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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Clarification of competing interests
- Giselle Jones (17 November 2006)
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Hidden conflict of interests
- Vasiliy Vlassov (17 November 2006)
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Author should disclose any links with the Plasma Products Industry
- Ian Roberts (17 November 2006)
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Albumin's Own Goal
- David Leopold (18 November 2006)
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What is the punishment for failing to declare a conflict of interest?
- Richard Smith (18 November 2006)
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Why use albumin?
- Iain R Crossingham (19 November 2006)
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The wrong trigger level for the administration of albumin
- Michael Poullis (21 November 2006)
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SAFE as SAC (Save Albumin Campain)
- Ahmed N Ghanem (22 November 2006)
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Message from BMJ ethics committee
- F Godlee (25 June 2007)
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Giselle Jones, Editorials editor BMJ
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The initial version of this editorial submitted by the authors did not state any competing interests. One day after the BMJ went to press the author declared the following competing interests: "Prof Vincent and his Department have received unrestricted grants from Baxter, Braun, Fresenius and PPTA." Competing interests: None declared |
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Vasiliy Vlassov, Director Russian branch of the Nordic Cochrane Centre
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Dear Editor, commentator not declared the obvious conflict of interests. He co- authored number of pro-albumin articles with M.M. Wilkes, R.J. Navickis. These last two were paid by albumin industry to produce the notorious industry review of 2001 to play down the results of Cochrane albumin review. While Cochrane review found that albumin does not help trauma patients, the pro-albumin industry authors claimed that it is safe. When SAFE trial found that albumin does not help trauma patients, the pro- albumin industry authors claimed that albumin may be good for specific subgroups of patients. Authors of Cochrane review after update of the review cautiously concluded that "in view of the absence of evidence of a mortality benefit from albumin and the increased cost of albumin compared to alternatives such as saline, it would seem reasonable that albumin should only be used within the context of well concealed and adequately powered randomised controlled trial." Because industry repeatedly claim that albumin is useful is specific groups of patients, SAFE group produced the analysis published in current issue of the BMJ. Found: The most important prospective group of such patients - patients with hypoalbuminemia - are not specifically benefited by albumin. This is not enough for J. Vincent, because the SAFE study "was not designed to show the beneficial effects of albumin administration in any particular group of patients." What trial, designed specifically for that, support the claim that albumin is useful for some specific group? No one. Why to publish again this call for new studies when only visible purpose of it is to prevent the reduction of sales of albumin? Probably Cochrane reviewers need to say not only that "albumin should only be used within the context of well concealed and adequately powered randomized controlled trial", but also reformulate that: "albumin must not be used in routine practice of trauma care before well designed studies prove its efficacy." Competing interests: None declared |
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Ian Roberts, Professor of Epidemiology LSHTM
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Editor - I was surprised that Professor Vincent did not declare any competing interests in relation to his editorial on human albumin administration. Professor Vincent and his colleagues Wilkes and Navickis from Hygeia Associates (a U.S based service company offering biomedical communications, research and analysis) has co-authored several papers supporting the use of albumin that were funded by the Plasma Protein Therapeutics Association.(1,2) Declaration of competing interests is particularly important in this context bearing in mind that in January 2000, the Cochrane Injuries Group received a leaked document from the European Plasma Fractionation Association (EPFA).(3) The document described the “Albumin Support Programme” an initiative by the European Association of the Plasma Products Industry (EAPPI) to resuscitate the ailing US $1.5 billion global albumin market. The objective of the programme was to disseminate medical evidence that supports the use of albumin. The programme included: (1) the preparation of literature reviews supporting the use of albumin to be sent to leading regulatory authorities, (2) preparation and dissemination of a Cochrane critique dossier, (3) the establishment of a medical advisory panel to write articles supporting the use of albumin. The albumin manufacturers had set aside US $2.2 million for the programme. 1. Vincent JL, Wilkes MM, Navickis RJ. Safety of human albumin—serious adverse events reported worldwide in 1998-2000. Br J Anaesth 2003;91:625-30 2. Vincent JL, Navickis RJ, Wilkes MM. Morbidity in hospitalized patients receiving human albumin: a meta- analysis of randomized controlled trials. Crit Care Med. 2004;32:2029- 2038. 3. Roberts I, Bunn F. Egg on their faces: the story of human albumin administration. Evaluation and the Health Professionals 2002;25:130-8. Competing interests: IR is a co-author of the Cochrane Injuries Group Systematic Review of Human Albumin Administration, the preparation of which did not receive any funding from the plasma products industry and was conducted entirely independent of this industry. |
