EDITORIAL

Plasma, guidelines, and evidence-based medicine

Roberto Reverberi
Servizio di Immunoematologia e Trasfusionale, Arcispedale S.Anna, Azienda Ospedaliera-Universitaria di Ferrara, Italy

The importance of the evidence-based medicine movement has progressively increased in the last two decades, so that it is not inappropriate to define this as a "paradigm shift"1 in the sense given to this term by T.S. Kuhn2.

What is "evidence-based medicine"?

Evidence-based medicine (EBM) purports to be the "use of current best evidence in making decisions about the care of individual patients " 3 . Its philosophical foundations date back to at least the 19th century 3 but its development had to await the widespread recognition of the randomised clinical trial as the best research methodology1. The main tenets of EBM are1: - clinical experience and instinct are very important but may at times be misleading. - Similarly, the understanding of pathophysiological principles is necessary but not sufficient to guide clinical practice. - Individual clinical expertise must be combined with the best external evidence, obtained from systematic research. - The credibility of authority and tradition must be assessed on the basis of the supporting evidence. A new skill is believed to be necessary for the clinician: the so called "critical appraisal" of scientific evidence1, which is the ability to search the scientific literature for the relevant studies, to decide whether their conclusions are applicable to the case in point, and to evaluate the strength they provide in support of alternative decisions.

traditional clinical expertise. Moreover, outside of academic institutions, access to scientifically valid medical literature is not so widespread as could be wished. It is not, therefore, surprising that the main offspring of the EBM movement has been a flourishing of systematic reviews of medical literature and of (it is hoped) evidence-based guidelines, by expert panels. Evidence-based guidelines are meant to alleviate the heavy burden of literature search and appraisal, providing the hungry clinician with a sort of pre-digested food, instead of the tough, raw product, or, if you find this metaphor a bit distasteful, distilling a few drops of crystalline wisdom out of a confused and verbose mass of obscure scientific jargon.

Are evidence-based guidelines based on evidence?

The habit of critical thinking is like a chain reaction: more and more aspects tend to be scrutinised. Sooner or later, the critical attitude turns self-critical, and rightly so. Thus, evidence-based guidelines have also been subjected to critical appraisal 4 . An appropriate methodology, the AGREE instrument5,6, has been devised, validated and applied. The results have been discomforting, but quite instructive.

Evidence-based or "eminence"-based7?
Even a guideline, issued through the concerted effort of six British scientific societies, has been judged of such low quality as to be inadvisable for use in clinical practice7. A recent caustic editorial8 made a severe diagnosis: if published guidelines are not making the difference they were expected to make, one of the reasons is that panellists do not refrain from expressing their personal opinions assertively, whereas lack of evidence should advise humbleness and
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Evidence-based medicine and evidence-based guidelines

This new skill is probably no easier to acquire than
Blood Transfus 2008; 6: 3-5 DOI 10.2450/2008.0052-07
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restraint. The recommendations in the guidelines must be supported by randomised clinical trials, otherwise they betray the basic tenets of EBM.

Guidelines for the use of plasma

In this issue of Blood Transfusion, we publish the first study9 that evaluates guidelines for the use of plasma by means of the AGREE instrument. The five guidelines considered were issued by prestigious institutions but all of them were far from being ideal and scored low, particularly as regards editorial independence, applicability and stakeholder involvement. The Authors also noted large differences in the recommendations and attributed the discrepancies to the lack or low quality of the available evidence. Another article10 provides a further thoughtprovoking example: it contains the recommendations on the use of solvent-detergent plasma, issued by the Tuscan transfusion system. The reader interested in assessing this document thoroughly is referred to the website of the AGREE Collaboration 11, which provides detailed instructions12. I will limit myself to a few considerations. These guidelines contain seven recommendations. None of them is graded as strong. None is supported by randomised clinical trials. Five out of seven recommendations are based on the opinion of experts, only.

felt they had to provide themselves with a set of rules for its clinical use. I think that their highest priority should instead be to collect the badly needed evidence we currently lack, through both haemovigilance and, preferably, randomised clinical trials. The scientific community (and patients) would greatly appreciate that.

