial, after attending a meeting of the Latin American Brain Injury Consortium in Brazil, wrote to me in my capacity as editor of the Cochrane Injuries Group about the inclusion of the Cruz trials in the Cochrane review:

"During the discussion some Brazilian physicians expressed some surprise with the inclusion of Julio Cruz's paper in the meta-analysis (Cruz 2004; J Neurosurgery, 100:376); off the record they expressed with self confidence that this paper is a fake because Cruz had no patients at his arrival to Brazil, back from USA where he had developed his research career…..I do not know what to do, but I feel betrayed. I guess that someone should contact the others authors and ask them. I feel that I can not stay passive, but I have no evidence."

The Cochrane Injuries Group conducted an immediate investigation into the matter and I hope that the results of this investigation will be published soon. However, because many CRASH collaborators regularly use mannitol in the emergency care of trauma patients the key correspondence is presented here.

Responses from co-authors:

05/15/06 4:34 pm

Dear prof. Roberts,

It was a pleasure for me to be included along the authors of the papers written by Julio Cruz on the use of high doses of mannitol in head trauma emergencies. My Unit and I did not provide to Dr. Cruz a personal series of randomized patients, but my contribution was discussing with him and sharing his assumption, because occasionally, in emergency situations, I have used and I still use with success aggressive high-dose mannitol approach.

I have met Doctor Julio Cruz in 1994 in Philadelphia, at the Hospital of the University of Pennsilvania, where I spent a period as a visiting fellow. After this period of study, we met two more times in Italy and one time in Bahamas for medical meetings. But, most important, we remained good friends, and we continued to remain in touch by phone and letter, discussing about our work, our clinical experience, and our life.

As you probably know, Julio Cruz died one year ago, and this is a great sorrow to me and to all my colleagues that had the opportunity to meet him. As regards the method of study, I and many colleagues are sure that his whole scientific production was based on the sistematic record of every single head injured patient, treated by Cruz either in USA or in Brazil, and collected in a huge data base.

As regards your systematic review, I well know and I appreciate very much the activity of Cochrane Collaboration, so I can imagine your concern about papers not supported by documentary evidence. At the same time, I hope that the scientific and human contribution of Julio Cruz in head trauma management cuold be aknowledged, also by planning new randomized controlled clinical studies.

I remain at your disposal for any further contact.

Sicerely yours,

Giulio Minoja
U.O. Anestesia e Rianimazione B
Ospedale di Circolo e Fondazione Macchi
21100 Varese - ITALY

05/19/06 3:10 pm

Dear Ian,

I would like to help you in your task, as I well know how important is to aknowledge the scientific eveidence and to find out unfounded data of medical articles. I think that patients were enrolled in USA and more recently in Brazil, but I honestly don't know the period and in what Institution. Again, I honestly must inform you that my friend Julio as from several years suffered from loneliness and depression, and dramatically died killing himself. So, the content of our more recent contacts frequently did not concern his professional and scientific activity. And it was very hard to get close to him, understand his problems and try to help. In conclusion, it was very touching to appear as a co-author of his last three articles: but this was the result of our friendship, more than of my active scientific cooperation.

Anyhow I hope that the powerful contribution of Julio Cruz produced during the last 20 years could be aknowledged. In this regard I am writing a paper reporting my experience in head trauma management based on his fundamental teaching. I am sure you understand my personal position, and I ask you to use reservedly my information. Please, let me know, if possible, the conclusion of your review.
Thank you very much for your attention.

Best regards,


Giulio Minoja
U.O. Anestesia e Rianimazione B
Ospedale di Circolo e Fondazione Macchi
21100 Varese - ITALY

05/18/06 6:06 am

Dear Dr. Roberts,

(JI would like to inform you of my concerns to the papers. Since I did not conduct any study related to the results of Dr Cruz $B!G (Js high-dose mannitol trials in Japan, I have no data to present you. I did not know any part of the paper before he called me about the acceptance in the journal every time. After I read his paper, I mailed him the impression concerning well-known drug, mannitol that I have used for a long time in my hospital. In Japan, we sometimes infused mannitol more than 1.4 g/kg for the treatment of acute subdural hematomas. But, we have not evaluated the high-dose effect compared with conventional dose in a strict manner. The journal editors appreciated his randomized trials clearly described benefits of high-dose.
I still believe him and I want him to clear up his doubts.

