Price, Susanna MBBS, MRCP, PhD; Pepper, John R. MChir, FRCS; Jaggar, Siân I. MBBS, FRCA, MD
Departments of Anesthesia and Critical Care and Cardiothoracic Surgery, Royal Brompton Hospital, London, UK
Dr. Price is the British Heart Foundation Jill Dando Fellow in Adult Heart Disease.
Accepted for publication January 25, 2005.
Address correspondence and reprint requests to Siân Jaggar, MBBS, FRCA, MD, Royal Brompton Hospital, Sydney Street, London SW3 6NP. Address e-mail to email@example.com.
Complex cardiac surgery often requires blood transfusion. Some patients refuse transfusion, even when it is potentially life-threatening to do so. Although recombinant human erythropoietin (rhEPO) has been used to reduce the need for blood transfusion, it has been considered ineffective in critically ill patients. The time course of hematological responses in a Jehovah’s Witness patient with acute renal failure and severe cardiac disease suggests that a trial of rhEPO should be considered for salvage therapy in critically ill patients.
Complex cardiac surgery often requires blood transfusion that Jehovah’s Witness patients often refuse, even when it can be lifesaving. Although recombinant human erythropoietin (rhEPO) has been used to reduce postoperative transfusion, its effectiveness is uncertain in the critically ill. We describe successful treatment of life-threatening anemia using rhEPO in a critically ill patient with an absolute contraindication to transfusion.
A 62-year-old female Jehovah’s Witness underwent aortic valve and aortic root replacement. Her preoperative left ventricular function was severely impaired and she had been previously declined surgery in two cardiac centers. She signed an advance directive refusing transfusion under any circumstances. Preoperative treatment with rhEPO (24,000 IU 3×/wk) resulted in hemoglobin (Hb) 14.6g/dL (Fig. 1).
Surgery was uneventful, with minimal blood loss. She was extubated and transferred to the ward the following day (Hb 11.7 g/dL) on continuing iron supplementation. The subsequent 4 days fluid balance was +175 mL/day (insensible losses). She was readmitted to the intensive care unit (ICU) obtunded, hypotensive, and anuric with atrial fibrillation and pulmonary edema. Laboratory data demonstrated marked lactic acidosis, Hb 7.6 g/dL (no evidence of bleeding/hemolysis), and creatinine 400 μmol/L. Mechanical ventilation, milrinone (0.7 μg · kg−1 · min−1), norepinephrine (0.02 μg · kg−1 · min−1), and antibiotics were commenced. Continuous venovenous hemodiafiltration (CVVHDF) for worsening acidosis/oliguria necessitated anticoagulation (activated partial thromboplastin time, 35–45). rhEPO was recommenced (24,000IU 3×/wk), iron supplementation was continued, and blood sampling was minimized. During CVVHDF fluid balance was +263 mL/day (insensible losses). Despite this, Hb decreased (4.2 g/dL). Therefore, rhEPO was increased (38,000 IU/day) together with iron sucrose (100 mg 3×/wk), hydroxycobalamin (1 mg 3×/wk), and folic acid (5 mg daily). Subsequently, Hb increased (10.1 g/dL) and polyuria developed (fluid balance −142 mL/day, 3% blood volume), allowing discontinuation of rhEPO/CVVHDF and discharge from ICU 11 days later.
A fall during mobilization resulted in a hematoma (8 × 5 cm, adductor magnus) requiring surgery. The reduction in Hb (3.6 g/dL) was treated with large-dose rhEPO. She was discharged 3 mo after initial surgery and remains well 15 mo later.
Despite various strategies, many patients undergoing cardiac surgery require transfusion (1). rhEPO has been used preoperatively to increase hematocrit and reduce transfusion (2) and accelerate recovery in hematocrit of routine postoperative patients (3). Although treatment reduces transfusion requirements, cost-effectiveness remains unclear (4–6).
Acute renal failure (ARF) requiring hemofiltration occurs in 1%–5% of cardiac surgery patients (7), requiring anticoagulation, recurrent blood sampling, and potential for blood loss when changing filters. In critically ill patients, both ARF and its management may result in major alterations in fluid balance, together with hemolysis. Seventy percent of the decline in Hb during ICU admission (inexplicable by acute blood loss) is unexplained by iatrogenic phlebotomy (8). Although patients with systemic inflammatory response syndrome may not exhibit laboratory or clinical signs of hemolysis, premature destruction of erythrocytes occurs (8,9), possibly accounting for the disproportionate decrease in Hb after surgery in this case.