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David Leopold, Consultant Physician Morriston Hopsital Swansea SA34JE
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Sir. The author's Conflicts of Interest are widely known. His regrettable oversight may prove more effective than any Scientific Study in settling any small remaining doubt about Albumin. Kind regards David Competing interests: None declared |
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Richard Smith, Grumpy old editor London SW4 0LD
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If Ian Roberts is right--and he usually is--then Professor Vincent seems to have more conflicts of interest than he belatedly declared. Could we also know the size of the grant in Euros? Is there a punishment for failing to declare a conflict of interest? If so, what is it? Richard Smith Competing interests: I was the editor of the BMJ for 13 years and fretted increasingly about conflicts of interest but never solved the problem. |
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Iain R Crossingham, SpR Trafford General Hospital, M41 5SL
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Dear Editor, Vincent makes several assertions regarding the SAFE study[1] in his editorial[2]. Firstly he implies that this study can't be used to exclude an advantage of albumin over saline. In fact the study was powered to detect a 3% absolute difference in mortality rate between the groups. Such a difference was not present. Secondly he states that most patients randomised would not have received albumin and therefore it is unreasonable to expect to see a benefit from albumin administration. However less than 2.6% of the albumin group did not receive this fluid. He concludes that there is insufficient evidence for a ban on albumin. He doesn't however explain quite why anyone would want to use albumin when saline is just as effective, cheaper and without the risk of hypersensitivity reactions[3][4]. [1] Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Eng J Med 2004; 350: 2247-56 [2] Vincent JL. Resuscitation using albumin in critically ill patients. BMJ 2006; 333: 1029-30 [3] Shimode N, Yasuoka H, Kinoshita M, et al. Severe anaphylaxis after albumin infusion in a patient with ahaptoglobinemia. Anesthesiology 2006; 105: 425-6 [4] Leach SR. Cardiovascular collapse following infusion of 5% albumin. AANA J 1991; 59: 592-4. Competing interests: None declared |
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Michael Poullis, Consultant Cardiothoracic Surgeon Liverpool. L14
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Dear Sir, Unfortunately this study group has have picked upon the wrong trigger level for the administration of albumin in their paper (1). Nobody would argue with albumin being ineffective and possibly harmful when administered to patients with normal albumin levels, so a level of 25g/dL which is “normal” amongst ITU patients is intuitively too high a trigger level. After cardiac surgery it is important to maintain a serum albumin level of about double the left atrial filling pressures to prevent the development of pulmonary oedema, due the Starlings Law. After optimum inotropic implementation, red blood cell transfusion, and renal support measures, albumin can be a very helpful adjunct to reduce pulmonary oedema. After liver resections when patients develop transient liver failure, albumin can be very effective in reducing the incidence of ascites, pleural effusions and generalised oedema. In nephrotic patients when the albumin drops below 10g/dL, they sometimes cease to pass urine and develop oedema. Albumin administration can help reduce the oedema, and in combination with frusemide aid resumption of urine output In summary unnecessary albumin administration does need to be halted in the ITU setting, but it still has a role in certain groups of patients, when used appropriately. This study group may have discovered this had they had the correct trigger point for albumin administration. 1 Human albumin administration in critically ill patients: systematic review of randomised controlled trials • Why albumin may not work Cochrane Injuries Group Albumin Reviewers and Cochrane Injuries Group Albumin Reviewers. BMJ 1998 317: 235-240. Competing interests: None declared |
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Ahmed N Ghanem, Urologist EDGH BN21 2UD
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Sir, I read with interest Professor Vincent1 editorial advocating “insufficient evidence to ban albumin” and calling for further trials. It is based on Professor Finfer’s analysis of “saline versus albumin fluid evaluation (SAFE) trial” 2 concluding: “fluid resuscitation with saline or albumin produces similar outcome”. In 1998, meta-analysis3 concluded albumin “may increase the risk of death” or worse outcome. This justified BMJ slogan “Why albumin may not work”. Is there a conflict here and why? What does similar outcome mean, does it mean saline is as bad as albumin or albumin is as good as saline? This is perplexing to practicing physician, requiring hard analysis interpretation and deductive thinking to decipher the verdict, and whatever one comes up with remains his own opinion! Is this the scientific medicine to burden physicians with and inherit next generations of researches? My aim of writing, however, is to say that all SAFE trials are missing the point of real difference to the outcome of the concerned ICU patients. The editorial1 mentioned other huge prospective controlled trials that concluded either similar or worse outcome. This is perhaps the best answer such trials can, and will, ever give! Vincent’s questions on sub- sub-groups are impossible for a trial to answer. The SAFE has