Yours sincerely
Kazuo Okuchi,M.D.

Department of Emergency and Critical Care Medicine, Nara Medical University
840 Shijo-cho, Kashihara, Nara 634-8522, JAPAN
Phone: +81-744-22-3051;Fax: +81-744-22-5992

From: Enrico Facco 05/22/06 4:02 pm

Dear Prof. Roberts, thank you for you message. The paper I am co-author, springs from the clinical experience I shared with Julio Cruz about the potential effectiveness of high doses of mannitol in selected very critical patients. I discussed with him (mainly by phone) about my anecdotical experience I never had the opportunity to check in a prosepctive study, and he also had the same clinical impression of its effectiveness. Since the eighties the use of lower doses (o.25 gr/kg b.w.) has been more and more emphasized, which is effective in most cases, but it may lead to underscore the possible benefits of higher doses in very critical patients. Following our discussion, he decided to test high mannitol doses in the emergency setting and involved me as co-author, but my role was "philosophical" rather than clinical: to my knowledge, the study was conducted personally by Julio, probably in Brazil, and I only helped him with discussion and text revision. I do not know whether the concerns you mention are grounded, but they seem to me hardly compatible with is personality. I met Julio in 1992 first; than we met in several meetings, giving rise to a good friendship. He was a very honest man and a very good clinician, despite his complex personality, which caused him increasing troubles, mainly due to his difficulty in human relationship. He detested prejudices and politics in the world of science, and whatever looked to be "politically correct", sometimes making him unduly aggressive: This probably caused him to loose friends and colleagues and isolate himself in the last part of his life.

Due to his intellectual honesty, I always appreciated, I am inclined to think that the concerns you mention be not grounded, because they contradict the kernel of his scientific faith, but I have no data to prove or disprove them. Moreover, He wrote this paper in a moment when He could not have any personal interest and his only aim was to publish what he found, with his personal style, before leaving us.

Anyway, whatever the source for concern, the study is to be considered as a first report only, suggesting to reappraise the appropriate doses of mannitol in selected cases and calling for further studies in larger series. I am sorry I cannot provide you facts and documents able to help you and I remain at your disposal for anything you may require.

With my warmest regards

Prof. Enrico Facco
Dept. of Pharmacology and Anesthesiology
University of Padua
via C. Battisti 267
35121 Padova, Italy


Response from Journal of Neurosurgery

July 14, 2006

Ian Roberts, M.B., B.Ch. MRCP, Ph.D.
Co-ordinating Editor Cochrane Injuries

Dear Doctor Roberts,

I have tried unsuccessfully to contact you by phone with regards to the Cruz papers. As you can tell by Dr. Marshall's editorial, we all doubted the data. But to doubt is different from concluding that Dr. Cruz fabricated the data. I thought he did, but hoped as stated in the editorial that publication would encourage repetition of the studies. My Editorial Board thought Dr. Cruz' work should be published. I wouldn't trust the data.


John A. Jane, Sr., M.D., Ph.D.
Editor, Journal of Neurosurgery


Letter to the Editor of Neurosurgery

5 September 2006

Dr Michael L.J. Apuzzo
Editor, Neurosurgery
1420 San Pablo Street, PMB A-106
Los Angeles, CA 90033

Dear Dr Apuzzo

Re: Clinical trials by Dr Julio Cruz

I am the co-ordinating editor of the Cochrane Injuries Group. The Cochrane Injuries Group is part of the Cochrane Collaboration and prepares systematic reviews of the effectiveness of treatments for trauma. One of our systematic reviews is about the effectiveness of mannitol in the treatment of patients with head injury. This review includes three papers by a Brazilian neurosurgeon, Dr Julio Cruz, two of which were published in your journal.

Cruz C, Minoja G, Okuchi K. Improving clinical outcomes from acute subdural hematomas with emergency preoperative administration of high doses of mannitol: a randomized trial. Neurosurgery 2001;49(4):864-71.

