Overview of session. Blood transfusions in advanced disease 3/21/18. Why am I interested in blood transfusions?

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1 Blood transfusions in advanced disease Dr Karen Neoh Registrar in Palliative Medicine, Leeds Teaching Hospital Trust and the Academic Unit of Palliative Care, University of Leeds Dr Jason Boland Senior Clinical Lecturer and Honorary Consultant in Palliative Medicine, Wolfson Centre for Palliative Care Research, Hull York Medical School, University of Hull Dr Lise Estcourt - Consultant Haematologist, NHS Blood and Transplant and Senior Clinical Lecturer, University of Oxford Overview of session Importance of anaemia in advanced disease National comparative audit of blood transfusion practice in palliative care Recommendations for practice Anaemia why is it important Common Anaemia 68-77% (Hb less than 100g/l) Symptoms non-specific Admission for red cell transfusion Do we wait too long to intervene? Causes of anaemia Reduction in the production of erythrocytes (bone marrow suppression, renal disease) Increased utilisation or loss of erythrocytes (haemolysis, bleeding) Haemoglobin synthesis (Nutritional: B12/folate/Iron deficiency anaemia, functional iron deficiency) Transfusion Strategies for Acute Upper Gastrointestinal Bleeding 921 patients with severe acute upper gastrointestinal bleeding Why am I interested in blood transfusions? RCT 461 restrictive strategy vs 460 liberal strategy Restrictive strategy led to improved survival and reduced rebleeding 51% restrictive vs 14% liberal did not receive transfusions 6 week survival higher in the restrictive group (95% vs. 91%) Further bleeding in 10% restrictive vs 16% liberal Adverse events restrictive 40% as compared with 48% Villanueva C et al, NEJM

2 Restrictive red cell transfusion policy Insufficient data to inform the safety of transfusion policies in certain subgroups including cancer, haematological malignancies, and bone marrow failure. Carson et al, Cochrane Database Syst Rev 2012, updated 2016 Carson et al. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database of Systematic Reviews 2016 Blood transfusions for anaemia in patients with advanced cancer Improved fatigue and breathlessness occurs in 31% to 70% of transfused patients, but this is often transient, lasting no more than days Median survival post first transfusion 42 days 25% to 35% patients died within two weeks of transfusion Preston NJ et al, Cochrane pain, palliative and supportive care group 2012 Potential harms Acute transfusion reactions, bacterial contamination and transfusion-associated circulatory overload (TACO) TACO is cardiogenic pulmonary oedema caused by the infusion of blood products. - can be triggered by <1 unit - risk factors include hypo-albuminaemia low body weight cardiac, respiratory or renal insufficiency older age - Symptoms include dyspnoea, cyanosis and tachycardia Functional iron deficiency Anaemia of chronic disease or anaemia of inflammation Iron stored in macrophages, enterocytes and hepatocytes Process regulated by ferroportin Ferroportin transports stored iron from inside these cells to outside Pro-inflammatory cytokines (IL-6 and TNF) induce hepcidin Hepcidin causes the destruction and endocytosis of ferroportin Bolton-Maggs et al, The 2015 Annual SHOT Report. Roubinian et al Vox Sang Tinegate et al British Journal of Haematology

3 Modulators of hepcidin. From Serum hepcidin: a novel diagnostic tool in disorders of iron metabolism Key: FPN Ferroportin. Fe - Iron Bergamaschi & Villani, 2009 Haematol Methods Patients with advanced cancer referred to 2 specialist palliative care services over 1 year Demographic and clinical data were linked with blood results Assessed the numbers of patients with abnormal values for Haemoglobin % hypochromic red cells (>5% indicates iron-restricted erythropoiesis) CRP (>10 indicates systemic inflammation) FID anaemia was likely when patients had all three abnormalities and ferritin ng/ml. Results 1797 patients; mean haemoglobin 116g/l 63% of patients were anaemic: mild 25%, moderate 35% and severe 3% (WHO criteria) Wide variation in anaemia prevalence across tumour sites 39% of patients who had all four parameters checked met criteria for FID anaemia Significant relationships between haemoglobin, %hypochromic red cells and CRP(p=0.0001) Anaemia estimated to be caused by FID in 66% of anaemic patients 3

