Erythropoietin and the ICU
Introduction
Anemia is a ubiquitous condition in the ICU with almost 95% of patients being
anemic by their third day 4. Studies of the last two decades have showed that around 50%
of all ICU patients and 85% of those with a stay lasting longer than a week were being
transfused at some point during their stay 4. But every transfusion has risks associated
with it and RBC transfusions specifically have been independently associated with
worsened clinical outcomes 4. The recombinant form of the natural hormone
erythropoietin has been proposed as a possible way to both treat anemia in the ICU while
also decreasing the use of blood transfusions.
Natural Physiology
Erythropoietin is the primary hormone responsible for stimulating erythropoiesis
. It is a glycoprotein of 165 amino acids and four oligosaccharide chains 1. It acts on the
bone marrow to increase the diversion of sensitive stem cells into the erythrocyte lineage
1
. It has little effect in states in which there are few sensitive stem cells to act on such as
in aplastic anemia and erythropoietin levels are naturally elevated in these patients 3. The
plasma concentration of erythropoietin shows a nearly linear response to the hematocrit
level unless renal disease is present 1.
1
Erythropoiesis is not the only physiological action of erythropoietin. EPO
receptors have been found on endothelial cells and within the CNS 11. This discovery led
to increased research towards the discovery of erythropoietin’s extra-hematological roles
11
. Erythropoietin was found to counter cellular apoptosis, antagonize proinflammatory
cytokines (such as tumor necrosis factor) and promote healing in tissues 11.
The majority of erythropoietin (about 85%) is synthesized by the kidneys in the
interstitial cells of the peritubular capillary beds 1. The liver also plays a role by
synthesizing the remaining 15% in perivenous hepatocytes 1. The synthesis of
erythropoietin is stimulated by low O2, cobalt salts, androgens, catecholamines, and
alkalosis 1. The low O2 sensor appears to be a dimeric transcription factor called hypoxiainducible factor (HIF)-1 5. HIF-1 consists of an α and β chain 5. The α chain is degraded
quickly in normoxic cells via the ubiquitin system 5. But in hypoxic cells the ubiquitin
system does not degrade this protein as effectively, and the α and a β chains combine to
form the functional HIF-1 transcription factor. This then upregulates the transcription of
the EPO gene 5.
Erythropoietin is inactivated by the liver. Its half-life is about five hours. The
recombinant form of erythropoietin was developed by Drs. Adamson and Eschbach and
approved by the FDA in 1989. Below is a listing of conditions in which the endogenous
erythropoietin levels can be elevated or depressed 2.
Elevated
Depressed
Tumors (renal cell, hepatoma)
Secondary polycythemia (high altitude, COPD)
Polycystic Kidney Disease
Bone Marrow unresponsiveness
Primary polycythemia
Bilateral nephrectomy
Anemia of chronic disease
Pharmacology
Two forms of recombinant erythropoietin are available: human erythropoietin
(rHuEPO or epoetin alpha) and darbepoetin alfa. The sole difference is that darbepoetin
alfa is glycosylated giving it a longer half-life 3.
Pharmacokinetics
After the administration of erythropoietin the reticulocyte count can be expected
to increase in about 10 days 3. An increase in hematocrit follows in two to six weeks 3.
Patients may require concurrent iron and folate supplementation for an erythropoietic
response to erythropoietin to occur 3. Whether this type of supplementation would be
necessary to obtain the anti-apoptotic effects of erythropoietin is a question I did not find
answered in the literature.
Anemia, EPO and the ICU
Anemia in the ICU
As stated in the introduction to this paper, 95% of ICU patients will become
anemic by day 3 of their ICU stay 4. It is beneficial before addressing the treatment of a
problem to assess what is causing the problem in the first place. There are several
mechanisms that may explain anemia in the ICU.
An obvious source of blood loss in the ICU is phlebotomy. Studies have found
that an average of 65 ml/day are drawn from ICU patients 4. One study stated that of
those ICU patients receiving transfusions, almost half had been phlebotomized of more
than 1 unit of blood 4.
Yet, phlebotomy is probably a minor player in the cause of ICU anemia. The
physiology of ICU patients differs from healthy individuals in many ways and
erythropoiesis seems to be no different. Anemia of critical illness seems to have its own
peculiar set of lab values such as decreased serum iron, decreased total iron binding
capacity (TIBC), decreased iron/TIBC ratio, and increased ferritin 4. EPO levels have
been shown to be higher in ICU patients than in healthy adults, but lower than in patients
outside the ICU with iron-deficiency anemia and a similar hematocrit 4. Inflammatory
cytokines seem to play a role in blunting erythropoiesis in the ICU patient by inhibiting
RBC production within the bone marrow and altering iron metabolism 4. This anemia of
underproduction is very similar to anemia of chronic inflammatory disease 10.
Other possible sources of blood loss and underproduction include surgical
procedures, trauma preceding ICU admission, B12/folate deficiency and blood loss from
erosive gastrointestinal mucosal disease or tissue trauma 5.
Transfusions have been the primary method of overcoming this anemia and
increasing oxygen delivery to tissues 10. There are problems with transfusions though.
Transfusions have not been demonstrated to consistently increase organ oxygen use 10.
