498 Pressure Sore Anemia: Response to Erythropoietin Rose M. Turba, MD, Victor L. Lewis, MD, David Green, MD, PhD ABSTRACT. Turba RM, Lewis VL. Green D. Pressure sore anemia: Response to erythropoietin. Arch Phys Med Rehabil 1992;73: 498500. l Anemia in patients with grade IV pressure sores is usually refractory to therapy with iron salts, and red cell transfu- sions are commonly required when reconstructive surgery is performed. The anemia is characterized by bypoferremia, reticulocytopenia, and normal-to-increased serum ferritin. Five patients with this anemia were treated with recombinant human erythropoietin (rHuEP0) in doses of 50 to lOOU/kg, given subcutaneously three times per week. The hemoglo- bin increased in every patient: the mean (*SD) value at the initiation of treatment was 8.8 -t 1 .Og/dL, and after a median of 4 weeks of therapy, it was 12.4 k lbg/dL (p < .OOl). No adverse effects of treatment were observed. It is concluded that rHuEP0 is a promising new agent for pressure sore anemia, but randomized, controlled clinical trials will be required to firmly establish its place in the management of patients with this type of anemia. 0 1992 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation Anemia in patients with pressure sores is common, debili- tating, and refractory to the usual hematinic agents such as iron and folic acid.’ It is the anemia of chronic disease in that the serum iron and total iron-binding capacity are de- pressed. the serum ferritin is increased. and there is reticu- locytopenia.‘,3 Although patients with this anemia usually do not complain of fatigue or shortness of breath. probably because they are bedfast, they often require blood transfu- sions in preparation for reconstructive surgery or in the immediate postoperative period. Recently, recombinant human erythropoietin (rHuEP0) has become available for the treatment of anemia. Prelimi- nary reports of improvement in the anemia of chronic renal failure,4 acquired immunodeficiency syndrome,5 and rheu- matoid arthritis6 prompted us to explore the use of rHuEP0 in patients with pressure sores awaiting or recover- ing from reconstructive surgery. Our experience with five patients is summarized in this report. METHODS The subjects of this report were paraplegic or quadriple- gic patients admitted to our hospital and rehabilitation insti- tute for management of grade IV pressure sores, Patients had hemoglobin values of lOg/dL or less, hypoferremia, relative reticulocytopenia, decreased total iron-binding ca- pacity, and normal-to-increased serum ferritin levels (ta- From the Diwion ofPlasticand ReconstructivcSurge~. the DepxtmentsofPhysi- cal Medicine and Rehabditauon and Surgery. and the Division of Hematology/On- cology. the Department of Medicine. Northwcstcrn Memorial Hospital and the Reha- bditation Institute of Chicago. Submitted for publication Januar) XX. 1991. Accepted in rewed form June I I. 1991. No commercial party havmgadirect or indirect mterest in thesubject mattcrofthis article has conferred or will confer a hen&it on the authors or on any organization with which the authors are associated. Reprint requests to David Green. PhD. MD. 3-1 E Superior St. Room 1407. Chicago, IL 606 I I. C! 1992 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation 0003-9993/97/7306-0019$3.00/O ble). Erythropoietina was given in various doses, subcutane- ously and three times a week. The highest hemoglobin concentration observed after therapy (usually after 4 weeks of erythropoietin) was compared with the immediate pre- treatment value using paired-sample T-tests. with values less than .05 (two-tailed) considered significant. CASE REPORTS Case 1. A 77-year-old woman with T7 paraplegia of 1 I years’ duration was admitted for a left ischial flap reconstruction of a grade IV pressure sore. Admission hemoglobin was 8.6g/dL. with 2% reticulocytes. She was given 2U of packed red blood cells (RBC) intraoperatively, and her postoperative hemoglobin was 10.6g/dL. However, duringthe next month the hemoglobin gradu- ally declined to 8.8g/dL. with a reticulocyte count of 2% despite the daily administration of iron. Serum albumin was 2.7g/dL. Subcutaneous doses of 8.OOOUrHuEP0 were begun three times a week. After 4 weeks of treatment (fig 1). the hemoglobin was 1 1.7g/dL with 4.8% reticulocytes. The rHuEP0 was then de- creased to 4.OOOU weekly, and her hemoglobin remained in the normal range during 5 weeks of follow-up. Case 