Any amendments to the guideline will be noted on the Scottish Intercollegiate Guidelines Network (SIGN) Web site.

• May 14, 2008, Trasylol (aprotinin injection): Following publication of the Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population (BART) study in the May 14, 2008 online issue of The New England Journal of Medicine, Bayer Pharmaceuticals notified the U.S. Food and Drug Administration (FDA) of their intent to remove all remaining supplies of Trasylol from hospital pharmacies and warehouses. Because Trasylol has been shown to decrease the need for red blood cell transfusions in patients undergoing coronary artery bypass surgery, future supplies of Trasylol will continue to be available through the company as an investigational drug under a special treatment protocol.

Additional Notices

• July 31, 2008, Erythropoiesis Stimulating Agents (ESAs): Amgen and the U.S. Food and Drug Administration (FDA) informed healthcare professionals of modifications to certain sections of the Boxed Warnings, Indications and Usage, and Dosage and Administration sections of prescribing information for Erythropoiesis Stimulating Agents (ESAs). The changes clarify the FDA-approved conditions for use of ESAs in patients with cancer and revise directions for dosing to state the hemoglobin level at which treatment with an ESA should be initiated.
• November 8, 2007 and January 3, 2008 Update, Erythropoiesis Stimulating Agents (ESAs): The U.S. Food and Drug Administration (FDA) notified healthcare professionals of revised boxed warnings and other safety-related product labeling changes for erythropoiesis-stimulating agents (ESAs) stating serious adverse events, such as tumor growth and shortened survival in patients with advanced cancer and chronic kidney failure.

*Note: On May 14, 2008, Bayer Pharmaceuticals notified the U.S. Food and Drug Administration (FDA) of their intent to remove all remaining supplies of Trasylol from hospital pharmacies and warehouses. Because Trasylol has been shown to decrease the need for red blood cell transfusions in patients undergoing coronary artery bypass surgery, future supplies of Trasylol will continue to be available through the company as an investigational drug under a special treatment protocol. See the U.S. Food and Drug Administration (FDA) Web site for more information.

Additional details can be found in the companion document titled "SIGN 50: A Guideline Developers' Handbook." (Edinburgh [UK]: Scottish Intercollegiate Guidelines Network. [SIGN publication; no. 50]). Available from the SIGN Web site.

The process for synthesizing the evidence base to form graded guideline recommendations is illustrated in the companion document titled "SIGN 50: A Guideline Developer's Handbook." (Edinburgh [UK]: Scottish Intercollegiate Guidelines Network. [SIGN publication; no. 50], available from the SIGN website.

Evidence tables should be compiled, summarizing all the validated studies identified from the systematic literature review relating to each key question. These evidence tables form an important part of the guideline development record and ensure that the basis of the guideline development group's recommendations is transparent.

In order to address how the guideline developer was able to arrive at their recommendations given the evidence they had to base them on, SIGN has introduced the concept of considered judgement.

Under the heading of considered judgement, guideline development groups are expected to summarise their view of the total body of evidence covered by each evidence table. This summary view is expected to cover the following aspects:

• Quantity, quality, and consistency of evidence
• Generalisability of study findings
• Applicability to the target population of the guideline
• Clinical impact (i.e., the extent of the impact on the target patient population, and the resources need to treat them.)

Guideline development groups are provided with a pro forma in which to record the main points from their considered judgement. Once they have considered these issues, the groups are asked to summarise their view of the evidence and assign a level of evidence to it, before going on to derive a graded recommendation.

The assignment of a level of evidence should involve all those on a particular guideline development group or subgroup involved with reviewing the evidence in relation to each specific question. The allocation of the associated grade of recommendation should involve participation of all members of the guideline development group. Where the guideline development group is unable to agree a unanimous recommendation, the difference of opinion should be formally recorded and the reason for dissent noted.

The recommendation grading system is intended to place greater weight on the quality of the evidence supporting each recommendation, and to emphasise that the body of evidence should be considered as a whole, and not rely on a single study to support each recommendation. It is also intended to allow more weight to be given to recommendations supported by good quality observational studies where randomised controlled trials (RCTs) are not available for practical or ethical reasons. Through the considered judgement process guideline developers are also able to downgrade a recommendation where they think the evidence is not generalisable, not directly applicable to the target population, or for other reasons is perceived as being weaker than a simple evaluation of the methodology would suggest.

On occasion, there is an important practical point that the guideline developer may wish to emphasise but for which there is not, nor is their likely to be, any research evidence. This will typically be where some aspect of treatment is regarded as such sound clinical practice that nobody is likely to question it. These are marked in the guideline as "good practice points." It must be emphasized that these are not an alternative to evidence-based recommendations, and should only be used where there is no alternative means of highlighting the issue.

Note from the National Guideline Clearinghouse (NGC): In August 2004 the Scottish Intercollegiate Guidelines Network (SIGN) released an update to this guideline, available on the SIGN Web site. None of the following recommendations were affected by the update.

Note from SIGN and NGC: In addition to these evidence-based recommendations, the guideline development group also identifies points of best clinical practice in the original guideline document.

