CRITICAL CARE

Pharmacokinetics and pharmacodynamics of six epoetin alfa dosing regimens in anemic critically ill patients without acute blood loss Crit Care Med. 2009 Feb 24. [Epub ahead of print]In this study of anemic critically ill patients treated with epoetin alfa, all dosing regimens were well tolerated and appeared to effect reticulocytosis, with a peak at day 11 or 15 in most patients. The pharmacokinetics of epoetin alfa did not predict pharmacodynamic response in anemic critically ill patients.

A US multicenter, retrospective, observational study of erythropoiesis-stimulating agent utilization in anemic, critically ill patients admitted to the intensive care unit. Clin Ther. 2008 Dec;30(12):2324-2334. A total of 438 patients were included in the analysis, of whom 201 (46%) were treated with darbepoietin alfa and 237 (54%) were treated with epoetin alfa. In both groups, the duration of therapy was </=1 week in ~50% of patients, and the mean change in hemoglobin concentration was 0.8 g/dL. Overall, 47% (darbepoietin alfa) and 44% (epoetin alfa) of patients were RBC transfusion independent (ie, did not require a transfusion during their ICU or hospital stay) after receiving the first ESA dose. Conclusion: Based on these results, it is apparent that the practice patterns associated with ESA treatment of critically ill patients admitted to the ICU between February 2005 and September 2005 were highly variable.

The role of erythropoietin in the acute phase of trauma management: Evidence today. Injury. 2008 Dec 29. [Epub ahead of print] Review.

Impact of delayed initiation of erythropoietin in critically ill patients.
BMC Blood Disord. 2007 Oct 4;7(1):1 [Epub ahead of print] Delayed initiation of rHuEPO for anemia of critical illness resulted in comparable hemoglobin and transfusion benefits. Future studies are needed to establish clinical benefit and role in therapy. RBC exposure may blunt the erythropoietic effects of rHuEPO, potentially frustrating benefits to those of greatest apparent need.

Efficacy and safety of epoetin alfa in critically ill patients.
N Engl J Med. 2007 Sep 6;357(10):965-76. The use of epoetin alfa does not reduce the incidence of red-cell transfusion among critically ill patients, but it may reduce mortality in patients with trauma. Treatment with epoetin alfa is associated with an increase in the incidence of thrombotic events.

Anemia in critical care patients: Incidence, etiology, impact, management, and use of treatment guidelines and protocols.
Am J Health Syst Pharm. 2007 Feb 1;64(3 Suppl 2):S14-21. Epoetin alfa increases hemoglobin concentrations and reduces the need for transfusion in critical care patients, including surgical patients with large anticipated blood losses. Epoetin alfa also appears to be effective for managing anemia in patients with multiple organ dysfunction syndrome. Iron supplementation is needed by most patients receiving erythropoietic therapy. Iron supplementation without erythropoietic therapy is inadequate to correct anemia unrelated to iron deciency. Concerns have been raised about a possible increased risk for infection when parenteral iron therapy is used in critical care patients. Developing treatment guidelines or protocols for managing anemia in critical care patients can minimize the need for transfusions and improve prescribing of erythropoietic therapy.

Recombinant human erythropoietin in severe anaemia: issues of dosing and duration.
Anaesth Intensive Care. 2006 Dec;34(6):793-6. This case report reviews the treatment of anaemia in critically ill Jehovah's Witness patients after surgery and discusses the potential need for higher RHuEPO dosing strategies and longer duration of therapy.

Iron Administration in the Critically III.
Semin Hematol. 2006 Oct;43(4 Suppl 6):S23-7. Anemia is a common pathology in intensive care unit (ICU) patients. The pathophysiology of anemia includes altered iron metabolism with decreased erythropoiesis. Under normal conditions, there is a balance between iron transport by transferrin, making iron available for incorporation in hemoglobin, and iron storage as ferritin. In inflammatory processes, this balance is disturbed and plays a central role in the development of anemia. Typically, the inflammatory process is associated with a low concentration of serum iron, high ferritin and low transferrin. Effective erythropoiesis requires both erythropoietin (EPO) and iron. Critically ill patients have inappropriately low EPO levels, and several studies have been conducted to assess the potential benefits of exogenous EPO supplementation. EPO treatment plus iron administration reduced the number of red blood cell (RBC) transfusions needed but had no effects on outcome in terms of ICU infection rates or mortality. Iron can have adverse effects, including inhibition of phagocytosis, inhibition of intracellular killing of bacteria, and altered polymorphonuclear cell function

Efficacy of recombinant human erythropoietin in critically ill patients admitted to a long-term acute care facility: a randomized, double-blind, placebo-controlled trial.
Crit Care Med. 2006 Sep;34(9):2310-6. Study drug (rHuEPO 40,000 units) or a placebo was administered by subcutaneous injection before day 7 of long-term acute care facility admission and continued weekly for up to 12 doses.  In patients admitted to a long-term acute care facility, administration of weekly rHuEPO results in a significant reduction in exposure to allogeneic red blood cell transfusion during the initial 42 days of rHuEPO therapy, with little additional benefit achieved with therapy to 84 days. Despite receiving fewer red blood cell transfusions, patients treated with rHuEPO achieve a higher hemoglobin level.