Cruz C, Minoja G, Okuchi K. Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupilary widening. Neurosurgery 2002;51(3):628-38.

Cruz J, Minoja G, Okuchi K, Facco E. Successful use of the new high-dose mannitol treatment in patients with Glasgow Coma Scores of 3 and bilateral abnormal pupillary widening: a randomized trial. Journal of Neurosurgery 2004;100(3):376-83.

Several doctors have raised serious concerns about these papers. Specifically, they have said that they may contain fabricated data. Because our reviews are disseminated widely and have a bearing on the clinical care of patients with head injury we need to find out if there is any basis for their concerns.

I would very much appreciate your help with this. I look forward to hearing from you.

Yours sincerely

Ian Roberts
Co-ordinating Editor Cochrane Injuries Group

To date, there has been no response from the editor.

Advice to Cochrane Injuries Group from Committee on Publication Ethics

This complicated case provoked much discussion. The advice was to reinstate the review but without the three disputed papers, adding a note to say that there is a potential problem with these three papers. It was felt that if the data are fabricated, there was a responsibility on the part of the editor not to publish the data as there might be a significant risk to patients if the trial was repeated.

As there has been no useful response from the other journal editors who published other papers by this author, it seems there is no point in pursuing this line of enquiry. However, the editorial procedures in these journals must be criticised as the editors strongly suspected that the data were fabricated but still went ahead and published the papers. COPE could take some action if they were members, but they are not.

The committee agreed that the best approach for the editor would be to seek a retraction of the papers from the co-authors on the basis of gift authorship. The advice was to write to the co-authors, ask for the data, and if not provided, ask them to withdraw the papers. In this way, it is not necessary to say that the data are fraudulent, with all its legal implications. It was felt that the co-authors must take responsibility for the data as their names are on the paper. It is not acceptable to say that their contribution was merely "philosophical". Gift authorship is not acceptable. Also, the co-authors' institutions should be contacted and informed of the situation. In this instance, the editor should write to the co-authors informing them that he has contacted their institutions.


Response from the co-authors:


Dear Dr. Roberts,

Thank you very much for your thoughtful suggestion. I would like to retract these papers from the journals because I am not able to take responsibility for the content. Could you let me know how to act formally for the purpose. I will tell the course of problem to the president of my university (Osamu Yoshida, M.D.) in a few days.

Contact address:
Prof. Kazuo Okuchi, M.D.,
Department of Emergency and Critical Care Medicine,
Osamu Yoshida, M.D
The president of Nara Medical University

Nara Medical University, 840 Shijo-cho Kashihara, Nara 634-8522, Japan
Phone: +81-744-22-3051, fax: +81-744-22-5992

Yours sincerely
Kazuo Okuchi, M.D.


Dear dr. Roberts,

Thank you very much for your support. On my last e-mail letter, I had mentioned withdrawal of the papers, however I found that I had no right to retract the papers from the journals. I think it depends on whether Dr Cruz will decide or not. I did not conduct any study related to the results of Dr Cruz $B!G (Js trials in Japan and I did not check the draft, but I informed him the clinical treatment methods for using mannitol in my department. Also, We discussed the measurement of jugular bulb oxyhemoglobin saturation in head injury. I will contact him in a few days.

Yours sincerely

Prof. Kazuo Okuchi, M.D.,
Department of Emergency and Critical Care Medicine,
Nara Medical University, 840 Shijo-cho Kashihara, Nara 634-8522, Japan


DEar Dr. Roberts, on behalf of Dr. Minoja and Dr. Okuchi, I am sending you the repaly to your letters. I apologize for the delay, due to academic and hospital duties.

I remain at your disposal for anything you may require.


Enrico Facco

Dear Dr. Roberts,

We apologize for replying so late to your persistent requests, but summer holidays first and, then, academic and hospital duties and congresses have prevented us to answer to your questions.

