Anaemia in the ICU: Is there an alternative to using blood transfusion?

Anaemia in the ICU: Is there an alternative to using blood transfusion? Tim Walsh Professor of Critical Care, Edinburgh University

World Health Organisation grading of the severity of anaemia Grade of anaemia Haemoglobin range (g.dl -1 ) 0 (none) >11 1 (mild) 9.5-10.9 2 (moderate) 8.0-9.4 3 (severe) 6.5-7.9 4 (life threatening) <6.5

No question! Not sure

Evolution of anaemia during intensive care ABC study (Europe) Vincent et al. JAMA 2002;288:1499-507 CRIT study (US) Corwin et al. Crit Care Med 2004;32:39-52

Epidemiology of blood transfusion Study (reference) Study acronym Study size Case mix Mean (SD) population APACHE II score Transfusion trigger Proportion of admissions transfused (%) Vincent et al. JAMA ABC study 3534 Mixed multi-centre ICUs 14.8 (7.9) Mean 8.4 (SD 1.3) 37 Rao et al Anaesthesia None 1247 Mixed multi-centre general ICUs Transfused patients 19.0 (8.8) Non-transfused patients 16.3 (9.3) haemorrhage 8.5 (IQR: 7.8-9.3) low haemoglobin 8.5 (IQR: 7.8-8.9) 53 Corwin et al CCM CRIT study 4892 Mixed multi-centre ICUs 19.7 (8.2) Mean 8.6 (SD1.7) 44 Bellomo et al Med J Aus None 1808 Mixed general ICU Not given Mean 8.2 (range: 4.4-18.7) 19.8 Walsh et al Transfusion; BJA; ICM ATICS study 1023 Mixed adult general ICUs (excluding cardiac) 19.8 (7.7) Median 7.8 (IQR: 7.3-8.5) 39.5 Approximately 40% of ICU patients receive blood in the ICU, even with restrictive triggers About half is for non-haemorrhage transfusions

Anaemia at ICU admission Variable Estimate of value or prevalence Mean haemoglobin concentration at ICU admission 10.5 to 11.3 g.dl -1 Proportion of patients with Haemoglobin concentration <12 g.dl -1 Haemoglobin concentration <9 g.dl -1 60-70% 20-30% Prevalence of pre-existing anaemia at ICU admission 13%

766 ICU survivors in 10 Scottish ICUs Figure 2. Percentage of survivors who had haemoglobin <90 g/l during ICU stay with 95% CI 100 90 80 70 % with Hb <90 g/l 60 50 40 30 20 10 0 < 24 hours 24-48 hours 48-144 hours > 144 hours Length of ICU stay Walsh et al. Intensive Care Medicine 2006; 32: 100-109

Ann Intern Med. 2012;157(1):49-58. doi:10.7326/0003-4819-157-1-201206190-00429

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: http://dx.doi.org/10.1136/bmj.h1354

Lecture plan Review the aetiology of anaemia during critical illness Consider the evidence for 3 nontransfusion interventions Minimisation of blood loss Iron therapy Erythropoietin therapy (with iron)

Lecture plan Review the aetiology of anaemia during critical illness Consider the evidence for 3 nontransfusion interventions Minimisation of blood loss Iron therapy Erythropoietin therapy (with iron)

Causes of anaemia during critical illness Pre-existing anaemia Acquired anaemia Haemodilution Blood loss Blood sampling Haemorrhage Reduced red cell survival Reduced red cell production Abnormal iron metabolism Nutritional deficiencies Inappropriate erythropoietin production Abnormal red cell production

Causes of anaemia during critical illness Pre-existing anaemia Acquired anaemia Haemodilution Blood loss Blood sampling Haemorrhage Reduced red cell survival Reduced red cell production Abnormal iron metabolism Nutritional deficiencies Inappropriate erythropoietin production Abnormal red cell production

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

Causes of anaemia during critical illness Pre-existing anaemia Acquired anaemia Haemodilution Blood loss Blood sampling Haemorrhage Reduced red cell survival Reduced red cell production Abnormal iron metabolism Nutritional deficiencies Inappropriate erythropoietin production Abnormal red cell production

Erythroid indices during critical lllness Serum iron Total iron binding capacity Serum iron/total iron binding capacity ratio Ferritin Transferrin Transferrin saturation Vitamin B12 and folate Erythropoietin concentration Reticulocytes Serum transferrin receptors Change N N/slight increase Non-anaemic levels Normal

