Patient Blood Management: Treating Patients Refusing Blood Transfusion

1. Methods of Patient Blood Management:How to treat the Patient who Declines Allogeneic Blood Transfusion Whitni Milton Final Presentation Transfusion Medicine February 5, 2014

2. Patient Blood Management • Society for the advancement of Blood Management’s definition of patient blood management: • “the timely application of evidence-based medical and surgical concepts designed to maintain Hb concentration, optimize hemostasis, and minimize blood loss in an effort to improve patient outcome • A proactive and culturally sensitive approach is a necessary part of managing patients who refuse allogeneic blood transfusion • Many of these principles can be extended to all patients

4. Patient’s Who Decline Allogeneic Blood Products • Jehovah’s witnesses are the largest patient population that decline the use and receipt of most allogeneic blood products • There are other patient populations that decline to receive allogeneic blood products for religious beliefs or other personal reasons • It creates a serious dilemma when critically ill patients with severe anemia need to increase their oxygen carrying ability but decline to receive allogeneic blood transfusions

5. Jehovah’s Witnesses: Why they decline blood • Based on this groups interpretation of the Bible • Leviticus 17:14 The life of every creature is its blood. That is why I have said to the Israelites, “You must not eat the blood of any creature, because the life of every creature is its blood; anyone who eats it must be cut off.” • Concept of spiritual purity (blood can spiritually pollute a person) • If a JW does accept blood products, they will be separated from God and excommunicated from their community

6. Jehovah’s Witnesses: What products do they decline WILL NOT accept WILL (potentially) accept Minor fractions of blood Autologous salvaged blood Albumin Cryoprecipitate Clotting factors Hemostatic agents Desmopressin, Crystalloid and colloid solutions Major fractions of blood • Whole blood • Packed red blood cells • Plasma • Platelets • White blood cells • Autologous product

7. Consequences of Severe Anemia

8. Severe Anemia • There is no universal definition of “severe anemia”, but it is generally accepted that the risk of mortality is inversely proportional to the decrease in hemoglobin • Severe anemia is generally accepted to be: • Hemoglobin of <5 g/dL • Hemoglobin of 5-7 g/dL WITH symptoms of hypoperfusion, lactic acidosis, shock, hemodynamic instability, or coronary ischemia

9. Bleeding and Severe Anemia • Three factors that have had an impact of bleeding related complications that increase the likelihood of becoming anemic • 1. widespread use of anti-coagulants and anti-platelet drugs • 2. technology to perform long, complex surgical procedures • 3. advancing age of general population with associate comorbidities

10. Bloodless Medicine and Surgery Program at Englewood Hospital Medical Center • previous study done by Carson et all in 2002 • Retrospective cohort study of surgical patients who declined allogeneic red blood cell transfusions and had a postoperative nadir hemoglobin measurement of 8 g/dL or less

11. Inclusion criteria • At least 18 years old • Undergoing surgery • At least 1 measurement of Hb 8 g/dL of less • Refusal of allogeneic blood transfusion during hospital stay • No recorded episode of RBC transfusion during the hospital stay

12. Mortality – death occurring anytime in the period after surgery until discharge or within 30 days • Morbidities • Sepsis • Pneumonia • Myocardial infarction • Deep wound infection • Congestive heart failure • Arrhythmia

14. Mortality associated with Hemoglobin Levels of 8 g/dL or less • N=293 • 288 identified as Jehovah’s Witnesses • Range 20-96 years old • Mean preoperative hemoglobin was 10 +/- 2.8 g/dL • 25.4% had hemoglobin level of 8 g/dL or less

16. Mortality rates in patients who decline blood transfusion stratified by nadir postoperative hemoglobin concentrations

17. Methods of Patient Blood Management

18. Patient Blood Management • Society for the advancement of Blood Management’s definition of patient blood management: • “the timely application of evidence-based medical and surgical concepts designed to maintain Hb concentration, optimize hemostasis, and minimize blood loss in an effort to improve patient outcome

