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%

< 24 hours 24 - 48 hours 48 - 144 hours > 144 hours

Length of ICU stay

0

10

20

30

40

50

60

70

80

90

100

% w

ith H

b <

90 g

/LFigure 2. Percentage of survivors who had haemoglobin <90 g/L during ICU stay with 95% CI

766 ICU survivors in 10 Scottish ICUs

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 non-

transfusion 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 non-

transfusion 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?

RCV 2L HCT 0.4

PV 3L

RCV 1.3L HCT 0.4

PV 1.7L

PV 5L

RCV 2L HCT 0.28

Haemorrhagic shock

2

4

6

0

8

Blood volume (L)

Healthy euvolaemic

Post-operative resuscitated

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 Change Serum iron

Total iron binding capacity

Serum iron/total iron binding capacity ratio

Ferritin

Transferrin

Transferrin saturation

Vitamin B12 and folate N

Erythropoietin concentration N/slight increase

Reticulocytes Non-anaemic levels

Serum transferrin receptors Normal

Weiss, G. and

Goodnough, L. T.

N Engl J Med 2005;352:1011

The anaemia of

chronic disease

Weiss, G. and

Goodnough, L. T.

N Engl J Med 2005;352:1011

The anaemia of

chronic disease

The inflammatory

“hit”

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

Weiss, G. and

Goodnough, L. T.

N Engl J Med 2005;352:1011

The anaemia of

chronic disease

“Acute phase”

effects on the liver

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

Weiss, G. and

Goodnough, L. T.

N Engl J Med 2005;352:1011

The anaemia of

chronic disease

Altered iron

handling by

macrophages and

RES

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

Weiss, G. and

Goodnough, L. T.

N Engl J Med 2005;352:1011

The anaemia of

chronic disease

Impaired

erythrogenesis

Pluripotential stem cells

Erythroid burst forming

unit

Pro-erythroblasts

Erythroblasts

Reticulocytes

Erythrocytes

Erythropoietin an

essential growth

factor

Erythroid colony forming

unit

IF- inhibits

and induces

apoptosis

TNF-, IL-1,

and other

cytokines may

also inhibit

maturation

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

0 1 3 6 9 13 2670

80

90

100

110

120

130

140

150

160All

Male

Female

30/30 29/30 21/22 16/20 12/19 10/1919/22

Weeks

Hb

g/L

Hb

g/L

Bateman et al. Critical Care Medicine; 37(6):1906-12, 2009

At 13 weeks: 32% Hb <11 g/dL

At 26 weeks: 16% Hb <11 g/dL

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 non-

transfusion 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 The lower the quality of evidence the weaker the recommendation

Relative importance of outcomes If values and results vary widely the weaker the recommendation

Baseline risk of outcomes The higher the risk, the greater the magnitude of effect

Magnitude of relative risk The greater the benefit the stronger the recommendation

Precision of the estimates of effect The greater the precision the stronger the recommendation

Cost The greater the cost the weaker the recommendation

Lecture plan

• Review the aetiology of anaemia during

critical illness

• Consider the evidence for 3 non-

transfusion 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 non-

transfusion 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 non-

transfusion 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 clinical-

effectiveness and safety and is not indicated