4 Other members of the project group Audit aims Ross Gray Project Lead, National Comparative Audit of Blood Transfusion, NHS Blood and Transplant John Grant-Casey Programme Manager, National Comparative Audit of Blood Transfusion, NHS Blood and Transplant Catherine Malia Nurse Consultant, St. Gemma s Hospice Prof Mike Bennett Professor of Palliative Medicine, Academic Unit of Palliative Care, University of Leeds To determine current national red blood cell transfusion practice in UK adult hospices To compare this against NICE and BSH (British Society of Haematology) guidelines To develop recommendations to improve practice All the staff who collected data! Methods Invited all UK adult hospices to participate Prospective data collected over 3 months (September - December 2016) in audit booklets/online. Anonymised information on: patients pre-transfusion investigations process of transfusion patient outcomes at 30 days post-transfusion NHSBT cleaned and collated data, supported hospices Project group analysed Audit standards based on NICE and BSH guidelines Standard 1 Standard 2 Standard 3 Standard 4 Standard 5 Standard 6 Standard 7 Standard 8 Local guidelines Hospices should ensure that local written guidelines for the management of blood component transfusions are available to clinical staff via local procedures for dissemination. Patient Investigations Patients are investigated for iron deficient anaemia before a red blood cell transfusion is given. Transfusion risks, benefits and alternatives Patients are informed of the risks, benefits and alternatives prior to transfusion. Measurement of pre-transfusion haemoglobin Patients have their haemoglobin measured prior to transfusion of red blood cells. Measurement of patient weight prior to transfusion Patients are weighed prior to transfusion of red blood cells. Evidence of patient consent All patients give either verbal or written consent to a red blood cell transfusion. Monitoring the patient Patient observations are taken before, during and after every unit of red blood cells transfused. Clinical review Patients are clinically reviewed between every unit transfused, as well as on completion of the transfusion episode. Results 139/210 hospices (66%) agreed to contribute to the audit 18 withdrew before data collection Data from 121 (58%) UK adult hospices 38 sites confirmed they did not perform a transfusion 465 RBC transfusion episodes administered at 83 sites 4

5 Patient characteristics Mean age - 71 years (92% were >50; 30% were >80 years) 53% were men Pre-transfusion PS recorded in 194 (42%) episodes (mostly AKPS) Median AKPS score was 60 96% (448) had cancer Predicted prognosis <4 weeks 15%; 1-3 months 46%, >3 months 39% Cancer type (n=448) Cancer Patient Specification n (%) Breast 27 (6) Prostate 78 (17) Lung 38 (8) Upper GI 59 (13) Lower GI 73 (16) Renal & Liver 17 (4) Haematological malignancies 54 (12) Gynaecological 37 (8) Bladder 16 (4) Other 38 (8) Not stated/ Unknown Primary 11 (2) Audit Standard 1 Hospices should ensure that local written guidelines for the management of blood component transfusions are available to clinical staff via local procedures for dissemination. 54 hospices (45%) provided organisational data: 96% had a policy in place Policies did not include all the essential points: o 67% did not include investigation for reversible causes of anaemia o 91% do not include routinely weigh patients ( TACO risk) o All hospices require consent; only 15% require WRITTEN o 81% require patients to be given written information about risks/ benefits/alternatives o All patients should wear ID during transfusion but this was rarely included in policies Audit Standard 2 Patients are investigated for anaemia before a red blood cell transfusion is given. Pre-transfusion investigations limited Ferritin recorded in 122 (26%) patients % hypochromic RBCs recorded in 64 (14%) B 12 recorded in 102 (22%) Folate recorded in 105 (23%) 343 (71%) did not have alternative treatments for anaemia prior to blood transfusion (e.g. iron/b12/folate/epo) Causes of anaemia 38% 24% 21% 9% 8% Causes of anaemia differed among cancer types Blood loss was the largest cause of anaemia associated with gastrointestinal (43%), renal and bladder (44%), and gynaecological malignancies (38%) Bone marrow failure was more commonly associated with prostate (42%) and haematological malignancies (82%) 5