2. A 34-year-old man had C6 complete quadriplegia for 2 years. He was admitted for treatment of a large grade IV left trochanteric pressure sore. After surgical debridement. his hemo- globin decreased from 9.2g/dL to 7.4g/dL. with a reticulocyte count of only 0.3%. He was given 7U of packed RBCs. raising his hemoglobin to 10.6g/dL. His serum albumin was 2.9g/dL. Three days later he was started on rHuEP0 in a dose of8,OOOU subcuta- neously three times a week. During the next 2 months. his hcmo- globin increased to 15.3g/dL (fig I). with 4. I%, reticulocytcs; an extensive flap reconstruction was performed. The rHuEP0 was continued. the surgical site showed excellent healing, and he was discharged with a hemoglobin of 13.9g/dL. with a prescription to continue on rHuEP0 once a week. Case 3. A 48-year-old man had T8 complete paraplegia of I5 years’ duration. He was admitted with a grade IV left ischial pres- sure sore with underlying osteomyelitis. His serum albumin was 3.0g/dL. He was treated with antibiotics and underwent a flap reconstruction 9 days after entry. His preoperative hemoglobin was 8.?g/dL; 4U of RBCs were given perioperatively, increasing Arch Phys Med Rehabil Vol73, June 1992
Pressure Sore Anemia: Response to Erythropoietin
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PII: 0003-9993(92)90043-V498
Pressure Sore Anemia: Response to Erythropoietin Rose M. Turba, MD, Victor L. Lewis, MD, David Green, MD, PhD
ABSTRACT. Turba RM, Lewis VL. Green D. Pressure sore anemia: Response to erythropoietin. Arch Phys Med Rehabil 1992;73: 498500. l Anemia in patients with grade IV pressure sores is usually refractory to therapy with iron salts, and red cell transfu- sions are commonly required when reconstructive surgery is performed. The anemia is characterized by bypoferremia, reticulocytopenia, and normal-to-increased serum ferritin. Five patients with this anemia were treated with recombinant human erythropoietin (rHuEP0) in doses of 50 to lOOU/kg, given subcutaneously three times per week. The hemoglo- bin increased in every patient: the mean (*SD) value at the initiation of treatment was 8.8 -t 1 .Og/dL, and after a median of 4 weeks of therapy, it was 12.4 k lbg/dL (p < .OOl). No adverse effects of treatment were observed. It is concluded that rHuEP0 is a promising new agent for pressure sore anemia, but randomized, controlled clinical trials will be required to firmly establish its place in the management of patients with this type of anemia. 0 1992 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation
Anemia in patients with pressure sores is common, debili- tating, and refractory to the usual hematinic agents such as iron and folic acid.’ It is the anemia of chronic disease in that the serum iron and total iron-binding capacity are de- pressed. the serum ferritin is increased. and there is reticu- locytopenia.‘,3 Although patients with this anemia usually do not complain of fatigue or shortness of breath. probably because they are bedfast, they often require blood transfu- sions in preparation for reconstructive surgery or in the immediate postoperative period.
Recently, recombinant human erythropoietin (rHuEP0) has become available for the treatment of anemia. Prelimi- nary reports of improvement in the anemia of chronic renal failure,4 acquired immunodeficiency syndrome,5 and rheu- matoid arthritis6 prompted us to explore the use of rHuEP0 in patients with pressure sores awaiting or recover- ing from reconstructive surgery. Our experience with five patients is summarized in this report.
METHODS
The subjects of this report were paraplegic or quadriple- gic patients admitted to our hospital and rehabilitation insti- tute for management of grade IV pressure sores, Patients had hemoglobin values of lOg/dL or less, hypoferremia, relative reticulocytopenia, decreased total iron-binding ca- pacity, and normal-to-increased serum ferritin levels (ta-
From the Diwion ofPlasticand ReconstructivcSurge~. the DepxtmentsofPhysi-
cal Medicine and Rehabditauon and Surgery. and the Division of Hematology/On-
cology. the Department of Medicine. Northwcstcrn Memorial Hospital and the Reha-
bditation Institute of Chicago. Submitted for publication Januar) XX. 1991. Accepted in rewed form June I I.
1991.
No commercial party havmgadirect or indirect mterest in thesubject mattcrofthis
article has conferred or will confer a hen&it on the authors or on any organization
with which the authors are associated.
