Anaemia

Reviewed and revised 11 July 2014

OVERVIEW

• The WHO definition of anaemia is a haemoglobin (Hb) concentration <120g/L (Hb<36%) in females and<130g/L (Hb<39%) in males
• the lower level of the reference range for Hb may vary between laboratories
• affects 80% of ICU patients, and over 50% of ICU patients have Hb <90 g/L on admission
• often multifactorial causes in the critically ill (e.g. underlying disease, blood sampling, nutritional, medications) and usually normocytic
• treatable causes must always be considered

PATHOPHYSIOLOGY

Erythropoiesis

• tissue hypoxia stimulates erythropoietin release by the kidneys
• EPO stimulates bone marrow erythropoiesis, if there are adequate supplies of iron, B12 and folate
• reticulocytes may be seen in the circulation when there is a rapid erythropoietic response (e.g. correction of a nutritional deficiency or response to haemorrhage/ haemolysis)
• anaemia of chronic disease is a ‘functional iron deficiency state’ mediated by cytokines and hepcidin from the liver, despite adequate iron stores, combined with decreased EPO production, bone marrow EPO sensitivity and decreased RBC lifespan

RBC lifespan

• RBC half life is normally 120 days, but this is reduced in disease states (e.g. inflammation, haemolysis, hemorrhage)
• RBCs are removed by the reticuloendothelial system including the spleen and liver

Effects of anaemia

• impaired oxygen delivery
• decreased blood viscosity

Response to anaemia

• Cardiac output increases
  • Anaemia causes a decrease in blood viscosity that reduces the resistance to blood flow
  • leads to increase in blood flow to and from the heart (increased preload and decreased afterload)
  • Increases in heart rate and/or myocardial contractility play a minor role as long as normovolaemia is maintained
• Oxygen extraction ratio (O2ER) increases
  • At the systemic level: redistribution of blood flow to areas of high demand, like the myocardium and the brain
  • At the micro-circulatory level: capillary blood flow is increased and pre-capillary oxygen loss is reduced
• 2,3-DPG increases
  • Occurs in chronic anaemia
  • increased concentration of 2,3-DPG  promotes offloading of oxygen to the tissues (right shift of the HbO2 dissociation curve)

CAUSES

Decreased production

• nutritional deficiencies/malabsorption (e.g. iron, folate, vitamin B12)
• bone marrow failure (e.g. infiltration, myelodysplasia, chemotherapy, radiotherapy)
• low levels of stimulating hormones (e.g. EPO, thyroid hormones)

Increased Destruction

• haemolytic anaemia

Bleeding

Haemodilution

Laboratory error

TYPES OF ANAEMIA

MICROCYTIC (MCV <80 fL)

• Iron deficiency anaemia
  • hypochromic
  • microcytic
  • high transferrin receptor concentration
  • low ferritin
  • pancytopenia (rare)
  • blood film: hypochromic, microcytic red cells, polychromasia and pencil cell poikilocytes
• Anaemia of Chronic Disease (see normocytic)
• Haemoglobinopathy (e.g. thalassemia)
• Rare: hyperthyroid, lead poisoning (basophilic stippling on blood film), bone marrow disorder, acaeruloplasminaemia

NORMOCYTIC (MCV 80-100 fL)

• Anaemia of Chronic Disease
  • mild microcytosis/normochromia
  • normochromia
  • absent reticulocyte response
  • low serum iron
  • low transferrin
  • low % saturation
  • normal ferritin (acute phase reactant)
  • transferrin receptor concentration (normal in chronic disease)
• Othen multifactorial (e.g. blood sampling, haemodilution, haematinic deficiency) and may result from combine low MCV and high MCV causes

Haemolysis

• low haptoglobins
• high LDH
• mildly increased bilirubin
• reticulocytosis
• haemoglobinaemia
• direct/indirect Coomb’s positive (if immune mediated)
• blood film: schistocytes, helmet cells

MACROCYTIC (>100 fL)

• Acute Blood Loss
  • macrocytic/ normocytic
  • normochromic
  • reticulocytosis
• Haemolysis (see haemolytic anaemia)
• Megaloblastic anaemia (e.g. >120 fL; B12, folate deficiency)
• Drugs (e.g. alcohol, some chemotherapy agents, hydroxycarbamide, methotrexate, azathioprine, zidovudine, phenytoin)
• bone marrow disorders (e.g. myelodysplasia)
• liver disease
• Hypothyroidism
• Spurious (e.g. underfilled tube, cold agglutinins, high WBC, hyperglycemia)

This classification is unreliable when anaemia is multifactorial!

