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Recombinant human erythropoietin in severe anaemia: issues of dosing and duration.

SUMMARY

The majority of Jehovah's Witnesses refuse blood product transfusion, even when it can be lifesaving. Treatment with recombinant human erythropoietin (RHuEPO) is a valuable adjunct in Jehovah's Witness patients undergoing surgery. A number of additional strategies, including acute normovolaemic haemodilution, intra-operative blood salvage and reinfusion, iron and folate supplementation are also utilized to avoid blood transfusion. Critically ill patients have blunted erythropoietin production and decreased endogenous iron availability. 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.

Key Words: erythropoietin, Jehovah's Witness, anaemia, critical illness

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Recombinant human erythropoietin (RHuEPO) has become a viable alternative to blood transfusion in patients with anaemia or other disorders precluding donation, patients with limited time to surgery and individuals who, due to religious beliefs, are unwilling to participate in an autologous blood donation program or blood transfusion. The religious beliefs of Jehovah's Witnesses prohibiting the acceptance of blood or blood product transfusion are well recognized; hence treatment options for these patients are limited. This is particularly true for operative procedures associated with significant blood loss.

CASE HISTORY

A 72-year-old female Jehovah's Witness presented to the oral and maxillofacial surgeons complaining of a three-month history of a lump on the palate with associated dysphagia, otalgia, changes in vision and headaches. Examination revealed a palpable swelling on the right side of the soft palate and lateral pharyngeal wall with no associated cervical lymphadenopathy. CT and MRI scans demonstrated a palatal mass with base of tongue involvement and extension into the pterygomaxillary fissure, pterygopalatine fossa and vidian canal leading to the cranial base. Biopsy confirmed adenoid cystic carcinoma.

Preoperatively, the patient declined any therapy involving blood or blood-related products including coagulation factors and autologous transfusion. A wide local excision involving the soft palate, right posterior maxilla and right pterygoid plates and right temporoparietal galeal flap reconstruction was performed with 500 ml estimated blood loss.

Admitted to the intensive care unit (ICU) in a stable haemodynamic condition, her haematocrit (Hct) fell from 41.7% preoperatively to 25.1% in the immediate postoperative period. Recombinant human erythropoietin (RHuEPO, 20,000 units subcutaneous) was initiated on the first postoperative day. Two days later, her Hct decreased significantly to 17.1% related to crystalloid fluid resuscitation for maintenance of optimal perfusion, substantiated by her positive fluid balance of 8.7 litres by postoperative day 2 (Table 1). A high-dose regimen of RHuEPO 40,000 units per day with intravenous iron sucrose 100 mg per day was initiated. (Table 2).

Additional strategies to prevent iatrogenic blood loss in the ICU included ordering only essential laboratory tests and using microsample analysers for all diagnostic laboratory testing. The RHuEPO dose was subsequently decreased to 20,000 units per week when the Hct increased to 22.1%. Furthermore, ferrous sulphate 300 mg p.o., t.i.d. and ascorbic acid 500 mg p.o., b.i.d. were administered until discharge on postoperative day 22 (Figure 1).

[FIGURE 1 OMITTED]

DISCUSSION

Erythropoiesis is regulated by the glycopeptide erythropoietin. Binding to BFU (burst-forming unit) and CFU (colony-forming unit) receptors of the premature erythrocyte, erythropoietin has a specific effect on the survival and maturation of precursor cells (1). Tissue hypoxaemia represents the maximum stimulus for increased endogenous erythropoietin release (2).

"Anaemia of critical illness" mimics the anaemia of chronic inflammatory disease with blunted endogenous erythropoietin production (3,4). Inadequate endogenous erythropoietin concentrations have been documented in anaemic, non-traumatized, critically ill patients (5-7). Furthermore, inadequate endogenous erythropoietin response to low haemoglobin was documented in multiply traumatized patients (8).