Reprint requests to David Green. PhD. MD. 3-1 E Superior St. Room 1407.
Chicago, IL 606 I I. C! 1992 by the American Congress of Rehabilitation Medicine and the American
Academy of Physical Medicine and Rehabilitation
0003-9993/97/7306-0019$3.00/O
ble). Erythropoietina was given in various doses, subcutane- ously and three times a week. The highest hemoglobin concentration observed after therapy (usually after 4 weeks of erythropoietin) was compared with the immediate pre- treatment value using paired-sample T-tests. with values less than .05 (two-tailed) considered significant.
CASE REPORTS
Case 1. A 77-year-old woman with T7 paraplegia of 1 I years’ duration was admitted for a left ischial flap reconstruction of a grade IV pressure sore. Admission hemoglobin was 8.6g/dL. with 2% reticulocytes. She was given 2U of packed red blood cells (RBC) intraoperatively, and her postoperative hemoglobin was 10.6g/dL. However, duringthe next month the hemoglobin gradu- ally declined to 8.8g/dL. with a reticulocyte count of 2% despite the daily administration of iron. Serum albumin was 2.7g/dL. Subcutaneous doses of 8.OOOU rHuEP0 were begun three times a week. After 4 weeks of treatment (fig 1). the hemoglobin was 1 1.7g/dL with 4.8% reticulocytes. The rHuEP0 was then de- creased to 4.OOOU weekly, and her hemoglobin remained in the normal range during 5 weeks of follow-up.
Case 2. A 34-year-old man had C6 complete quadriplegia for 2 years. He was admitted for treatment of a large grade IV left trochanteric pressure sore. After surgical debridement. his hemo- globin decreased from 9.2g/dL to 7.4g/dL. with a reticulocyte count of only 0.3%. He was given 7U of packed RBCs. raising his hemoglobin to 10.6g/dL. His serum albumin was 2.9g/dL. Three days later he was started on rHuEP0 in a dose of8,OOOU subcuta- neously three times a week. During the next 2 months. his hcmo- globin increased to 15.3g/dL (fig I). with 4. I%, reticulocytcs; an extensive flap reconstruction was performed. The rHuEP0 was continued. the surgical site showed excellent healing, and he was discharged with a hemoglobin of 13.9g/dL. with a prescription to continue on rHuEP0 once a week.
Case 3. A 48-year-old man had T8 complete paraplegia of I5 years’ duration. He was admitted with a grade IV left ischial pres- sure sore with underlying osteomyelitis. His serum albumin was 3.0g/dL. He was treated with antibiotics and underwent a flap reconstruction 9 days after entry. His preoperative hemoglobin was 8.?g/dL; 4U of RBCs were given perioperatively, increasing
Arch Phys Med Rehabil Vol73, June 1992
ERYTHROPOIETIN FOR PRESSURE SORE ANEMIA, Turba
Patient
Baseline Characteristics of the Anemia in the Five Patients With Pressure Sores -.____
Hb (g/dl,)/Hematocrit Reticulucyte Serum Iron TIBC (%I (%I wg/mL crg/mL
Ferritin
nfz/mL
0.3 17 I IO IO08 1 .o 28 045
4 8.3/25.2 ‘.I 38 167 550 5 8. 1126.1 1.5 18 132
Normal Range I4.0- I8.0/40-54 O.I-I.0 40- 170 100-400 70-300
Ahhreviation: TIBC‘. total iron binding capacity.
the hemoglobin to 9.5g/dL, postoperatively. During the following month. the wound opened and required additional surgery. Preop- erative hemoglobin was 8.4g/dL. with reticulocytes of I’%. Once again. 4U of RBCs were needed. To stabilize his hemoglobin, rHuEP0 therapy was begun on the first postoperative day in a dose of 8,000U three times a week. His reticulocyte count rose to 2.5% and during a I-month period. the hemoglobin increased to I I .Sg/dL (fig 2), and the surgical wound healed uneventfully.