6 Audit Standard 3 Staff discuss with patient the risks, benefits and alternatives prior to transfusion. Audit Standard 4 Clinical staff measure Hb prior to transfusion of red blood cells in patients. 71% of patients had the risks and benefits of transfusion explained 98% (457) of patients had haemoglobin checked prior to transfusion 70% (323) were results checked within 3 days of transfusion 11% (49) were more than a week before transfusion 1% (5) the timing of the transfusion or the haemoglobin result were unknown Pre-transfusion parameters Mean pre-transfusion haemoglobin was 75g/L Most (69%) patients had a pre-transfusion haemoglobin level less than or equal to 80g/L Table 3 Pre-transfusion Hb (n=465) Hb (%) 70g/L 132 (28) 71-80g/L 191 (41) 81-90g/L 107 (23) g/L 23 (5) >100g/L 4 (1) No Record 8 (2) Reason for red cell transfusion (more than one option could be selected; n=614) Breathlessness and low Hb 182 Low Hb 237 Maintenance treatment for 43 haematology patient Patient request 24 Other 53 No reason other than fatigue 75 Audit Standard 5 Staff weigh patients prior to transfusion of red blood cells. Red blood cell units given 85% (397/465) not weighed prior to transfusion Mean patient weight 67kg, median weight 64kg Patient weight (n=68) (%) <50kg 10 (15) 51-70kg 34 (50) >70kg 24 (35) 909 units of blood were transfused Mean number of units transfused 2; median 2 35 patients under 70 kg and 10 patients under 50kg had 2 or more units transfused exposing them to high risk of TACO Number of units transfused (%) One 75 (16) Two 347 (75) Three 33 (7) Four + 10 (2) 6

7 Audit Standard 6 All patients give either verbal or written consent to a red blood cell transfusion. Audit Standard 7 Patient observations are taken before, during and after every unit of red blood cells transfused. There was documented evidence that 91% of patients had provided mostly verbal consent to transfusion 91% had observations pre transfusion, at 15 minutes and 60 minutes Audit Standard 8 Patients are clinically reviewed between every unit transfused, as well as after the transfusion episode are complete. 1% of patients had a haemoglobin check after each unit 28% had a post haemoglobin check at any time point Mean Hb 93g/L Post-transfusion Hb Hb (%) 70g/L 9 (2) 71-80g/L 9 (2) 81-90g/L 32 (7) g/L 42 (9) >100g/L 37 (8) No Record 336 (72) 30 day outcome (%) Patient still admitted with no improvement 21 (5) Patient still admitted with transient improvement in symptoms lasting <14 days Patient still admitted with improvement in symptoms still noted at 30 days 28 (6) 10 (2) Patient at home with no improvement 29 (6) Patient at home with transient improvement in symptoms lasting <14 days Patient at home with improvement in symptoms still noted at 30 days 114 (25) 73 (16) Patient died 150 (32) Not recorded 40 (9) 83 (18%) had an improvement still noted at 30 days 150 (32%) were dead at 30 days, over double predicted 142 (31%) transient improvement, 50 (11%) no improvement Change in performance status 14% (53) patients had a pre- and post- transfusion PS recorded Different scales were used but overall 17% (9) had an increase in score 43% (23) had no change 40% (21) had a lower score Recommendation 1 Hospice guidelines should be in line with national guidelines In total 83% showed no improvement in performance status post-transfusion Many factors influence PS but if a transfusion is aimed at improving a patients global function then a measurement of change in PS could guide future management 7