The pathogenesis of the inadequate endogenous erythropoietin response in critically ill patients is multifactorial, including down-regulation of the erythropoietin gene by inflammatory cytokines, a direct inhibitory effect on bone marrow red blood cell production and maturation by inflammatory cytokines (interleukin-1 and tumor necrosis factor-[alpha]) and altered iron metabolism (low transferrin, high ferritin) during systemic inflammatory states and sepsis.

The mechanisms underlying the anaemia of inflammation are complex (9). Inflammation leads to activation of T cells (CD3+) and monocytes. These cells induce immune effector mechanisms, thereby producing cytokines such as interferon (from T cells) and tumor necrosis factor (TNF-[alpha]), interleukin (IL)-1, IL-6, and IL-10 (from monocytes or macrophages). Interleukin-6 and lipopolysaccharide stimulate hepatic expression of the acute-phase protein hepcidin, which inhibits duodenal absorption of iron. Interferon-gamma and lipopolysaccharide also increase the expression of divalent metal transporter 1 on macrophages and stimulate the uptake of ferrous iron. The anti-inflammatory cytokine IL-10 upregulates transferrin receptor expression and increases transferrin-receptor-mediated uptake of transferrin bound iron into monocytes.

Additionally, activated macrophages phagocytose and degrade senescent erythrocytes for iron recycling, a TNF[alpha] induced process via damaging of erythrocyte membranes and stimulation of phagocytosis. Interferon-gamma and lipopolysaccharide down-regulate the macrophage iron transporter ferroportin 1 expression, thus inhibiting iron export from macrophages, a hepcidin-mediated process. Simultaneously, TNF[alpha], IL-1, IL-6 and IL-10 induce ferritin expression and stimulate macrophage storage and retention of iron.

In summary, these mechanisms initiate a decreased iron concentration in the circulation, thereby limiting iron availability for erythroid cells. TNF[alpha] and interferon-gamma inhibit renal erythropoietin production. TNF[alpha], interferon-gamma, and IL-1 directly inhibit differentiation and proliferation of erythroid progenitor cells. Additionally, limited iron availability and decreased biologic activity of erythropoietin cause inhibition of erythropoiesis and the development of anaemia.

RHuEPO enhances endogenous erythropoiesis, and is accepted by most Jehovah's Witnesses. Optimal dose and dosing regimen of RHuEPO remains unclear, especially when treating critically ill patients with life-threatening acute blood loss and those with severe acute anaemia who refuse transfusion (10).

The role of RHuEPO has been investigated in a simulated peri-surgical setting (11). With differing RHuEPO dosing regimens, the study showed a consistent rise in absolute reticulocyte count within four to five days and increased haemoglobin and haematocrit within seven days with a peak at 14 days. In a study of 201 patients undergoing hip arthroplasty, the peri-operative use of RHuEPO caused an increased reticulocyte count by day 4 after the initial dose. The greatest increase in reticulocyte count occurred in patients who received the high dose (40,000 units weekly) (12).

A prospective, randomized, placebo-controlled trial documented that RHuEPO (300U/kg daily for 5 days, then every other day dosing) was associated with increased erythrocyte production and decreased blood transfusion requirements in the critically ill (13). A subsequent prospective randomized study in 1302 critically ill patients confirmed that weekly administration of 40,000 units of RHuEPO also reduced allogeneic blood transfusion and increased haemoglobin concentration (14).

Georgopoulos et all (15), in a prospective randomized trial in critically ill patients, compared RHuEPO at 40,000 units per week (group A) vs 40,000 units three time a week (group B) for a maximal three-week duration, compared to a control group that received intravenous (IV) iron only. A significantly greater mean haematocrit increase was documented with the higher RHuEPO dosing (group B) schedule. Thus, we chose empirically a high dose of 600 IU/[kg.sup.-1] everyday for a week in this patient with severe acute anaemia.

Another small study confirmed low endogenous erythropoietin concentrations in critically ill patients (16). Patients were randomized to RHuEPO (300 IU/kg every other day) with IV iron (20 mg daily) and folate vs. folate only or IV iron and folate. Reticulocyte count and serum transferrin receptor increased significantly only in the RHuEPO group.