References
1) Evidence-Based Medicine Working Group. Evidencebased medicine. A new approach to teaching the practice of medicine. JAMA 1992; 268: 2420-5. 2) Kuhn TS. The structure of scientific revolutions . Chicago, Ill. 1970. University of Chicago Press. 3) Sackett DL, Rosenberg WMC, Gray JAM, et al. Evidence based medicine: what it is and what it isn't. BMJ 1996; 312: 71-2. 4) Shaneyfelt TM, Mayo-Smith MF, Rothwangl J. Are guidelines following guidelines? The methodological quality of clinical practice guidelines in the peerreviewed medical literature. JAMA 1999; 281: 1900-5. 5) Cluzeau FA, Littlejohns P, Grimshaw JM, et al. Development and application of a generic methodology to assess the quality of clinical guidelines. Int J Qual Health Care 1999; 11: 21-8. 6) The AGREE Collaboration. Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project. Qual Saf Health Care 2003; 12; 18-23. 7) Minhas R. Eminence-based guidelines: a quality assessment of the second Joint British Societies' guidelines on the prevention of cardiovascular disease. Int J Clin Pract 2007; 61: 1137-44. 8) Wright JM. Practice guidelines by specialist societies are surprisingly deficient. Int J Clin Pract 2007; 61: 1076-7. 9) Iorio A, Basileo M, Marchesini E et al. The good use of plasma. A critical analysis of the main international guidelines. Blood Transfus 2008; 6: 18-24. 10) Liumbruno GM, Sodini ML, Grazzini G. Recommendations from the Tuscan Transfusion System on the appropriate use of solvent/detergent-inactivated fresh-frozen plasma. Blood Transfus 2008; 6: 25-36. 11) http://www.agreecollaboration.org. 12) http://www.agreecollaboration.org/pdf/aitraining.pdf. 13) Horowitz B, Lazo A, Grossberg H, et al. Virus inactivation by solvent/detergent treatment and the manufacture of SD-plasma. Vox Sang 1998; 74 Suppl 1: 203-6. 14) Yarranton H, Cohen H, Pavord SR, et al. Venous thromboembolism associated with the management of acute thrombotic thrombocytopenic purpura. Br J Haematol 2003; 121: 778-85. 15) de Jonge J, Groenland TH, Metselaar HJ, et al. Fibrinolysis during liver transplantation is enhanced by using solvent/detergent virus-inactivated plasma (ESDEP). Anesth Analg 2002; 94: 1127-31.

Where is the evidence?

The fact is that, again, we lack the evidence on which to base our clinical decisions. Even though 35 million doses of solvent-detergent plasma had already been transfused 10 years ago13, we are still very uncertain about the safety profile of this product14-16. At present, solvent-detergent plasma has supplanted fresh frozen plasma in at least three nations (Norway, Belgium, Ireland)17 but, in the USA, solvent-detergent plasma was withdrawn from the market, because of a cluster of six intra-operative deaths associated with its use18.

How are we going to improve the situation?

I think that the major problem of EBM lies not so much in transferring the scientific evidence to the bedside, as in generating the evidence we need. The Tuscan transfusion system decided a few years ago to produce solvent-detergent plasma. As a consequence of the availability of this product, they

Blood Transfus 2008; 6: 3-5 DOI 10.2450/2008.0052-07

Plasma, guidelines, and Evidence-Based Medicine 16) Magner JJ, Crowley KJ, Boylan JF. Fatal fibrinolysis during orthotopic liver transplantation in patients receiving solvent/detergent-treated plasma (Octaplas). J Cardiothorac Vasc Anesth 2007; 21: 410-3. 17) Doyle S, O'Brien P, Murphy K, Fleming C, O'Donnell J. Coagulation factor content of solvent/detergent plasma compared with fresh frozen plasma. Blood Coagul Fibrinolysis 2003; 14: 283-7. 18) Coignard BP, Nguyen GT, Tokars J et al. A cluster of intra-operative deaths in a liver transplant centre associated with the use of solvent/detergent plasma. California, 2000. In: Abstracts, SHEA, 11th Annual Meeting. Mt. Royal (NJ): Society for Healthcare Epidemiology of America; 2001.

Correspondence: Dr. Roberto Reverberi Servizio di Immunoematologia e Trasfusionale Arcispedale S.Anna Corso Giovecca 203 44100 Ferrara - Italy e-mail: sitfe@ospfe.it

Blood Transfus 2008; 6: 3-5 DOI 10.2450/2008.0052-07