Red Cell Transfusion triggers: A moving target When, who, and how much?

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1 Red Cell Transfusion triggers: A moving target When, who, and how much? Tim Walsh Professor of Critical Care, Edinburgh University

2 A transfusion threshold of 70 g/l or below, with a target Hb range of g/l, should be the default for all critically ill patients, unless specific co-morbidities or acute illness-related factors modify clinical decisionmaking. Grade 1B Transfusion triggers should not exceed 90 g/l in most critically ill patients. Grade 1B

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4 Key Priorities for Implementation: Red blood cells Thresholds and targets When using a restrictive red blood cell transfusion threshold, consider a threshold of 70 g/litre and a haemoglobin concentration target of g/litre after transfusion. Doses Consider single-unit red blood cell transfusions for adults (or equivalent volumes calculated based on body weight for children or adults with low body weight) who do not have active bleeding

5 Thresholds and targets Consider a red blood cell transfusion threshold of 80 g/litre and a haemoglobin concentration target of g/litre after transfusion for patients with acute coronary syndrome.

6 6 potential precision-medicine opportunities 1. Transfuse blood when it obviously saves lives But consider hypervolaemia as an adverse effect

7 Hb 70g/L versus 90g/L Exclusions Massive exsanguinating bleeding Cardiovascular disease Stratified for presence of cirrhosis Single unit transfusions 8 hourly Hb during first 48 hours; daily thereafter All endoscoped within 6 hours (banding, sclerotherapy Portal hypertension: somatostatin infusion; prophylactic antibiotics Portal pressure measures within 48 hours and repeated after 2-3 days 31% cirrhosis; 49% peptic ulcer bleeding

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9 Outcomes Absolute risk difference for mortality in cirrhotic group 11 vs 18% (NNT 14) Overall excess deaths in liberal group from uncontrolled bleeding (0.7 vs 3.1%) More re-bleeding and rescue therapy in liberal group Small (significant) increase in PPG in liberal group vs no change in restrictive group More pulmonary oedema and cardiac adverse events in liberal group

10 Ann Intern Med. 2012;157(1): doi: /

11 6 potential precision-medicine opportunities 1. Transfuse blood when it obviously saves lives But consider hypervolaemia as an adverse effect 2. Think about haemoglobin in the context of volume status

12 What does haemoglobin concentration or HCT mean? 8 Haemorrhagic shock Healthy euvolaemic Post-operative resuscitated 6 4 PV 3L PV 5L 2 0 Blood volume (L) PV 1.7L RCV 1.3L HCT 0.4 RCV 2L HCT 0.4 RCV 2L HCT 0.28 Hb 13g/dL Hb 13g/dL Hb 9 g/dl

13 6 potential precision-medicine opportunities 1. Transfuse blood when it obviously saves lives But consider hypervolaemia as an adverse effect 2. Think about haemoglobin in the context of volume status 3. Use single unit RBC transfusions in non-bleeding patients

14 6 potential precision-medicine opportunities 1. Transfuse blood when it obviously saves lives But consider hypervolaemia as an adverse effect 2. Think about haemoglobin in the context of volume status 3. Use single unit RBC transfusions in non-bleeding patients 4. Early sepsis might be different But only when there is clear evidence of tissue hypoxia

15 Early sepsis: the first golden 6 hours? Goal directed therapy works if applied early (Rivers E. NEJM 2001;345: ) Transfusing red cells to achieve a HCT >0.3 (Hb >10 g/dl) was part of the protocol Only introduced if ScvO 2 <70%

16 Further down the River(s) Propensity-matched studies: Association between early transfusion and improved outcome in sepsis Trials of EGDT ProMISE (UK) negative PROCESS (USA) negative ARISE (Australasia) negative TRISS trial (NEJM 2014;371: ) Not an early sepsis intervention trial Not guided by algorithm based on correction of inadequate oxygen delivery

17 Comparing the Rivers and ARISE trials Rivers ED admission to randomisation 1.5 hours ARISE 2.8 hours APACHE II score Process Usual EGDT Usual EGDT ScVO 2 49% 49% - 73% Antibiotics 89% in first 6 hours 100% (median time 70 minutes) Fluids 0-6 hours (2600) 2000 (2500) RBCs (% transfused) Vasopressors (22) 67 (22) Dobutamine hour parameters Lactate ScVO 2 66% 77% - 76%