Jehovah's Witnesses have challenged the traditional approach to transfusion therapy. While many clinicians would consider blood transfusions for a patient with a haemoglobin level of less than 7-8 g/dl, it appears that acute morbidity and mortality generally does not occur in this patient population until the haemoglobin drops below 5-6 g/dl. Survival has been reported in a few cases of Jehovah's Witnesses undergoing operative procedures with haemoglobin ranging from 2.2-3.0 g/dl (17-19).

In this case, severe anaemia occurred post-operatively related to surgical blood loss and haemodilution. The increase in haematocrit was attributable to treatment of anaemia with RHuEPO and reduced phlebotomy. Alternative blood management strategies that were considered in this patient included the use of pre-operative RHuEPO approximately three to four weeks before the anticipated surgery. However, a higher than normal haematocrit (42%) in the preoperative period precluded its utility. Preoperative anaemia would have warranted the use of RHuEPO with iron, folate and Vitamin C and surgery would have been delayed until haematocrit was optimized. Other feasible strategies included acute normovolaemic haemodilution (ANH). Intra-operative blood salvage and reinfusion in oncologic surgery is relatively contraindicated because of the risk of tumor cell dissemination. However, intra-operative blood salvage with blood irradiation has shown promise in the presence of malignant disease (20). Meticulous surgical haemostasis is paramount.

The most common adverse event related to RHuEPO therapy is a 'flu-like' illness which responds well to simple supportive treatment. Hypertension, thrombocytosis and thrombosis, allergic or anaphylactoid reactions, seizure and hyperkalaemia have also been reported (21). They are associated with a rapid rise in haematocrit during RHuEPO therapy and clinical vigilance will minimize these adverse reactions. A rare complication, pure red cell aplasia, has been reported due to the development of antibodies to Eprex, an epoetin alpha product available outside the U.S. (22).

The high-dosing strategy of RHuEPO for the treatment of severe anaemia in this critically ill patient has demonstrated its safety, utility and feasibility. Because of enhanced erythropoiesis with RHuEPO, iron, folate and ascorbic acid supplementation should be administered routinely. Adequate nutrition is also important in sustaining erythropoiesis. The use of high-dose daily RHuEPO and iron in managing Jehovah's Witnesses with severe anaemia, in addition to existing strategies of blood conservation, should be considered by clinicians caring for these challenging patients. Further research is warranted regarding optimal dosing and duration of RHuEPO in critically ill patients with severe anaemia related to reduced endogenous erythropoietin production and decreased iron availability.

Accepted for publication on August 23, 2006.

REFERENCES

(1.) Cazzola M, Mercuriali F, Brugnara C. Use of recombinant human erythropoietin outside the setting of uremia. Blood 1997; 89:4248-4267.

(2.) Wang GL, Semenza GL. Molecular basis of hypoxia-induced erythropoietin expression. Curr Opin Hematol 1996; 2:156-162.

(3.) Corwin HL. Anaemia in the critically ill: the role of erythropoietin. Semin Haematol 2001; 38:24-32.

(4.) Von Ahsen N, Muller C, Serke S et al. Important role of nondiagnostic blood loss and blunted erthropoietic response in the anaemia of medical intensive care patients. Crit Care Med 1999;27:2630-2639.

(5.) Rogier P, Zhang H, Leeman M et al. Erythropoietin response is blunted in critically ill patients. Intensive Care Med 1997; 23:159-162.

(6.) Krafte-Jacobs B, Levetown ML, Bray GL et al. Erythropoietin response to critical illness. Crit Care Med 1994; 22:821-826.

(7.) VanIperen CE, Gaillard CA, Kraaijenhagen RJ et al. Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in ICU patients. Crit Care Med 2000; 28:2773-2778.

(8.) Hobisch-Hagen P, Wiedermann F, Mayr A et al. Blunted erythropoietic response to anemia in multiply traumatized patients. Crit Care Med 2001; 29:743-747.

(9.) Weiss G, Goodnough LT Anemia of chronic disease. N Engl J Med 2005; 352:1011-1023.