Alternatives to blood product transfusion in the critically ill: erythropoietin.
Crit Care Med. 2006 May;34(5 Suppl):S160-9. Review. ICU-associated anemia is largely the result of the cumulative effects of blood loss and decreased RBC production. Blood loss in critically ill patients may be overt, occult, or due to phlebotomy. Decreased RBC production is the other major factor influencing the development of anemia. Decreased RBC production is due to the combined effects of abnormal iron metabolism, inappropriately low erythropoietin production, diminished response to erythropoietin, and direct suppression of RBC production. Inflammatory mediators play a pivotal role in the pathogenesis of decreased RBC production. Clinical trials have shown that, compared with nontreated subjects, rHuEPO-treated ICU patients will have increased serum erythropoietin concentrations, increased reticulocyte counts, and increased hemoglobin and hematocrit values and require fewer RBC transfusions.

Pathophysiology of intensive care unit-acquired anemia.
Crit Care. 2004;8 Suppl 2:S9-10. Epub 2004 Jun 14. Review. The formation of red blood cells (RBCs) in the bone marrow is regulated by erythropoietin in response to a cascade of events. Anemia in the intensive care unit can be caused by a host of factors. Patients in the intensive care unit may have decreased RBC production and a blunted response to erythropoietin. Administration of recombinant human erythropoietin may stimulate erythropoiesis, increase hematocrit levels and hemoglobin concentration, and reduce the need for RBC transfusions.

Anemia in the critically ill.
Crit Care Clin. 2004 Apr;20(2):159-78. Review. A recent randomized trial enrolled over 1300 critically ill patients to receive either 40,000 units of exogenous erythropoietin or placebo. These authors found that patients randomized to erythropoietin received significantly less allogeneic RBC transfusions and had significantly greater increases in hemoglobin. Although no differences were found between groups in gross clinical outcomes (ie, death, renal failure, myocardial infarction), this study did not have the power to identify small differences in outcomes. This and other studies of exogenous erythropoietin therapy in critically ill patients clearly demonstrate that the bone marrow in many of these patients will respond to the administration of erythropoietin despite their illness, suggesting a blunted production of erythropoietin rather than a blunted response to erythropoietin. Exogenous erythropoietin therefore represents a therapeutic option for treating anemia in critical illness

Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial.
JAMA. 2002 Dec 11;288(22):2827-35. In critically ill patients, weekly administration of 40 000 units of rHuEPO reduces allogeneic RBC transfusion and increases hemoglobin. Further study is needed to determine whether this reduction in RBC transfusion results in improved clinical outcomes. FULL TEXT

SURGERY

[Usefulness of the administration of intravenous iron sucrose for the correction of preoperative anemia in major surgery patients.] Med Clin (Barc). 2009 Mar 7;132(8):303-6. Epub 2009 Feb 14. Spanish. Because of the low incidence of side effects and the rapid increase of hemoglobin levels, intravenous iron sucrose emerges as a safe, effective drug for treating preoperative anemia in these patient populations

Cost Minimization Analysis of Preoperative Erythropoietin vs Autologous and Allogeneic Blood Donation in Total Joint Arthroplasty. J Arthroplasty. 2008 Dec 2. [Epub ahead of print] A strategy that combines autologous blood donation with EPO for patients who cannot donate autologous blood may provide the greatest cost savings and minimize allogeneic blood transfusion.

Erythropoietin and intravenous iron therapy in postpartum anaemia.
Acta Obstet Gynecol Scand. 2007;86(8):957-62. In comparison to intravenous iron alone, the addition of rhEPO did not further increase haemoglobin concentration in women with postpartum anaemia.

Pre-operative oral iron supplementation reduces blood transfusion in colorectal surgery - a prospective, randomised, controlled trial.
Ann R Coll Surg Engl. 2007 May;89(4):418-21. Controlled trial of oral ferrous sulphate 200 mg TDS for 2 weeks' pre-operatively versus no iron therapy. At admission to hospital, the iron-supplemented group had a higher haemoglobin than the non-iron treated group (mean haemoglobin concentration 13.1 g/dl [range, 9.6-17 g/dl] versus 11.8 g/dl [range, 7.8-14.7 g/dl]; P = 0.040; 95% CI 0.26-0.97) and were less likely to require operative blood transfusion (mean 0 U [range, 0-4 U] versus 2 U [range, 0-11 U] transfused.

Preoperative haematinics and transfusion protocol reduce the need for transfusion after total knee replacement.
Int J Surg. 2007 Apr;5(2):89-94. Epub 2006 Apr 27. Patients undergoing surgery for primary TKR,  receivee iron ferrous sulphate (256mg/day; 80mg of Fe(2+)), vitamin C (1000mg/day) and folic acid (5mg/day) during the 30-45days preceding surgery, and who are transfused if Hb <80g/L and/or clinical signs/symptoms of acute anaemia/hypoxemia.  This protocol seems to be effective for avoiding ABT in non-anaemic TKR patients, whereas for anaemic patients another blood saving strategy, such us preoperative erythropoietin administration or postoperative blood salvage, should be added to further increase its effectiveness.