The strength of recommendation grading (A-D) and level of evidence (I++-4) are defined at the end of the "Major Recommendations" field.

Risks of Allogeneic Blood Transfusion

Immunomodulation

B: Transfusion of leucodepleted allogeneic blood should not be limited by concerns over increased cancer recurrence or perioperative infection.

Procedural Error

D: The British Committee for Standards in Haematology (BCSH) collaborative guideline for the administration of blood and blood components and management of transfused patients (Transfus Med 1999;9:227-38) should be implemented in all Scottish hospitals where transfusion takes place.

All Risks

D: Given the potential risks, however small, each allogeneic transfusion must have a valid, defined and justifiable indication.

Preoperative Anticoagulant Therapy

D: All surgical and anaesthetic units should have protocols: to prepare anticoagulated patients for all types of surgery; for deep vein thrombosis prophylaxis in the preoperative period

Haemoglobin Transfusion Thresholds

Preoperative

C: Where possible, anaemia should be corrected prior to major surgery to reduce exposure to allogeneic transfusion.

Postoperative

D: Transfusion is unjustified at haemoglobin levels >100 g/l.

D: Transfusion is required at haemoglobin levels <70 g/l.

C: Patients with cardiovascular disease, or those expected to have covert cardiovascular disease (e.g., elderly patients or those with peripheral vascular disease) are likely to benefit from transfusion when their haemoglobin level falls below 90 g/l.

Aids to Effective Blood Ordering

Predictors of Allogeneic Transfusion

C: When ordering blood, all nine factors (listed below) determining the risk and degree of transfusion should be taken into account, for example by using Mercuriali's formula.

The factors determining risk of allogeneic transfusion are:

• Low preoperative haemoglobin/hematocrit, either before intervention or on day of surgery
• Low weight
• Small height
• Female sex
• Age over 65 years
• Availability of preoperative autologous blood donation
• Estimated surgical blood loss
• Type of surgery
• Primary or revision surgery

Blood Ordering Equations

C: All hospitals should use a maximum surgical blood ordering schedule to provide concentrated red cells.

Transfusion Protocols

D: Transfusion guidelines should be combined with audit and/or educational initiatives to reduce the number of allogeneic transfusions.

Blood Sparing Strategies

Preoperative Autologous Blood Donation

D: Preoperative autologous blood donation should be offered only when it is possible to guarantee admission and operative dates.

B: Preoperative autologous blood donation can be used to reduce allogeneic blood exposure, although it does increase the total number of transfusion episodes.

C: Preoperative autologous blood donation can be used safely in elderly populations with diverse comorbidities.

C: Preoperative autologous blood donation should be targeted to men who present with haemoglobin 110 to 145 g/l and women who present with haemoglobin 130 to 145 g/l.

Erythropoietin

B: Erythropoietin use should be targeted to patients aged under 70 years who are scheduled for major blood losing surgery and who have a presenting haemoglobin <130 g/l.

D: Erythropoietin can be used to prepare patients with objections to allogeneic transfusion for surgery that involves major blood loss.

Combination of Preoperative Autologous Blood Donation and Erythropoietin

B: In fit patients undergoing major surgery, erythropoietin can be used in combination with autologous blood collection to reduce allogeneic transfusion.

B: In fit patients undergoing major surgery, erythropoietin can be used to obtain multiple autologous red cell donations while maintaining an adequate day of surgery haemoglobin.

Acute Normovolemic Haemodilution

D: Acute normovolemic haemodilution should be limited to patients with a haemoglobin level sufficiently high to allow 1,000 ml of blood to be removed, and in whom a relatively low target haemoglobin is deemed appropriate.

Cardiac Surgery

Aprotinin* and Antifibrinolytic Drugs

B: The use of aprotinin or tranexamic acid is recommended for patients undergoing cardiac surgery which carries a high risk of transfusion (e.g. repeat cardiac operations, multiple valve replacements, thoracic aortic operations, patients on preoperative aspirin therapy and procedures with anticipated long bypass times).

*Note: On May 14, 2008, Bayer Pharmaceuticals notified the U.S. Food and Drug Administration (FDA) of their intent to remove all remaining supplies of Trasylol from hospital pharmacies and warehouses. Because Trasylol has been shown to decrease the need for red blood cell transfusions in patients undergoing coronary artery bypass surgery, future supplies of Trasylol will continue to be available through the company as an investigational drug under a special treatment protocol. See the U.S. Food and Drug Administration (FDA) Web site for more information.

Cell Salvage

C: Reinfusion of washed shed mediastinal blood may be used to reduce allogeneic transfusion in cardiac surgery.

Orthopaedic Surgery

Aprotinin*

B: Aprotinin may be considered to reduce blood loss in hip and knee arthroplasties but its use should be restricted to procedures with an increased risk of high blood loss (e.g., bilateral and revision) and to circumstances when other blood conservation techniques are not appropriate (e.g., treatment of Jehovah's Witnesses).