We hold the Cochrane Injuries Group and his co-ordinating editor in the highest attention and regard. On the other hand, the authors of the paper also deserve a full respect: Dr. Okuchi is a Japanese board certificate neurosurgeon, Dr. Minoja is the head of NICU dept. in the University hospital of Varese and Prof. Facco is professor of Anesthesiology and Intensive care at the University of Padua. All of us have over 20 year clinical experience in the management of head injury and in the use of mannitol, as well as all other aspect of management: we cannot help with rejecting any possible insinuation about our honesty, professionalism and skill. Dr. Cruz has been a leading authority in the field of head injury in the eighties and nineties and was the most honest, rigorous researcher and bright clinician we met. Any charge of falsity is indeed incompatible with his personality, professionalism and biography. For all of us even the slightest intention of doing something false would be simply unconceivable.
We cannot exclude that, in our previous correspondence, something might have been misunderstood, despite we only told you the truth and this is our only aim. Therefore, now we have joined to give all our information and opinion, then you will decide what is right to do.

As you have already be informed by us, we had only a minor role in the papes by J. Cruz you mentioned, despite we think that it was not a gift-authorship. In fact, as you know, we did not participate in data collection, but all of us had a good clinical experience with the use of high dose mannitol before starting the study, and all of us, including Dr. Cruz, discussed together and shared our clinical experience: we participated in conceiving the study, namely, in defining the aims and study design. Dr. Cruz collected the data, a relatively small sample when the last paper is concerned (44 cases), because the protocol called for very early mannitol administration in the emergency room, that is, before the admission to the NICU (authors working NICU did not work in the emergency room and could not collect the data). Probably, this is the simple reason for your uncertainty about the centres involved in data collection: the study has been conducted in Brazil only, instead of 3 Countries, due to our impossibility of treating the patients in the emergency room.

Of course, none of us claimed to remain in the study as an author, due to our incapability of collecting the cases, but Julio kindly recognized our contribution, which was only "philosophical" but, anyway, relevant, since it sprang from our experience and discussion. We do not think that it can be considered as a mere gift-authorship, but, so far, we have done absolutely nothing to claim or get something undue. On the other hand, you should grant that data collection is only one of the manifold aspects of a study, and the choice of including or withdrawing co-authors according to their involvement is up to the main author only.

Further aspects to be taken into account are the following:

1. The paper has been published in an international, peer reviewed journal, where the full author's responsibility is an essential part of the process of submission: it seems to us that this should be enough. Any doubt about that, would involve the journal and its editor in the charge of misconduct.

2. None of us has ever doubted about the existence of the patients and correctness of results: we do know that he has done data collection rigorously, because we know him very well and we do know that he would never have been able to do something false. Such a charge is simply unconceivable for a rigorous, keen, honest scientist, as he has been throughout his professional life. In our previous correspondence we told you that we were not responsible for data collection because we did not collect them directly, but we have no doubt about them.

3. The main problem is that Dr. Cruz is dead, and, thus, you cannot ask him directly: this is the only reason for your doubts. He already took full responsibility and, would he be still alive, he would strongly confirm it to you again, with no doubts. On our opinion, it looks questionable doing it again: in fact, no dead scientist can confirm the responsibility he took during his life. As a consequence, for the sake of coherence, one should retract all the published papers, once the authors are dead.

4. The results of the study are not only true, but also are confirmed by our clinical experience and there is no reason for considering them as false and even harmful.

5. We have no right at all of retracting the paper from the journal: it might be decided by J. Cruz only. But, please, consider again that everything, including responsibility has been done when required. A bright scientist as J. Cruz was, deserves the highest esteem during his life and after his death, and all of us are to keep a good memory of him, instead of trying to kill him for the second time, with no reasons.

In conclusion, we have nothing to claim for ourselves, but we are to reject any charge. We do believe that your concerns are not grounded, despite some possible misinformation in your process of reviewing. We feel able to witness the absolute honesty and correctness of Dr. Cruz, who has always detested any bias, falsity, prejudices and politics in the world of science, as well as whatever looked to be not true or "politically correct". We cannot retract the paper (we have not the right to do it) and we believe that it would be conceptually wrong: if you believe that the paper is true, you can include it in your review process; otherwise, you can simply skip it, if some doubt persists, despite the paper, the patients are true, the results are good, reliable and useful to the patients, with no harm: in deeply comatose, decerebrated patients the only harm would be denying them the proper dose of mannitol.

