The investigations and management of anaemia in ICU have been explored to a great depth in Question 9 from the second paper of 2005 and the identical Question 4 from the first paper of 2003. There have been numerous other questions about anaemia (eg. Question 18.1 and Question 18.2 from the first paper of 2015, or the identical Question 12.1 and Question 12.2 from the first paper of 2019) but they have generally been more concerned with the interpretation of iron studies and morphological abnormalities of red blood cells.

Probably the best single reference for this topic is this excellent article from the Mayo Clinic Proceedings (2003). In addition to this generic anaemia chapter, one may also wish to look at the chapter on haemolytic anaemia broadly, and autoimmune haemolysis specifically: these disorders seem to come up rather frequently in the exam papers, more so than one might expect from their community prevalence.

Classification of anaemia

Together with the low haemoglobin result one usually also gets a whole panel of RBC volume and Hb content indices, which immediately allows one to classify the anaemia into groups. These groups are organised by corpuscular haemoglobin content and RBC size. Alternatively, one could classify anaemia according to the pathophysiological mechanism, as in this article by Berlot et al (2014).

Dilution of RBC concentration

  • dilutuonal anaemia with fluid replacement
  • Artifactual anaemia due to sampling of a vessel with diluted content (i.e. the vein that has the fluids running through it).

Increased loss of RBCs

  • Extravascular loss
    • Bleeding:
      • Traumatic blood loss
      • Upper or lower GI blood loss, eg. gastric erosion/ulceration
      • Iatrogenic loss through samling and surgery
  • Intravascular loss
    • Intravascular haemolysis, eg. autoimmune hemolytic anaemia
    • DIC
    • Mechanical haemolysis, eg. due to extravascular perfusion circuits, dialysis filters, or mechanical heart valves
    • Appropriate reticuloendothelial sequestration of abnormal haemoglobin
      • Thalassaemias
      • Methaemoglobinaemia
      • Sickle cell anaemia

Decreased production of RBCs

  • Decreased hematinics
    • B12/folate deficiency
    • Drugs which interfere with B12/folate metabolism
    • Iron deficiency
  • Decreased proliferation signals
    • Decreased EPO in renal failure
    • Anaemia of chronic inflammatory states

Mechanism of anaemia of inflammation

This has come up twice in past papers, as Question 12.1 from the first paper of 2019 and the almost identical Question 18.1 from the first paper of 2015. In short, for 20% of the marks, the college wanted a brief explanation of how anaemia of inflammation causes the classical pattern of iron study abnormalities. A good article to answer this question is Nemeth & Ganz (2014). The mechanism of anaemia of inflammation can be summarised as follows:

  • Decreased iron availability
    • Cytokine release in inflammation stimulates the synthesis of hepcidin, a regulatory molecule which controls the release of iron into the circulation.
    • A high hepcidin level decreases the availability of iron by promoting "iron trapping" within the bone marrow and macrophages. Thus, the iron stores in this form of anaemia are normal, which renders iron infusion pointless.
    • In the absence of circulating iron, erythropoiesis is restricted.
  • Increased erythrocyte phagocytosis
    • Cytokine-activated macrophages destroy red cells at an increased rate
    • This reduces the lifespan of erythrocytes.
  • Decreased erythropoiesis signals
    • Cytokines act directly on the bone marrow to reduce the rate of erythropoiesis, independent of the levels of circulating erythropoietin
    • Occasionally the level of erythropoietin is also suppressed, which is thought to be a cytokine-related effect acting on its renal secretion.

Investigations for anaemia

  • History of fluid resusictation or trauma
  • Resampling to confirm the diagnosis
  • Imaging to look for obvious blood loss
  • Faecal occult blood test and/or endoscopy to exclude GI blood loss
  • Direct Coombs test, formal blood film, conjugated/unconjugated bilirubin, LDH, haptoglobin and reticulocyte count to investigate haemolysis
  • RBC folate and B12 levels
  • Iron studies
  • Coagulation screen (looking for DIC and MAHA)
  • Renal function tests and/or EPO levels

Management of anaemia in ICU

It is important to consider whether there is a genuine iron deficiency, or whether the inflammatory state has decreased access to the otherwise normal iron stores. Obviously, in a perfect world the iron-deficient patient would have some iron supplements, and the patient with inflammatory anaemia would have transfusions of blood and some sort of specific management aimed at the cause of inflammation.