Case 4. A 27-year-old woman with a 4-year history of T12 complete paraplegia was admitted after falling and fracturing her left femur. She was found to have a grade IV sacral pressure sore and a hemoglobin of 8.8g/dL. Open reduction and internal fixa- tion of the fracture were performed; 5U of RBCs were given perio- peratively. During the month after surgery, her albumin was 3.3g/ dL. and the hemoglobin gradually declined to 8.3g/dL; 1U of RBCs was given before sacral flap reconstruction. Her postopera- tive hemoglobin was 9.2g/dL. A dose of 5,OOOU rHuEP0 was initiated subcutaneously three times a week. During the next 3 weeks, the hemoglobin increased to I lg/dL (tig 2). and the rHuEP0 was decreased to 5,000U weekly. On discharge. her he- moglobin was 12.4g/dL.
Case 5. A 32-year-old man, with TlO paraplegia for IO years, was admitted because of fever and a grade IV left ischial pressure sore. His admission albumin was 2.8g/dL and hemoglobin was 8,4g/dL. He had been treated in the past with ferrous sulfate but was noncompliant in taking this medication, and. therefore, he was begun on iron dextran complex. 2mL intramuscularly and daily. After completion of a 20-day course oftherapy, his hemoglo- bin was unchanged at 8.1 g/dL. and the reticulocyte count was only 1.5%. Doses of rHuEP0 were started at 4,OOOU three times a week. Four days later he underwent debridement and flap recon- struction: 4U of packed RBCs were required intraoperatively. Ten
Hemoglobin 16. ~~----
-6 -4 -2 0 4 6 8
1
10
Fig I-Hemoglobin response of patients 1 and 2 to rHuEP0, begun at week 0. Patient 1 (+ ); patient 2 ( +).
days after starting rHuEP0, the hemoglobin was 8.7g/dL and the reticulocyte count was 2.9%. The rHuEP0 dose was increased to 1 O.OOOU three times a week, and the hemoglobin rose to IO.4g/dL (fig 2). No further transfusions were required, and the surgical flap healed uneventfully.
In summary, all patients had an increase in hemoglobin concen- tration, with values rising from 8.8 -t 1 .Og/dL pretherapy to 12.4 + 1.6g/dL (p < .OO I ) after a median of 4 weeks of treatment. The rHuEP0 was well tolerated. and no adverse effects were observed in any patient.
DISCUSSION
The five patients described in this report had a number of features in common; hemoglobin on admission ranged from 8.2g/dL to 10.1 g/dL, and they had relative reticulocy- topenia, hypoferremia, decreased total iron-binding capac- ity, and normal-to-increased serum ferritin (table). These are characteristics that define the anemia of chronic dis- ease.2.3 In addition, they all required transfusions in the perioperative period. Because they remained anemic after reconstructive surgery, treatment with rHuEP0 was initi- ated.
All patients responded to this treatment with improve- ment in hemoglobin concentration and there were no fur- ther transfusions, even though some patients required addi- tional surgery. Although iron supplementation has been recommended for some patients receiving erythropoietin therapy, it was not given to patients I, 7, 3, and 4 because their ferritin levels were more than SOOng/mL, and patient
hemoglobin (G/dl) 14 /pp- ~----
I
Fig 2-Hemoglobin response of patients 3, 4, and 5 to rHuEP0, begun at week 0. Patient 3 (+); patient 4 ( -t ); and patient 5
( A 1.
Arch Phys Med Rehabil Vol73, May 1992
500 ERYTHROPOIETIN FOR PRESSURE SORE ANEMIA, Turba
5 had just received a course of iron dextran. None of the patients developed signs or symptoms of iron deficiency after erythropoietin treatment.
Why does the anemia of chronic disease respond to rHuEP0 therapy? Studies in animals who were made ane- mic by infliction of turpentine abscesses showed that eryth- ropoietin levels were lower than in iron-deficient animals who had a comparable degree of anemia.’ The erythropoie- tin response to hypoxia has also been shown to be less in animals with chronic inflammation than in control ani- mals.8
It is also possible that the bone marrow in subjects with chronic disease may be less responsive to erythropoietin.’ Administration of exogenous erythropoietin may raise lev- els of the hormone enough to overcome resistence of the marrow erythroid precursors. Whatever the mechanism, it is clear from studies of various populations with chronic disease that erythropoietin improves hemoglobin concen- trations in many patients.
The ability to pharmacologically increase hemoglobin in patients with pressure sores has obvious benefits. First, by avoiding transfusion, patients are spared exposure to blood- borne infectious diseases, as well as transfusion reactions and sensitization to foreign antigens. Second, by increasing hemoglobin and oxygen delivery to the tissues,” the healing of pressure sores may be improved. Third, energy level and mental status may be enhanced: this has been reported in patients with chronic renal failure who were treated with rHuEP0.l’ Finally, increased exercise tolerance enables greater participation in rehabilitation programs.