Stored RBCs also have a reduced p50 and a reduced 2,3-DPG content 10. Thirdly, the
ABC and CRIT studies both showed that transfusions were independently associated with
worsened outcomes in critically ill patients 10.
Adverse Reactions of Transfusions
Transfusions have many adverse reactions associated with their use. These can
range from simple febrile reactions to viral infection to transfusion-associated circulatory
overload and transfusion-related acute lung injury 7. Aside from direct reactions, the use
of blood transfusions may increase the mortality in critically ill patients 8. These issues
have driven erythropoietin research.
EPO’s Affect on Transfusion Rates and ICU Outcomes
Zarychanski published a meta-analysis of erythropoietin trials in critically ill
patients this year. In his analysis of 9 studies of erythropoietin use in the ICU, no
significant decrease in mortality was seen, especially in “studies of high methodologic
quality” 7. Erythropoietin use did not shorten a patient’s length of stay in the ICU, nor did
it decrease ventilator use 7. Whether the administration of erythropoietin decreases the
use of blood transfusions may depend on what criteria is used to define the need for
transfusion 7. Due to the ABC and CRIT trials, transfusions are being held until
hemoglobin levels are lower than would have been thought safe before. When a more
restrictive transfusion protocol was considered (transfusion at a hemoglobin of less than
or equal to 8.0 g/dL) there was no decrease in transfusion rates in patients given
erythropoietin 7.
Corwin from Dartmouth-Hitchcock published a new erythropoietin trial this year
in which he conducted a randomized controlled trial of 1460 ICU patients who were
either given erythropoietin or placebo on study days 1, 8 and 15 (corresponding to at least
ICU days 3, 10 and 17) 8. Patient randomization was stratified according to three groups:
trauma, surgical non-trauma, and medical non-trauma because his prior research had
hinted that there may be a difference between them 8. Corwin showed that at day 29 there
was a statistically significant rise in the absolute hemoglobin concentration from
10.8±1.7 g/dL in the placebo group versus 11.2±1.8 g/dL in the erythropoietin group 8.
Although statistically significant, I am not convinced of the clinical significance of this
increase. The clinical benefit may be better observed in the mortality data that showed
that mortality at day 29 was significantly lower in the epoetin alfa group at 8.5% versus
11.4% in the placebo group 8. Erythropoietin did not decrease the length of stay either in
the ICU or in the hospital, nor did it decrease the median duration of mechanical
ventilation 8.
Overall there was no reduction in the use of transfusions between the
erythropoietin group and placebo 8. This finding was inconsistent with the results Corwin
had obtained during previous trials and the authors proposed that this may be due to a
lowering of the mean pretransfusion hemoglobin concentration from 8.5 g/dL in prior
studies to 8.0 g/dL in the more recent study 8.
Because of the stratification of participants into trauma, surgical non-trauma, and
medical non-trauma groups, Corwin was able to tease out the affect of erythropoietin on
mortality better than in prior studies 8. This study discovered that the decreased mortality
associated with erythropoietin use was found in the trauma group but not in the surgical
or medical non-trauma groups 8. Of note is also the fact that the trauma group had a
significantly different makeup than the other two groups in regards to other
characteristics such as age 8. Corwin suggests that the reduced mortality in this group was
not due to the erythropoietic effect of erythropoietin, but possibly due to its antiapoptotic
activity 8.
Adverse Events with EPO use
Since erythropoietin is an endogenous hormone, adverse reactions and allergies
are limited 3. The two most common adverse reactions are hypertension and thrombosis 3.
In Corwin’s study of 1460 ICU patients a significant increase in thrombotic
vascular events was seen in patients given erythropoietin 8. Participants in the
erythropoietin groups had 120 thrombotic vascular events as compared to 83 in the
placebo group 8. This led the authors to suggest that prophylactic heparin could be
considered for ICU patients who receive erythropoietin 8. This problem has also arisen in
other trials such as a study of erythropoietin use in patients scheduled for orthopedic
surgery with showed an increase in deep venous thrombosis 9.
There have also been reports of chronic renal failure patients using erythropoietin
developing anti-EPO antibodies that have led to pure red cell aplasia 10.
EPO and Stroke
It is interesting that there has also been much recent interest in using
erythropoietin and other colony stimulating factors as neuroprotective agents since it was
discovered that the CNS was one of the sites outside the bone marrow in which EPO-
receptors can be found 12. Several small trials of stroke patients have shown that
erythropoietin and colony-stimulating factors may reduce brain damage, improve
outcome and lead to the release of stem cells into the circulation that could possibly help
in the post-stroke repair process 12. Further research is currently being done to clarify the
roles of erythropoietin and other colony stimulating factors use in stroke 12.
Summary
Decreased transfusion rates in critically ill patients using erythropoietin has not
been well established when restrictive transfusion protocols are in place. There are signs
that there may be a mortality benefit with erythropoietin use in select patients. Any
benefit in outcomes that may be established would also require further investigation to
discover whether the benefit was derived from increased erythropoiesis, antiapoptotic
activity or a decreased transfusion rate 10. Also, the cost-effectiveness of erythropoietin
use would also need to be defined for these benefits 10.
References
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illness? Clinical Therapeutics 2004; 26; 6; 819-828
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Medicine Reviews 2006; 20; 1: 27-33
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