However, in critical illness it is possible to have both issues simultaneously.

Iron infusion

It is therefore difficult to say conclusively that any given critically ill patient will or will not benefit from a blood transfusion. Obviously some patients trend to one group or another. For instance, trauma patients can be expected to develop iron deficiency associated with their blood loss. A study which focused on trauma patients (Pieracci et al, 2014) enrolled 150 patients, of whom the majority demonstrated iron studies consistent with iron deficiency. Some were then randomised to receive 100mg of iron sucrose. In them, serum ferritin increased (presumably reflecting that the iron stores were replenished), albeit not quite back to the normal range. Unfortunately, nothing else happened. Neither did the haemoglobin increase, nor did the red cell count, nor was the need for transfusion affected. Mortality and ICU stay were also unaffected.

The IRONMAN trial is mentioned in Question 18.2 from the first paper of 2015; it aimed to answer the question of whether IV iron administered to anaemic ICU patients reduces their need for blood transfusion. The hypothesis was that yes, it will (unless you are severely septic, erythropoiesis should be stimulated by the infusion of 500 mg of ferric carboxymaltose). The authors enrolled seventy patients into each arm. The main positive finding was that the iron-infused patients left hospital with an extra 7g/L of haemoglobin (107 g/L vs 100 g/L), but there was noo overall difference in transfusion requirements. In their answer to Question 12.2 from the first paper of 2019, the college also mentioned an increased rate of adverse events (including infection), which probably refers to the finding that the iron-infused group has an increased nosocomial infection rate (28.6% vs. 22.9%).

Erythropoietin supplementation

Question 18.1 and Question 18.2 from the first paper of 2015 reported erythropoietin levels alongside conventional iron studies. This is odd, because it is not a part of the normal panel. The glorious RPCA Manual lists it as one of the tests "occasionally indicated" to discriminate primary from secondary erythrocytosis.

Erythropoietin, however, is one of the potential treatments for anaemia. Recombinant human  EPO was used in this manner by  Corwin et al (2002), whose group was able to achieve a 19% decrease in RBC transfusions. Without transfusions, the treatment group still ended up with a higher haematocrit than the placebo group. This had no impact on mortality outcome or duration of ICU stay. This decrease in blood transfusion seems to come at the cost of a significantly increased risk of thrombotic events (according to a 2013 meta-analysis by Mesgarpour et al). That is not to mention the actual dollar cost of EPO, which is comparable with the cost of RBC transfusion (if not greater). In any case, EPO is off-label for anything other than the chronic anaemia of renal failure.

Blood transfusion is of course the last option. As such, the pros and cons of  blood transfusion in the ICU are discussed in greater detail elsewhere.

References

Walsh, T. S. "Anaemia during critical illness." British journal of anaesthesia97.3 (2006): 278-291.

Vincent, Jean Louis, et al. "Anemia and blood transfusion in critically ill patients." Jama 288.12 (2002): 1499-1507.

Tefferi, Ayalew. "Anemia in adults: a contemporary approach to diagnosis."Mayo Clinic Proceedings. Vol. 78. No. 10. Elsevier, 2003.

Pieracci, Fredric M., et al. "A Multicenter, Randomized Clinical Trial of IV Iron Supplementation for Anemia of Traumatic Critical Illness*." Critical care medicine 42.9 (2014): 2048-2057.

Litton, Edward, et al. "The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia." Crit Care Resusc 16 (2014): 285-290.

Corwin, Howard L., et al. "Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial." Jama 288.22 (2002): 2827-2835.

Mesgarpour, Bita, et al. "Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis." Intensive care medicine 39.11 (2013): 1896-1908.

Berlot, Giorgio, and Perla Rossini. "Anemia in the Critically Ill Patient." Hematologic Problems in the Critically Ill. Springer Milan, 2015. 21-35.

Nemeth, Elizabeta, and Tomas Ganz. "Anemia of inflammation." Hematology/Oncology Clinics 28.4 (2014): 671-681.

Litton, Edward, et al. "Intravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial." Intensive care medicine 42.11 (2016): 1715-1722.