*Note: On May 14, 2008, Bayer Pharmaceuticals notified the U.S. Food and Drug Administration (FDA) of their intent to remove all remaining supplies of Trasylol from hospital pharmacies and warehouses. Because Trasylol has been shown to decrease the need for red blood cell transfusions in patients undergoing coronary artery bypass surgery, future supplies of Trasylol will continue to be available through the company as an investigational drug under a special treatment protocol. See the U.S. Food and Drug Administration (FDA) Web site for more information.

Tranexamic Acid

B: Tranexamic acid can be used to reduce blood loss and transfusion requirements in patients undergoing knee replacement surgery, when other blood conservation techniques are inappropriate and where major blood loss is anticipated.

Cell Salvage

D: Unwashed postoperative salvage using drains should be considered in patients in whom a postoperative blood loss of between 750 ml and 1,500 ml is anticipated (e.g., bilateral joint replacement).

B: Washed intraoperative salvage should be considered in patients in whom an intraoperative blood loss of more than 1,500 ml is anticipated (e.g., major pelvic, spinal or non-infected revision surgery).

B: In orthopaedic surgery, cell salvage using either unwashed or washed red blood cells may be considered as a means of significantly reducing the risk of exposure to allogeneic blood.

Definitions:

Grades of Recommendation

A: At least one meta-analysis, systematic review, or randomized clinical trials rated as 1++, and directly applicable to the target population; or

A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results

B: A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 1++ or 1+

C: A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 2++

D: Evidence level 3 or 4; or

Extrapolated evidence from studies rated as 2+

Good Practice Points: Recommended best practice based on the clinical experience of the guideline development group.

Levels of Evidence:

1++: High quality meta-analyses, systematic reviews of randomized clinical trials, or randomized clinical trials with a very low risk of bias

1+: Well-conducted meta-analyses, systematic reviews, or randomized clinical trials with a low risk of bias

1-: Meta-analyses, systematic reviews, or randomized clinical trials with a high risk of bias

2++: High quality systematic reviews of case control or cohort or studies

High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal

2+: Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal

2-: Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal

3: Non-analytic studies, e.g. case reports, case series

4: Expert opinion

*Note: On May 14, 2008, Bayer Pharmaceuticals notified the U.S. Food and Drug Administration (FDA) of their intent to remove all remaining supplies of Trasylol from hospital pharmacies and warehouses. Because Trasylol has been shown to decrease the need for red blood cell transfusions in patients undergoing coronary artery bypass surgery, future supplies of Trasylol will continue to be available through the company as an investigational drug under a special treatment protocol. See the U.S. Food and Drug Administration (FDA) Web site for more information.

Tranexamic acid

The major risk with tranexamic acid is the potential risk of thrombosis.

Subgroups Most Likely to be Harmed:

Evidence from observational studies suggests that the elderly and those patients suffering from cardiovascular and peripheral vascular disease are less tolerant of perioperative anaemia and should therefore be transfused at a higher haemoglobin level (i.e., a lower threshold for transfusion).

The guideline developer refers users to the section of the original guideline document titled Implementation and Audit for additional information.

For information about availability, see the "Availability of Companion Documents" and "Patient Resources" fields below.

Any amendments to the guideline will be noted on the Scottish Intercollegiate Guidelines Network (SIGN) Web site.

• HTML format
• Portable Document Format (PDF)

Electronic copies of Addendum: Available from the SIGN Web site.

• Quick reference guide: Perioperative blood transfusion for elective surgery. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network, 2001. 2 p. Available in Portable Document Format (PDF) from the Scottish Intercollegiate Guidelines Network (SIGN) Web site.
• Guideline 54: perioperative blood transfusion for elective surgery. Supporting material [online]. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network, 2001. Available from the SIGN Web site.
• SIGN 50: A guideline developer's handbook. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network, 2001 Feb. (SIGN publication; no. 50). Electronic copies available from the SIGN Web site.
• Appraising the quality of clinical guidelines. The SIGN guide to the AGREE (Appraisal of Guidelines Research and Evaluation) guideline appraisal instrument. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network, 2001. Available from SIGN Web site.

• HTML format
• Portable Document Format (PDF)

Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

Users wishing to use, reproduce, or republish SIGN material for commercial purposes must seek prior approval for reproduction in any medium. To do this, please contact sara.twaddle@nhs.net.

Additional copyright information is available on the SIGN Web site.

Guidelines represented on the NGC Web site are submitted by guideline developers, and are screened solely to determine that they meet the NGC Inclusion Criteria which may be found at http://www.guideline.gov/about/inclusion.aspx .

NGC, AHRQ, and its contractor ECRI Institute make no warranties concerning the content or clinical efficacy or effectiveness of the clinical practice guidelines and related materials represented on this site. Moreover, the views and opinions of developers or authors of guidelines represented on this site do not necessarily state or reflect those of NGC, AHRQ, or its contractor ECRI Institute, and inclusion or hosting of guidelines in NGC may not be used for advertising or commercial endorsement purposes.

Readers with questions regarding guideline content are directed to contact the guideline developer.