The anaemia of chronic disease Weiss, G. and Goodnough, L. T. N Engl J Med 2005;352:1011

The inflammatory hit The anaemia of chronic disease Weiss, G. and Goodnough, L. T. N Engl J Med 2005;352:1011

Effects of inflammation Inhibition of renal erythropoietin production Blunted inappropriate response to anaemia Direct effects on erythropoiesis in bone marrow Effects on acute phase proteins

Acute phase effects on the liver The anaemia of chronic disease Weiss, G. and Goodnough, L. T. N Engl J Med 2005;352:1011

Acute phase effects on the liver Up-regulation of ferritin production Increased storage iron Down-regulation of transferrin production Decreased iron availability for erythropoiesis Up-regulation of hepcidin production Decreased duodenal iron absorption

Altered iron handling by macrophages and RES The anaemia of chronic disease Weiss, G. and Goodnough, L. T. N Engl J Med 2005;352:1011

Effects on macrophage and RES Increased iron uptake Increased ferritin Opening of divalent metal transported protein Closure of ferroportin 1 Hepcidin mediated Increased phagocytosis of senescent red cells by activated macrophages Increased uptake of transferrin bound iron Functional iron deficiency

Impaired erythrogenesis The anaemia of chronic disease Weiss, G. and Goodnough, L. T. N Engl J Med 2005;352:1011

IF- inhibits and induces apoptosis TNF-, IL-1, and other cytokines may also inhibit maturation Pluripotential stem cells Erythroid burst forming unit Erythroid colony forming unit Pro-erythroblasts Erythroblasts Reticulocytes Erythrocytes Erythropoietin an essential growth factor Lack of reticulocyte response

Last Hb prior to ICU discharge among male and female ICU survivors (n = 766) Males Females Last Hb value in ICU 10.0 (9.0 11.7) 9.8 (8.8 11.0) Median (IQR) g/dl Last Hb in ICU < ref range 87.0 79.6 [M <13; F <11.5 g/l] % Last Hb in ICU <9 g/dl 24.1 27.9 % Walsh et al. Intensive Care Medicine 2006; 32: 100-109

Prevalence of different degrees of anaemia at hospital discharge. Hb level Males (n=161) N (%) Females (n=122) N (%) All patients (n=283) N (%) Hb < 90 g/l 14 (8.7) 18 (14.8) 32 (11.3) Hb < 100g/L 48 (29.8) 44 (36.1) 92 (32.5) Hb < reference range. 137 (85.1) 82 (67.2) 219 (77.4) Median days from ICU discharge to hospital discharge 13 (7.5, 24) days 50% of patients still in hospital after 3 weeks discharged with Hb < 10 g/dl 50% of all patients spending > 7 days in ICU discharged with Hb < 10 g/dl Walsh et al. Intensive Care Medicine 2006; 32: 1206

Characteristics of anaemia at hospital discharge Males n (%) Females n (%) n = 97 n = 65 Normochromic normocytic 76 (78) 56 (86) Normocytic hyperchromic 10 (10) 4 (6) Normo/microcytic hypochromic 5 (5) 3 (5) Other 6 (6) 2 (3) Walsh et al. Intensive Care Medicine 2006; 32: 1206

Hb g/l Hb g/l 160 150 140 130 120 110 100 90 80 70 30/30 29/30 21/22 16/20 19/22 12/19 10/19 0 1 3 6 9 13 26 Weeks All Male Female At 13 weeks: 32% Hb <11 g/dl At 26 weeks: 16% Hb <11 g/dl Bateman et al. Critical Care Medicine; 37(6):1906-12, 2009

Factors associated with slow or failure to recover Higher circulating inflammatory markers following discharge (IL-6 and CRP) Lack of reticulocyte response Erythropoietin concentrations inappropriately low in all patients No evidence of nutritional deficiency Inflammatory anaemia

Summary With restrictive transfusion anaemia is highly prevalent in the ICU Anaemia is multifactorial, but inflammation is an important mechanism About 25% of patients are discharged with Hb <90 g/l Recovery is slow; anaemia is frequently moderate at hospital discharge In many patients anaemia persists for months The importance of anaemia to recovery after critical illness is unknown