19. Multimodal approaches to manage a Jehovah’s Witness patient or patient any who declines allogeneic blood products with anemia • Lower transfusion thresholds • Iron supplementation • Erythropoesis stimulating agents (ESAs) • Minimizing iatrogenic anemia • Hemoglobin based oxygen carriers (HBOCs) • Intraoperative autologous blood salvage • Intraoperative strategies such as topical hemostatics • Future development of blood substitutes

20. Multimodal approach to managing a Jehovah’s Witness patient or patient who refuses allogeneic blood products Algorithm developed by the Department of Surgery at the University of Michigan

21. Iron Supplementation • Functional iron deficiency is seen commonly in critically ill patients (anemia of chronic disease) • Inflammation induces increased production of hepcidin (acute phase reactant) which decreases absorption of iron in the intestines, and decreases the release of iron from the reticuloendothelial system and macrophages • Adequate iron stores are necessary for effective erythropoesis • May be given alone (po or IV) • May be given in conjunction with ESAs

22. Erythropoeisis Stimulating Agents • These agents induce proliferation and terminal differentiation of endogenous erythroid cells and prevent erythroid apoptosis in the bone marrow • May also affect renal tubular function causing a relative increase in hemoglobin • An increase in reticulocyte count is observed around day 3 of therapy in patients who are iron replete • Some studies suggest there is an increased risk of venous thromboembolism with the use of ESAs

23. Minimizing Iatrogenic Blood Loss A patient can lose up to 50 ml or 1% of their blood volume per day through phlebotomy (negate the effects of physiological erythropoesis Only order essential tests Use of microtainer tubes http://www.pic2fly.com/Microtainers.html

24. Blood Substitutes • It is desirable to have blood substitutes as an alternative to allogeneic blood transfusions • Limited supply of blood • Difficulties in storage (refrigeration necessary) • Storage lesions • Pre-transfusion testing increases time of delivery of product to patient • Infectious disease risks • Immunomodulatory effects

25. Hemoglobin Based Oxygen Carriers • Cell free hemoglobin derived from human and animal sources • Other chemical modifications can be used (pyridoxal phosphate, glutaraldehyde  crosslinking) • Equilibrium between tetramers and dimers http://www.medgadget.com/200 us_navy_to_trial_hemopure_stabilized_hemoglobin_1.html

26. Toxicity of HBOCs • Free hemoglobin reacts to form several compounds including nitric oxide • Nitric oxide is essential in regulating systemic and pulmonary vascular tone • Some side effects are hypertension, myocardial damage including infarction, abdominal pain, increased infection (free iron may lead to bacterial proliferation) http://media.corporate-ir.net/media_files/NSD/bpur/reports/ar01/02.htm

27. Cell free hemoglobin exists in dimers and tetramers • Dissociated dimers undergo rapid renal clearance which leads to renal tubular toxicity and acute renal failure • This adverse effect can be overcome by chemical crosslinking or polymerization of the dimers to prevent dissociation and therefore renal toxicity

28. Hemoglobin Based Oxygen Carriers

30. Topical Hemostatics: Decreasing Intraoperative Blood Loss • 1. Mechanical barrier agents • 2. Biologically active agents • 3. Flowable sealants • 4. Fibrin sealants

31. Topical Hemostatics Mechanical Barriers Biologically Active Agents Promote fibrin clot formation through direct action on fibrinogen by thrombin (thrombin containing agents) Do not need intact coagulation system, but do need adequate levels of fibrinogen Minor bleeding or oozing Bovine, human, or recombinant Sensitization to bovine proteins can cause immune mediated coagulopathy upon re-exposure • Form a physical barrier that blocks blood flow and creates a thrombogenic surface • Minor bleeding • Patient needs to have intact coagulation system • Can cause problems due to expansion (ex. Spinal cord) • Products made with animal materials can cause allergic reaction

32. Topical Hemostatics Flowable Topical Hemostatics Topical Fibrin Sealants Contain supra-physiologic levels of fibrin plus thrombin (bovine, human or recombinant) Some may contain calcium Can be used in patients who are coagulopathic • Combine thrombin and mechanical • Mechanically obstruct blood flow and actively convert fibrinogen to fibrin • Can conform to shape of wound