We hope that our comments can meet your requirements and remain at your disposal for anything right you may require.


Details of lead authors affiliation

None of the reports indicated where the patients came from. All of them stated that "institutional review board approval was obtained" but with no further details. On each report, the lead author's affiliation was "The Comprehensive International Centre for Neuroemergencies (CICNEM) and Federal University of Sao Paulo." Reprint requests were to CICNEM at a postal box address in Sao Paulo. We were unable to find any further information about CICNEM. In October 2006, the Federal University of Sao Paulo stated in response to our inquiry that Dr Cruz had never been employed by the University.

Message from Eliane S. Azevedo who investigated the Cruz trials on behalf of Corina Bontempo de Freitas, Executive Secretary of the National Commission for Research Ethics - CONEP - Brazil

Salvador, September 24th, 2006.

Dear Dr. Ian Roberts

Dr. Corina Freitas send me the reprints of Dr. Julio Cruz papers she received from you. She knows my interest in good science education which implies misconduction disclosure as well. Thus, we gave a closer look on Dr. Julio Cruz doings and found things that, I hope, be of helping to you:

In an interviews given to the "Comunicação unifesp - jornal da paulista - pesquisa" year 16; no. 176. fev. 2003, Dr. Cruz informed that his studies on the 141 comatose patients were conduct in eight (8) hospitals in Brazil, Italy and Japan.
My comments: Considering that in his paper reporting the study of these 141 patients (Neurosurgery 51:628-638,2002), he does not mention the hospital, neither the city nor the country were the research was conducted, the real origin of the data became more questionable. By the way, as you remember, none of his three papers gives information on place of data collection (hospital, city, country).

In this same note the reporter also interviewed Dr. Italo Suriano, Coordinator of the Neurosurgery Emergency at the Hospital São Paulo, about the use of mannitol. Dr. Suriano answered as follows "Over here we adopt several measures to improve the comatose patients, such as, monitorization of brain oxygenation; well equipped UTI; and also, in some cases we give high doses of the medication. There are many factors associated with the patients´ recovery. Until the present moment, I do not have, in this Hospital, statistical data which would allow me to say that the mega-dose of mannitol is what makes the difference. However, I have the impression that the patients are improving more rapidly when treated with mannitol"
My comments: Considering that the interview occurred after the publication of the 2001 and 2002 papers, the insecurity of Dr. Suriano regarding the mannitol data needs an explanation.

In three other internet notes (1-Inter-Especiais.: Brasil; 2- inventabrasilnet; 3- Inventores Brasileiros - Fármacos), Dr. Julio Cruz is mentioned as one of the 200 greatest world intellectual according to the Cambridge International Biographic Center awarded by the Excellency Order of XXI Century.
My comments: This institution, which I assume is in UK, must have some information on Dr. Julio Cruz.

My own comments regarding the papers: - All three papers refer to mortality rates at six month in both groups: mannitol and control. Also, all three papers give Tables on clinical outcomes at six months. The numbers of patients in these Tables adds up to the total number without mortality. When did the mortality occur? I printed these and others internet notes I found in Brazil. They are in Portuguese. I shall be glad in sending it to you. If you wish so, please send me you postal address.

Finally, I feel that I must let you know that I am a MD from Brazil; a PhD in Genetics from USA and a former Fellow of the Galton Laboratory, University College, London (1972-73). Now I am a busy 70y Emeritus Professor. For the last 14 years I gave up experimental work on human genetics and dedicated myself to Bioethics. More recently I am also giving talks and publishing on scientific integrity. I feel that I really need to learn how to discover frauds and other misconduction of science. That is my present challenge… Any suggestions?

Sincerely yours

Eliane S. Azevedo.

Response of the Cochrane Injuries Group

Because the Cochrane Injuries Group investigation was unable to confirm the validity of the trials by Cruz and colleagues these trials have been withdrawn from the Cochrane Review.