(10.) Rasanayagam SR, Cooper GM. Two cases of severe post-partum anaemia in Jehovah's witnesses. Int J Obstet Anesth 1996;5:203-205.

(11.) Rutherford CJ, Schneider TJ, Dempsey H et al. Efficacy of different dosing regimens for recombinant human erythropoietin in a simulated perisurgical setting: the importance of iron availability in optimizing response. Am J Med 1994; 96:139-145.

(12.) Feagan BG, Wong CJ, Kirkley A et al. Erythropoietin with iron supplementation to prevent allogeneic blood transfusion in total hip joint arthroplasty. A randomized, controlled trial. Ann Intern Med 2000;133:845-854.

(13.) Corwin HL, Gettinger A, Rodriguez RM et al. Efficacy of recombinant human erythropoietin in the critically ill patient. A randomized, double-blind, placebo-controlled trial. Crit Care Med 1999; 27:2346-2350.

(14.) Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Shapiro MJ, Corwin MJ, Colton T, EPO Critical Care Trials Group. Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA 2002; 288:2827-2835.

(15.) Georgopoulos D, Matamis D, Routsi C, Michalopoulos A, Maggina N, Dimopoulos G, Zakynthinos E, Nakos G, Thomopoulos G, Mandragos K, Maniatis A. Critical Care Clinical Trials Greek Group. Recombinant human erythropoietin therapy in critically ill patients: a dose-response study. Crit Care 2005; 9:R508-R515.

(16.) van Iperen CE, Gaillard CA, Kraaijenhagen RJ, Braam BG, Marx JJ, van de Wiel A. Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients. Crit Care Med 2000; 28:2773-2778.

(17.) Ferzli GS, Hurwitz JB, Fiorillo MA et al. Laparoscopic splenectomy in a Jehovah's Witness with profound anaemia. Surg Endosc 1997; 11:850-851.

(18.) Kunz J, Mahr R. Management of severe blood loss after tumor resection in a Jehovah's Witness. Gynakol Geburtshilfliche Rundsch 1995; 35:34-37.

(19.) Madura JA. Use of erythropoietin and parenteral iron dextran in a severely anemic Jehovah's Witness with colon cancer. Arch Surg 1993;128:1168-1170.

(20.) Hansen E, Bechmann V, Altmeppen J. Intraoperative blood salvage in cancer surgery: safe and effective? Transfus Apher Sci 2002; 27:153-157.

(21.) Ng T, Marx G, Littlewood T, Macdougall I. Recombinant erythropoietin in clinical practice. Postgrad Med Journal 2003; 79:367-376.

(22.) Casadevall N, Mayeux P Pure red-cell aplasia and recombinant erythropoietin. N Engl J Med 2002; 346:1585.

A. CHARLES *, M. PURTILL ([dagger]), L. M. NAPOLITANO ([double dagger])

Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, Michigan, United States

* M.D., F.R.C.S.I., Surgical Critical Care Fellow. ([dagger]) M.D., Surgical Critical Care Fellow. ([double dagger]) M.D., F.A.C.S., F.C.C.P, F.C.C.M., Professor of Surgery.

Address for reprints: Dr L. M. Napolitano, University of Michigan Health System, Room 1C421 University Hospital, Box 0033, 1500 E. Medical Center Drive, Ann Arbor, Mt 48109-0033, U.S.A.
TABLE 1
Daily 24 hour fluid balance in the first postoperative week

Post-op 0 1 2 3 4 5 6 7
day

Fluid +3.8 +2.7 +2.2 0 -1 +0.1 +1.4 +1.8
balance
(litres)

TABLE 2
Dosing and duration schedule for RHuEPO and iron administration

Post-op day 1-2 3-10 11-22

RHuEPO 20,000 units 40,000 units 20,000 units
 daily daily weekly

Iron IV 100 mg
 daily

Iron PO 300 mg t.i.d.
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Title Annotation:Case Reports
Author:Charles, A.; Purtill, M.; Napolitano, L.M.
Publication:Anaesthesia and Intensive Care
Date:Dec 1, 2006
Words:2395
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