33. Topical Hemostatics: Decreasing Intraoperative Blood Loss 1. http://www.haemonetics.com/ 3. www.ethicon.com

34. Topical Hemostatics: Decreasing Intraoperative Blood Loss www.tisseelhernia.com www.baxterhealthcare.uk.co

35. Topical Hemostatics: decreasing intraoperative blood loss

37. Cell-Saver Autologous cell recovery Not recommended to be used with procoagulant agents May cause equipment to clot http://www.haemonetics.com/Products/Devices/Surgical%20-%20Diagnostic%20Devices/~/media/5D321707EA0445E3ABFD694CF2361F44.pdf

38. Risk adjusted, propensity score-matched, retrospective case-control study of clinical outcomes for inpatients who did not accept allogeneic blood products • Multidisciplinary specialized care was given to the bloodless group • Differences in hemoglobin, mortality, 5 morbid outcomes, and hospital costs were analyzed • Looked at patients undergoing multiple types of surgeries (not just cardiac) • Looked at medical patients • Looked at morbidities, not just mortality • Control group “To our knowledge this is the first study to report propensity-matched, risk adjusted outcomes in patients receiving bloodless care that includes patients other than those undergoing cardiac surgery”

39. 196 medical bloodless group • 98 in surgical bloodless group • 1197 control patients matched • 4 controls to each bloodless patient (increase power)

40. Bloodless group • Diagnosis and treatment of pre-hospital anemia • Reduce intraoperative blood loss • Autologous blood salvage • Intraoperative normovolemic hemodilution • Minimizing iatrogenic blood loss • Lower transfusion thresholds • IV iron and ESAs

41. Results • Bloodless patients had similar or better outcomes than those who accepted ABT • Hemoglobin concentrations were similar suggesting that multimodal blood conservation methods were successful • Providing bloodless care was 20% less the cost than those treated with ABT

42. Patient Blood Management • Society for the advancement of Blood Management’s definition of patient blood management: • “the timely application of evidence-based medical and surgical concepts designed to maintain Hb concentration, optimize hemostasis, and minimize blood loss in an effort to improve patient outcome • A proactive and culturally sensitive approach is a necessary part of managing patients who refuse allogeneic blood transfusion • Many of these principles can be extended to all patients

43. Conclusions on Managing Patients Who Decline the Use of Allogeneic Blood Products • There are basic principles that apply to patient blood management • These treatment methods are the best that are available to optimize the outcomes of patients that decline ABT • Some studies suggest that “bloodless medicine” may have some benefits over ABT including decreased infectious risks and decreased cost • Development of a blood substitute is continuing, and HBOCs are used in dire circumstances in these patients with severe anemia • It is always essential to provide the best possible patient care with optimal outcomes while respecting the patient’s beliefs and autonomy

44. Thank you for your time and attention

45. References • Posluszny J, Napolitano L (2014) How do we treat life threatening anemia is a Jehovah’s witness patient? Transfusion 54 pp 3026-3034 • Shander, A et al. (2014)Topical Hemostatic Therapy is Surgery: Bridging the Knowledge and practice gap. J Am Coll Sur (219) pp 570-579 • Frank, S et al. (2014) Risk adjusted clinical outcomes in patients enrolled in a bloodless program. Transfusion 54 pp 2668-2677 • McCartney S et al (2014) Jehovah’s Witnesses and cardiac surgery:a single institutions experience. Transfusion (54) pp 2745-2752 • Elmer, J, Hasan B, Wilcox S (2012) Hemoglobin based carriers for hemorrhagic shock, Resuscitation (83) pp. 285-292 • Shander A, Javidroozi, et al (2014) An update on mortality and morbidity in patients with very low postoperative hemoglobin levels who decline blood transfusion. Transfusion. Volume 54 pp26882695 • Bock, G (2012) Jehovah’s Witnesses and autonomy: honouring the refusal of blood transfusions. J Med Ethics 38 pp 656652