CLINICAL FEATURES

Assess for cause

• acute or chronic?
• comorbidities? e.g. renal, cardiac, chronic inflammation
• isolated?
• also thrombocytopenia? (e.g. sepsis, MODS, acute blood loss, DIC, thrombotic microangiopathy)
• part of pancytopenia? (e.g. bone marrow failure or infiltration, infection, HLH, hypersplenism, drugs, autoimmune disease or megaloblastic anaemia )
• history of blood loss
• drugs
• nutrition
• symptoms of anemia: SOBE, pallor, fatigue, weakness, syncope, ischaemia, tinnitus
• jaundice
• hepatosplenomegaly (especially if thrombocytopenia or pancytopenia)

INVESTIGATIONS

• Mean cell volume (MCV) – classification of causes by MCV is primarily of value in isolated anaemia)
• blood film
• reticulocytes
• B12 and folate
• iron studies: ferritin, iron, total iron binding capacity (ferritin rises in inflammation and a normal level does not exclude iron deficiency in the critically ill)
• haemolysis screen: haptoglobins, Coomb’s test, urine Hb, LDH, autoimmune screen
• Hb electrophoresis (if target cells, long-standing microcytosis, iron replete or not of northern European ethnicity)
• bone marrow biopsy (if pancytopenia)
• LFTs
• TFTs
• Lead level if basophilic stippling on blood film
• consider septic screen
• coagulation profile (e.g. DIC, Haemophagocytic lymphohistiocytosis)

MANAGEMENT

• seek and treat cause
• find and control bleeding and correct coagulopathy
• ensure adequate oxygen delivery
• Consider:
  — EPO
  — RBC
  — Iron supplementation (usually oral, occasionally IV infusion)
• Supplement: nutrition, iron, B12, folate
• anaemia less tolerated in: older patients, the severely ill, coronary, cerebrovascular or respiratory disease
• Consider haematology consult

EVIDENCE

• the risks of anaemia in many clinical situations and benefits of RBCs transfusion are still inadequately characterized despite much investigation in last 20 years.

Observational Studies

• Hebert and colleagues
  — n = 4470, patients with cardiovascular disease -> increased mortality in patients with a Hb < 95g/L + decreased mortality with larger RBC transfusions
• Wu and associates
  — n = 78,974, patients with a AMI -> RBC transfusion associated with reduced 30 day mortality if their admitting haematocrit was < 33% but an increase in mortality if they were transfused when HCT > 36%
• Carson et al
  — n = 8787, NOF patients, if transfused at a Hb of 80g/L -> patients had a lower mortality
• Vincent et al
  — prospective cross sectional study, n = 3,534, patients who were transfused were 33% more likely to die.
• GUSTO, PURSUIT, PARAGON:
  — anaemia and ACS, looked at post randomization for other therapies, n = 24,000, pooled data, not well matched but after adjustment -> blood transfusion + ACS associated with worse outcome in those who are not anaemic or have HCT > 25%

Randomised Control Trials

• Herbet, PC., et al (1999) “Transfusion Requirements in Critical Care (TRICC) Investigators, Canadian Critical Care Trials Group. A multicenter, randomized, controlled trial of transfusion requirements in critical care.” N Engl J Med 340:409-417

• n = 838
• inclusion criteria: critical ill, normovolaemic, non-bleeding
• Hb 70g/L VS 100g/L
  -> no difference in mortality @ 30 days
  -> significant reduction in blood exposure in the more restrictive group
  -> not powered to look at patients with cardiovascular disease (suggestion of decreased survival with a restrictive strategy)
  -> significantly lower mortality in the less sick in the restrictive transfusion strategy group
  -> no differences in duration of MV or ventilator free days
  -> increased complications in liberal strategy group (APO, ARDS)

AN APPROACH

• Assess for symptoms of anaemia and evidence of end-organ ischaemia
• Seek and treat haemorrhage and underlying bleeding diathesis
• Find and treat other cause(s) for anaemia (Is it isolated or not? Review history, perform clinical examination and obtain investigations)
• Supplement: nutrition, iron, B12, folate
• a restrictive  strategy (transfuse < 70g/L) is usually appropriate but risk stratify according to physiological reserve (e.g. age, co-morbidities especially cardiac) and predicted cause of illness (e.g. risk of bleeding) to determine threshold for transfusion
• consider EPO in appropriate circumstances

References and Links

LITFL

• ICU Mind Maps — Anaemia