been extensively reported and debated since the use of isotonic fluids for resuscitating the victims of WW2. Another trial will be just fuel for f fire of everlasting debate. Years of hard work, painstaking analysis and millions of money down the drain, companies going bankrupt and patients continue to die. Repeating trial using the concept of comparing only the types of SAFE fluids will not change practice or improve outcome. I see no point of repeating such trials unless, a new concept or evidence is considered! Another trial may conclude similar or worse outcome, so what? This will neither resolve the SAFE controversy, nor restore confidence in albumin, nor identify the real cause of multiple vital organ failure (MVOF) syndromes. It is deadlock situation; the reason for it is undoubtedly extremely complex but can be traced to a simple fresh (old) concept that may perhaps lead to a feasible solution. Has it ever been considered to evaluate the volume or quantity along with the type of SAFE fluids? Is there a single existing study providing such data? If there is one I wish to know about. So, highlighting the overlooked volume issue and proposing original research concepts4-8 may resolve the problems. The concept of Volumetric Overload (VO) over Time (VO/T) remains overlooked or ignored. My first letter at BMJ6 was in 1985 and the latest7 RR in 2004, with many in between8. Evidence was reported in 19904 and other in 20015. Most VO occurs during the resuscitation time and stay after shit to ICU. To clarify, if data on MVOF patients’ body weight on ICU is compared to weight on hospital admission, a staggering VO is revealed that is directly related to the severity of MVOF4! This VO is also related to outcome as patients who die go with it and survivors must lose it. Weight gain on ICU is cumulative VO of retained fluid - evident mainly on fluid balance data during resuscitation, but it may or may not show on the ICU daily fluid balance chart. A grossly swollen MVOF patient on ICU is so common that his gross oedema does not raise and eye brow, perhaps thought the norm! No doubt ventilation and dialysis have improved outcome but MVOF remains an enormous ICU problem the World over. Finally, on repeating SAFE trial, should a 3rd and perhaps 4th arm therapy group be added? The VO/T harm originates from excess isotonic fluid infusion, at resuscitation and on ICU, is due to faulty scientific basis4-8, research suggest4 if both SAFE isotonic fluids are withheld (3rd arm), or careful infusion of hypertonic 5% NaCl (4th arm) used instead of, not as well as, SAFE fluids, the new groups may have superior outcome! Yours truly, Ahmed N Ghanem, MBChB, MD (Urology), FRCS. an_ghanem@yahoo.com Conflict of interest: None in reality one in a dream. References 1. Vincent JL. Editorial. Resuscitation using albumin in critically ill patients: Research in patients at high risk of complications is now needed. BMJ; 333:1029-30. (18 November 2006) 2. Finfer S. Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ; 333: 1044-6. (18 November 2006) 3. Cochrane Injuries Group. Human albumin administration in the critically ill patients: systemic review of randomized controlled trials: Why albumin may not work. BMJ 1998; 317: 235-40. 4. Ghanem A. N., Ward J. P. Osmotic and metabolic sequelae of volumetric overload in relation to the TURP syndrome. Br J Urol 1990; 66: 71–78. 5. Ghanem AN. Magnetic field-like fluid circulation of a porous orifice tube and relevance to the capillary-interstitial fluid circulation: Preliminary report. Medical Hypotheses 2001 Mar; 56 (3): 325- 334. 2001 Mar; 56(3):325-34. 6. Ghanem AN. Hypoalbuminaemic hyponatraemia: a new syndrome. BMJ 1985; 291: 1502 7. Ghanem AN. Albumen does not work: should its scientific basis be questioned and what alternative hypothesis for the capillary-interstitial transfer is there. http://bmj.com/cgi/eletters/382/7444/852-a#56675, 14 April 2004 8. Ghanem AN. Shock in Poly-trauma: Highlighting Volumetric Overload/Time (VO/T) shock and new hydrodynamic phenomenon that proposes new hypothesis on capillary circulation and redefine shock. http://bmj.com/cgi/eletters/327/7424/1119#41644, 27 Nov 2003 9. Please see the other letter to Editor on the article2. Competing interests: None in reality one in a dream! If any company offered half the money, half the work force of independent analyzers, reviewers, statisticians and journal negotiators. The team and I will deliver the real needed answers and I could afford to, and would, buy shares in that company! I might even donate 1-2 ideas of medicines that work. |
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F Godlee, Editor, BMJ BMJ, BMA House, London WC1H 9JR
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Further to the correction alerting readers to the author’s conflict of interest in relation to this editorial, we referred the case to the BMJ’s ethics committee. We also, in preparation for the discussion at the ethics committee, wrote to the senior author of the article to which the editorial relates, Professor Simon Finfer. We wanted his help with the question of whether we would have commissioned and published the editorial from Professor Vincent if we had known of his connections with the industry. We wanted Professor Finfer’s view as to whether the editorial presented a reasonable view of the issues or appeared in any way obviously biased. Professor Finfer responded with the view that “overall, the editorial may be viewed as taking a more pro-albumin than anti-albumin position, but I do not think it seriously misrepresents either our data or the current state of knowledge.” In view of this, and the retrospective declaration of conflict of interest by Professor Vincent, the ethics committee took the view that no further action was required. Competing interests: I am the editor of the BMJ and a member of the BMJ’s ethics committee |
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