Erythropoietin Mimics the Acute Phase In Critical Illness
Background: In a prospective observational study, we examined the temporal relationships between serum erythropoietin (EPO) levels, haemoglobin concentration and the inflammatory response in critically ill patients with and without acute renal failure (ARF).
Patients and method: Twenty-five critically ill patients, from general and cardiac intensive care units (ICUs) in a university hospital, were studied. Eight had ARF and 17 had normal or mildly impaired renal function. The comparator group included 82 nonhospitalized patients with normal renal function and varying haemoglobin concentrations. In the patients, levels of haemoglobin, serum EPO, C-reactive protein, IL-1




, IL-6, serum iron, ferritin, vitamin B ₁₂ and folate were measured, and Coombs test was performed from ICU admission until discharge or death. Concurrent EPO and haemoglobin levels were measured in the comparator group.
Results: EPO levels were initially high in patients with ARF, falling to normal or low levels by day 3. Thereafter, almost all ICU patients demonstrated normal or low EPO levels despite progressive anaemia. IL-6 exhibited a similar initial pattern, but levels remained elevated during the chronic phase of critical illness. IL-1



was undetectable. Critically ill patients could not be distinguished from nonhospitalized anaemic patients on the basis of EPO levels.
Conclusion: EPO levels are markedly elevated in the initial phase of critical illness with ARF. In the chronic phase of critical illness, EPO levels are the same for patients with and those without ARF, and cannot be distinguished from noncritically ill patients with varying haemoglobin concentrations. Exogenous EPO therapy is unlikely to be effective in the first few days of critical illness.


Progressive anaemia is common in critical illness and often requires treatment with repeated blood transfusions, which are costly and not without risk. The anaemia is usually multifactorial; causes include repeated venesection for diagnostic tests, nutritional depletion of haemopoietic factors, haemolysis, blood loss from the gastrointestinal tract or extracorporeal circuits, or depression of haemopoiesis related to the inflammatory response, referred to as the anaemia of chronic disease. In this latter category, a relative deficiency in erythropoietin (EPO) or resistance to the action of EPO has been identified in several studies. Because recombinant human EPO is widely used as replacement therapy to treat the anaemia of chronic renal failure, and in pharmacological doses as a substitute for blood transfusion in Jehovah's witnesses, it is now being investigated as a treatment for the anaemia of critical illness. EPO therapy has been shown to result in a reduction in blood transfusion requirements in one such study, although the cost-efficacy of this approach is not certain.

EPO is an essential growth factor for erythropoiesis; the stimulus for induction of EPO gene expression is a reduction in blood oxygen availability from hypoxaemia or anaemia. EPO is produced mainly by renal interstitial fibroblasts and to a lesser extent by the liver. Suppression of EPO production or effect may be mediated by the inflammatory response. In animal models IL-1, IL-6 and tumour necrosis factor can all suppress erythropoiesis, and IL-1 and TNF can inhibit EPO production, the effects being reversed by exogenous EPO.

In chronically anaemic humans, there is an inverse log/linear relationship between serum EPO levels and haemoglobin concentration. In patients with acute renal failure (ARF), EPO production may be impaired from loss of EPO-producing renal interstitial fibroblasts. In critically ill children without renal insufficiency a blunted EPO response to acute anaemia and acute hypoxaemia was seen, when compared with similar stimuli in noncritically ill patients. Most studies in critically ill adults focus on the longer stay patients and report an impaired EPO response to anaemia, based on comparison either with normal reference ranges or with a control group of patients with nonrenal anaemia. In contrast, one study of 10 patients with sepsis or septic shock in the first 4 days following admission demonstrated marked increases in EPO levels in those patients who subsequently died, paralleling changes in the acute phase response. If exogenous EPO therapy is to have a cost-effective role in the treatment of the anaemia of critical illness, then these patients should be excluded. We therefore chose to examine temporal changes in EPO concentrations during both the acute and chronic phases of critical illness, in patients with and without ARF. We also attempted to relate these findings to haemoglobin concentrations and markers of the inflammatory response.