The use of rhEPO in chronic renal failure is established (10), although its use in ARF remains controversial. Erythropoietic balance in critical illness is poorly understood. Although animal studies have suggested that EPO is potentially beneficial, human studies in critically ill patients demonstrate elevated levels of endogenous EPO (suggesting exogenous treatment may be ineffective) (11,12). However, in such patients there is reduced production/survival of erythrocytes, and decreased iron availability for erythropoiesis despite adequate (or supra-normal) iron stores (13). Thus, despite endogenous EPO increase, the reticulocyte response is blunted. The situation is complicated by inflammatory/antiinflammatory cytokines, each affecting erythropoiesis (including bone marrow suppression, decreased iron availability, and reduced EPO production). Moreover, in critically ill patients iron is sequestered by macrophages, reducing availability for erythropoiesis (13). Therefore, iron or EPO administered alone may be ineffective (14) and the magnitude of response may be unpredictable (15).
When exogenous EPO has been used in critically ill patients, the complex interactions described result in variable delays to increases in EPO/Hb levels (2–6 wks) and reticulocyte count (7–21 days). Attributing a precise temporal relationship to any treatment in this scenario is impossible. In the case described, there were no transfusion/major fluid balance changes. It is therefore difficult to explain the increase in Hb (4.2 to 10.1 g/dL) other than by increased erythropoiesis. Although the reticulocyte levels (>2%) indicated active erythropoiesis, Hb levels continued to decrease, suggesting relatively inadequate reticulocytosis. In healthy volunteers EPO showed a dose-response between 500 IU/kg and 1000 IU/kg (16). The 444 IU/kg dose administered to this patient resides to the left of the dose-response curve, and increasing the dose to 700 IU/kg would be predicted to elicit greater effect.
Despite theoretical concerns regarding efficacy of rhEPO in the critically ill, some studies report its use in the ICU (8,9,12,13,17). However, many have excluded severely ill patients and those with ARF or cardiac disease, and used either reticulocyte count or time to transfusion as the primary end-point. The case presented here differs in that the patient had ARF and severe cardiac disease, there was no possibility of transfusion, and the doses of rhEPO used were larger than in many published studies. Our intention is to alert ICU physicians to a potential salvage treatment when transfusion is contraindicated.
We would like to thank Dr. J. Burman, Dr. S. Davidson and the ICU staff at the Royal Brompton Hospital for their help in the management of this patient.
1. Cross MH. Autotransfusion in cardiac surgery. Perfusion 2001;16:391–400.
2. Yazicioglu L, Eryilmaz S, Sirlak M, et al. Recombinant human erythropoietin administration in cardiac surgery. J Thorac Cardiovasc Surg 2001;122:741–5.
3. Atabek U, Alvarez R, Pello MJ, et al. Erythropoietin accelerates hematocrit recovery in post-surgical anemia. Am Surg 1995;61:74–7.
4. Coyle D, Lee KM, Fergusson DA, Laupacis A. Cost effectiveness of epoetin-alpha to augment preoperative autologous blood donation in elective cardiac surgery. Pharmacoeconomics 2000;18:161–71.
5. Hardy JF. Pharmacological strategies for blood conservation in cardiac surgery: Erythropoietin and antifibrinolytics. Can J Anaesth 2001;48:S24–31.
6. Laupacis A, Fergusson D. Erythropoietin to minimize perioperative blood transfusion: A systematic review of randomized trials. The International Study of Peri-operative Transfusion (ISPOT) Investigators. Transfus Med 1998;8:309–17.
7. Conlon PJ, Stafford-Smith M, White WD, et al. Acute renal failure following cardiac surgery. Nephrol Dial Transplant 1999;14:1158–62.
8. von Ahsen N, Muller C, Serke S, et al. Important role of non-diagnostic blood loss and blunted erythropoietic response in the anemia of medical intensive care patients. Crit Care Med 1999;27:2630–9.
9. Eckardt K. Anaemia of critical illness: Implications for understanding and treating rHuEPO resistance Nephro Dial Transplant 2002;17:48–55.
10. Santoro A. Anemia in renal insufficiency. Rev Clin Exp Hematol. 2002;Suppl 1:12–20.
11. Nemoto T, Yokota N, Keane WF, Rabb H. Recombinant erythropoietin rapidly treats anemia in ischemic acute renal failure. Kidney Int 2001;59:246–51.
12. Elliot JM, Virankabutra T, Jones S, et al. Erythropoietin mimics the acute phase response in critical illness. Crit Care 2003;7:R35–40.
13. Scharte M, Fink MP. Red blood cell physiology in critical illness. Crit Care Med 2003;31:S651–7.
14. Major A, Mathez-Loic F, Rohling R, et al. The effect of intravenous iron on the reticulocyte response to recombinant human erythropoietin. Br J Haematol 1997;98:292–4.
15. Danielson B. R-HuEPO hyporesponsiveness: Who and why? Nephrol Dial Transplant. 1995;10 Suppl 2:69–73.
16. Flaharty KK, Caro J, Earsley A, et al. Pharmacokinetics and erythropoietin response to human recombinant erythropoietin in healthy men. Clin Parmacol Ther 1990;47:557–64.
17. Corwin HL, Gettinger A, Pearl RG et al. Efficacy of recombinant human erythropoietin in critically ill patients: A randomized controlled trial. JAMA 2002;288:2827–35.