8 3/21/18 Recommendation 2 Investigate cause of anaemia To transfuse or not to transfuse? Is your patient anaemic; Male- Hb < 130g/L Female-Hb < 120g/L Consider oral tranexamic acid to decrease blood loss Check Haematinics (Iron studies, B12 and folate.) YES Haematinic deficiency Is cause of anaemia chronic blood loss? Risk Factors for TACO Low weight Renal impairment Hypoalbuminaemia Congestive cardiac failure Severe aortic stenosis Moderate LV dysfunction Respiratory diseases Peripheral oedema Pulmonary oedema Significant positive fluid balance Concomitant fluids Folate < 4.5nmol/L Oral folic acid B12 < 200ng/L IM or oral Hydroxocobalamin Ferritin < 30 OR Ferritin < 100 active infection/inflammation, renal impairment, or cardiac failure Low iron, high TIBC AND transferrin Sats <20% Is patient symptomatic or compromised from anaemia? YES Recommendation 3 Symptomatic Fe deficiency anaemia Fe deficiency anaemia IV Iron Oral Iron Evidence-based discussion of risks and benefits Is patient at risk of Transfusionassociated circulatory overload? Do benefits of transfusion outweigh the risks? Make decision with patient YES TRANSFUSE Max 1 Unit per 24 hours Re-assess between units Re-check Hb Monitor for complications 5 questions patients should ask 1. Do I really need this transfusion? 2. What are the benefits? 3. What are the risks or side-effects? 4. Are there simpler safer options? 5. What happens if I don t have it? 8

9 Recommendation 4 Restrictive red cell transfusion policy Adopt restrictive trigger for transfusion TRIST trial 2016 Recommendation 5 Recommendation 6 All patients must be weighed to determine transfusion requirements There should be documented evidence of consent Transfusing a volume of 4ml/kg will typically give a haemoglobin increment of 10g/L 2014 Audit of Patient Information & Consent 21% did not feel involved in decision making about transfusion (462/2243) Recommendation 7 Awareness and vigilant observations of TACO are needed 38% 8% received information about the possible risks of transfusion (858/2243) received information about alternatives to transfusion (184/2243) NCABT 9

10 Recommendation 8 Rigorous clinical review of outcome References Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manage. 2006;31(1): Dunn A, Carter J, Carter H. Anemia at the end of life: prevalence, significance, and causes in patients receiving palliative care. J Pain Symptom Manage. 2003;26(6):1132- Villanueva C, Colomo A, Bosch A, et al. Transfusion stratgies for acute upper gastrointestinal bleeding. NEJM 2013; 368(1): Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev 2012; 18:4. Preston NJ, Hurlow A, Brine J, Bennett MI. Blood transfusions for anaemia in patients with advanced cancer. Cochrane pain, palliative and supportive care group: 15 FEB 2012;2:CD Bergamaschi G, Villani L Serum hepcidin: a novel diagnostic tool in disorders of iron metabolism Haematol: 94 (12) Neoh K, Stanworth S, Pasricha SR, Bennett MI. Estimating prevalence of functional iron deficiency anaemia in advanced cancer. Support Care Cancer. 2017;25(4): Bolton-Maggs PE et al (2016) The 2015 Annual SHOT Report. Final-bookmarked.pdf accessed 25/5/17 (Accessed January 2018) Roubinian NH, Hendrickson JE, Triulzi DJ, Gottschall JL, Chowdhury D, Kor DJ, Looney MR, Matthay MA, Kleinman SH, Brambilla D, Murphy EL; NHLBI Recipient Epidemiology and Donor Evaluation Study-III (REDS-III). Incidence and clinical characteristics of transfusion-associated circulatory overload using an active surveillance algorithm. Vox Sang Jan;112(1):56-63 Tinegate H et al (2012) Guideline on the investigation and management of acute transfusion reactions Prepared by the BCSH Blood Transfusion Task Force. British Journal of Haematology 2012;159(2)