Lecture plan Review the aetiology of anaemia during critical illness Consider the evidence for 3 nontransfusion interventions Minimisation of blood loss Iron therapy Erythropoietin therapy (with iron)

GRADE RECOMMENDATIONS 1: Summary of the Grade Recommendations Determination of the quality of evidence - Underlying methodology A. Randomised control trial B. A downgraded randomised control trial or high quality observational studies C. Well-done observational studies D. Case series or expert opinion - Factors that may decrease the strength of evidence 1. Poor quality of planning and implementation of available randomised control studies, increasing the risk of bias 2. Inconsistency of results 3. Indirectness of evidence 4. Imprecision of results 5. High likelihood of reporting bias - Main factors that may increase the strength of the evidence 1. Large magnitude of effect (direct evidence, relative risk >2, with no plausible confounders) 2. Very large magnitude of effect with RR >5 and no threats to validity 3. Dose respondent gradient Factors determining strong vs. weak recommendations Quality of evidence Relative importance of outcomes Baseline risk of outcomes Magnitude of relative risk Precision of the estimates of effect Cost The lower the quality of evidence the weaker the recommendation If values and results vary widely the weaker the recommendation The higher the risk, the greater the magnitude of effect The greater the benefit the stronger the recommendation The greater the precision the stronger the recommendation The greater the cost the weaker the recommendation

Lecture plan Review the aetiology of anaemia during critical illness Consider the evidence for 3 nontransfusion interventions Minimisation of blood loss Iron therapy Erythropoietin therapy (with iron)

Minimisation of blood loss Reducing phlebotomy frequency Reducing phlebotomy volumes Reinfusion devices for blood discards Low quality evidence Likely to decrease transfusion requirement and other costs Specific re-infusion devices available Needs system level change

Lecture plan Review the aetiology of anaemia during critical illness Consider the evidence for 3 nontransfusion interventions Minimisation of blood loss Iron therapy Erythropoietin therapy (with iron)

Iron therapy Most critically ill patients have a functional iron deficiency Oral iron unlikely to be absorbed and has risk of GI complications Few studies during critical illness Iron therapy does not increase reticulocyte counts No high quality studies showing benefit for important clinical outcomes, including blood transfusion Intravenous iron No high quality trials showing benefit during general critical illness No benefit in trauma critical care Crit Care Med 2014; 42:2048 2057 Concern in sepsis from risk of infection Association between IV iron and increased infection in non-critical care settings Systematic review BMJ 2013;347:f4822 doi: 10.1136/bmj.f4822

Lecture plan Review the aetiology of anaemia during critical illness Consider the evidence for 3 nontransfusion interventions Minimisation of blood loss Iron therapy Erythropoietin therapy (with iron)

Erythropoietin therapy Corwin, H. L., et al (2002) Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial (EPO Critical Care Trials) JAMA, 288:2827-2835 MC DB RCT; n = 1302 weekly recombinant EPO (40,000IU) vs placebo 20% reduction in RBC transfusion in the treatment group Mean Hb transfusion trigger 90g/L Corwin, H. L, et al (2007) Efficacy and Safety of Epoetin Alfa in Critically Ill Patients NEJM, 357:10 pages 965-76 MC DB RCT; n = 1460 medical, surgical and trauma patients (high proportion trauma patients) EPO vs placebo for 3 weeks no change in RBC transfusion mean haemoglobin transfusion trigger 80g/L higher Hb trend towards mortality advantage (more pronounced in trauma patients) significant increase in thrombotic events (especially among patients not receiving thromboprophylaxis)

Interpreting the erythropoietin literature Trial populations of interest; low risk of transfusion Balance of early therapy versus enrolment of patients with low transfusion requirements Transfusion practice; most did not use restrictive haemoglobin triggers close to 70g/L Uncertain benefit for long term patients at risk of chronic anaemia Variable dose and use of iron therapy Uncertain safety profile (especially thrombotic events) Uncertain cost-effectiveness

Summary Anaemia during critical illness is multifactorial Inflammation is a major mechanism resulting in functional iron deficiency and marrow suppression Minimising blood loss through sampling is simple and effective Based on current evidence routine use of oral or intravenous iron is not indicated Erythropoietin has unproven clinicaleffectiveness and safety and is not indicated