A Randomized, Parallel-Group, Open-Label Trial of Recombinant Human Erythropoietin vs Preoperative Autologous Donation in Primary Total Joint Arthroplasty Effect on Postoperative Vigor and Handgrip Strength.
J Arthroplasty. 2007 Apr;22(3):325-33. Multivariate analyses found a significant treatment effect favoring EPO over PAD for vigor, but not for handgrip strength. Patients in the EPO group had higher hemoglobin levels and required fewer transfusions. Both treatments were well tolerated.

Erythropoiesis in multiply injured patients.
J Trauma. 2006 Nov;61(5):1285-91. Review. Posttraumatic anemia in multiply injured patients is caused by hemorrhage, reduced red blood cell survival, and impaired erythropoiesis. Trauma-induced hyperinflammation causes impaired bone-marrow function by means of blunted erythropoietin (EPO) response, reduced iron availability, suppression and egress of erythroid progenitor cells. To treat posttraumatic anemia in severely injured patients, symptomatic therapy by blood transfusion is not sufficient. Furthermore, EPO, iron, and the use of red cell substitutes should be considered. The posttraumatic systemic inflammatory response syndrome (SIRS) induces posttraumatic anemia. Thus, a worsening of SIRS by a "second-hit" through blood transfusion ought to be avoided.

Stimulating Erythropoiesis: Future Perspectives.Kidney Blood Press Res. 2008 Jun 28;31(4):234-246. Review 

Synergy between erythropoietin and stem cell factor during erythropoiesis can be quantitatively described without co-signalling effects.
Biotechnol Bioeng. 2007 Oct 29; [Epub ahead of print] SCF promoted the early proliferation of primitive cells, while EPO primarily promoted the survival of differentiating erythroid progenitor cells. Our analysis demonstrates that EPO and SCF have distinct and predominantly sequential effects on erythroid differentiation.

Hematopoietic Growth Factors in the Treatment of Acquired Bone Marrow Failure States.
Semin Hematol. 2007 Jul;44(3):138-147. Review

Three-year Single Institution Audit on Transfusion Requirements in Oncology Patients.
Clin Oncol (R Coll Radiol). 2007 May;19(4):223-7. Epub 2006 Dec 11. This audit gives a detailed view on rising trends in transfusion requirements (increase in transfusions of 25%  in 3 years) and, in light of anticipated restrictions on resources, it identifies high-risk areas, where the use of alternatives, such as erythropoietin, could be considered.

Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy.
Oncologist. 2007 Feb;12(2):231-42. For cancer patients with chemotherapy-related anemia receiving epoetin alfa, FG produces a significantly greater increase in Hb and Hb response compared with oral iron or no iron, supporting more aggressive treatment with IV iron supplementation for these patients.FULL TEXT

Phase II study of two dose schedules of C.E.R.A. (Continuous Erythropoietin Receptor Activator) in anemic patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy.
Trials. 2007 Mar 6;8(1):8 [Epub ahead of print] C.E.R.A. administered once weekly (QW) or once every 3 weeks (Q3W) showed clinical activity and safety in patients with NSCLC. There were dose-dependent increases in Hb responses. C.E.R.A. appeared to be more effective when the same dose over time was given Q3W than QW, with a suggestion that C.E.R.A. 6.3 mcg/kg Q3W provided best efficacy in this study. However, further dose-finding studies using higher doses are required to determine the optimal C.E.R.A. dose regimen in cancer patients receiving chemotherapy

Phase II study of three dose levels of continuous erythropoietin receptor activator (C.E.R.A.) in anaemic patients with aggressive non-Hodgkin's lymphoma receiving combination chemotherapy.
Br J Haematol. 2007 Mar;136(5):736-44. Continuous erythropoietin receptor activator (C.E.R.A.) appeared to have dose-dependent clinical activity in most anaemic patients with aggressive NHL who were receiving chemotherapy.

Epoetin alfa 60,000 U once weekly followed by 120,000 U every 3 weeks increases and maintains hemoglobin levels in anemic cancer patients undergoing chemotherapy.
Oncologist. 2004;9(1):90-6. Erratum in: Oncologist. 2004;9(2):240. Once-weekly epoetin alfa at a dose of 60,000 U effectively increased Hb levels by week 8; 86% of patients achieved rises of at least 2 g/dl or Hb levels > or = 12 g/dl. Moreover, epoetin alfa at doses of 120,000 U every 3 weeks maintained or increased Hb levels. Results from this pilot study suggest that higher initial once-weekly dosing of epoetin alfa followed by less frequent maintenance dosing appears to be feasible for treating anemia in cancer patients undergoing chemotherapy. Further evaluation of these and other epoetin alfa dosage regimens is warranted. FULL TEXT

Androgens and Erythropoiesis: A Review. J Endocrinol Invest. 2009 Apr 7. [Epub ahead of print] Review. Association between androgens and erythropoiesis has been known for more than seven decades. Androgens stimulate hematopoietic system by various mechanisms. These include stimulation of erythropoietin release, increasing bone marrow activity and iron incorporation into the red cells.