18 Hb 70g/L vs 90g/L Transfusion exposure: restrictive liberal 64% (median 1 unit) 99% (median 3 units)

19 Mean time to recruitment 21 hours post-icu admission

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21 6 potential precision-medicine opportunities 1. Transfuse blood when it obviously saves lives But consider hypervolaemia as an adverse effect 2. Think about haemoglobin in the context of volume status 3. Use single unit RBC transfusions in non-bleeding patients 4. Early sepsis might be different But only when there is clear evidence of tissue hypoxia 5. Patients with cardiovascular disease may require more liberal practice

22 Differentiation between myocardial infarction (MI) types 1 and 2 according to the condition of the coronary arteries. Thygesen K et al. Eur Heart J 2012;eurheartj.ehs184

23 40% prevalence of elevated cardiac troponin (non-highly sensitive assay) Consistent association with higher mortality TROPICCAL study (ongoing; UKCRN: 19253) Critically ill patients with concurrent CVD 100% detectable hstroponin I at ICU admission 65% rise/fall pattern with peak >40 ng/l (peak 2-3 days) Only 6% clinical diagnosis of ACS

24 Four scenarios All-comers (populations with and without known cardiovascular disease) Populations with cardiovascular disease experiencing non-cardiac illness Populations with acute coronary syndrome Cardiac surgery

25 Four scenarios All-comers (populations with and without known cardiovascular disease) Populations with cardiovascular disease experiencing non-cardiac illness Populations with acute coronary syndrome Cardiac surgery

26 TRICC NEJM g/L vs 100g/L

27 Cardiac complications in TRICC

28 Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis Lars B Holst et al. BMJ 2015; 350 doi: Cannot exclude a difference as large as 15% in myocardial infarction

29 Four scenarios All-comers (populations with and without known cardiovascular disease) Populations with cardiovascular disease experiencing non-cardiac illness Populations with acute coronary syndrome Cardiac surgery

30 Is low transfusion threshold safe in critically ill patients with cardiovascular disease? Hebert PC et al. Crit Care Med 2001; 29: 227 Subgroup of 357 patients with cardiovascular disease Subgroup of 257 patients with ischaemic heart disease 30 day mortality Difference 4.9% (-15.3% to 5.6%)

31 Patients aged >50 years with cardiovascular disease or risk factors Mean age 82 years; cardiovascular disease 63% Protocolised liberal versus clinician judgement restrictive No difference in death or physical ability No difference in cardiovascular complications Trend to higher rates of MI

32 Acute coronary syndrome and pulmonary oedema in patients with chronic cardiovascular disease Docherty AM, et al. BMJ. Mortality at 30 days: RR 1.15 (0.88 to 1.50); I 2 14%

33 Acute coronary syndrome and pulmonary oedema in patients with chronic cardiovascular disease Docherty AM, et al. BMJ. ACS: RR 1.71 (0.11 to 2.65); I 2 0% Absolute risk difference 2%; NNT 50

34 Four scenarios All-comers (populations with and without known cardiovascular disease) Populations with cardiovascular disease experiencing non-cardiac illness Populations with acute coronary syndrome Cardiac surgery

35 Liberal or restrictive transfusion after cardiac surgery. Murphy GJ; Pike K; Rogers CA; Wordsworth S; Stokes EA; Angelini GD; Reeves BC; TITRe2 Investigators New England Journal of Medicine. 372(11): , 2015 Mar 12. DOI: /NEJMoa Hb 75g/L versus 90g/L Randomisation post-surgery Transfusion exposure 53% versus 92% Median 1 unit versus 2 units 2

36 Sensitivity analyses suggested greater AKI

37 Indications for red blood cell transfusion in cardiac surgery: a systematic review and meta-analysis Patel et al. Lancet Haematology

38 6 potential precision-medicine opportunities 1. Transfuse blood when it obviously saves lives But consider hypervolaemia as an adverse effect 2. Think about haemoglobin in the context of volume status 3. Use single unit RBC transfusions in non-bleeding patients 4. Early sepsis might be different But only when there is clear evidence of tissue hypoxia 5. Make individual judgements for patients with cardiovascular disease 6. For younger patients and those without comorbidity don t transfuse unless the Hb is <70g/L

39 Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis Lars B Holst et al. BMJ 2015; 350 doi: 30 days mortality All comers (including CVD): RR 0.86 (0.74 to 1.01) Restricted to CVD: RR 1.15 (0.88 to 1.50)

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41 Summary: a precision approach in critical (and other?) illness Use a default trigger of 70g/L when: Patient is young and has no comorbidity No evidence of impaired tissue oxygenation (ScVO 2 <70% or high lactate (>2-4mmol/L) Consider a higher trigger (?80g/L) when the patient has chronic cardiovascular disease or an acute coronary syndrome Consider a higher trigger in early sepsis with clear evidence of significant tissue hypoxia Use single unit transfusions

42 @Ed_TimWalsh

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