The adverse effects of rHuEP0 include an increase in blood pressure, shunt occlusion, and seizuresI but these generally occur in patients with preexisting hypertension and renal failure. Other side effects, such as myalgias and headache, are mild, rarely limit therapy, and were not ob- served in any of our patients. The current major problem with the use of rHuEP0 is the high cost of treatment. The efforts made by consumers, physicians, government, and third-party payers may be effective in making this new ther- apeutic agent more affordable. In view of the many poten- tial advantages of rHuEP0, randomized controlled trials to rigorously assess its cost-benefit ratio are clearly warranted.
CONCLUSION
In the preliminary studies described in this report, rHuEP0 seemed to be a safe and effective method for the treatment of anemia associated with pressure sores.
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References Esparaz B, Green D. Anemia in the chronically disabled. In: Green D. ed. Medical management of long-term disability, Rockville. MD: Aspen 1990;~~ 197-206. Cash JM, Sears DA. The anemia of chronic disease: Spectrum of associated diseases in a series of unselected hospitalized patients. Am J Med 1989;87:638-44. Lee GR. The anemia of chronic disease. Semin Hematol 1983;20:6 I-80. Watson AJ, Gimenez LF, Cotton S. Walser M. Spivak JL. Treatment ofthe anemia ofchronic renal failure with subcuta- neous recombinant human erythropoietin. Am J Med 1990; 89:432-S. Fischl M, Galpin JE, Levine JD, et al. Recombinant human erythropoietin for patients with AIDS treated with zidovu- dine. N Engl J Med 1990;322: 1488-93. Pincus T. Olsen NJ, Russell IJ, et al. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med 1990;89: 16 1-8. Zucker S. Lysik R. Bone marrow erythropoiesis in anemia of inflammation. J Lab Clin Med 1974;84:620-3 I. Lukens JN. Control oferythropoiesis in rats with adjuvant-in- duced chronic inflammation. Blood 1973;4 1:37-44. Erslev AJ. Wilson J, Caro J. Erythropoietin titers in anemic, nonuremic patients. J Lab Clin Med 1987:109:429-33. Robertson HT, Haley NR, Guthrie M, et al. Recombinant erythropoietin improves exercise capacity in anemic hemodi- alysis patients. Am J Kidney Dis 1990; 15:325-32. Wolcott DL. Marsh JT, La Rue A, Carr C. Nissenson AR. Recombinant human erythropoietin treatment may improve quality of life and cognitive function in chronic hemodialysis patients. Am J Kidney Dis 1989; 14:478-85. Eschbach JW. Abdulhadi MH. Browne JK, et al. Recombi- nant human erythropoietin in anemic patients with end-stage renal disease. Ann Intern Med 1989; I 11:992- 1000.
Supplier Epogen, Amgen Inc.. Amgen Center, Thousand Oaks. CA 91320-1789.
Arch Phys Med Rehabil Vol73, June 1992
Pressure Sore Anemia: Response to Erythropoietin Rose M. Turba, MD, Victor L. Lewis, MD, David Green, MD, PhD
ABSTRACT. Turba RM, Lewis VL. Green D. Pressure sore anemia: Response to erythropoietin. Arch Phys Med Rehabil 1992;73: 498500. l Anemia in patients with grade IV pressure sores is usually refractory to therapy with iron salts, and red cell transfu- sions are commonly required when reconstructive surgery is performed. The anemia is characterized by bypoferremia, reticulocytopenia, and normal-to-increased serum ferritin. Five patients with this anemia were treated with recombinant human erythropoietin (rHuEP0) in doses of 50 to lOOU/kg, given subcutaneously three times per week. The hemoglo- bin increased in every patient: the mean (*SD) value at the initiation of treatment was 8.8 -t 1 .Og/dL, and after a median of 4 weeks of therapy, it was 12.4 k lbg/dL (p < .OOl). No adverse effects of treatment were observed. It is concluded that rHuEP0 is a promising new agent for pressure sore anemia, but randomized, controlled clinical trials will be required to firmly establish its place in the management of patients with this type of anemia. 0 1992 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation
Anemia in patients with pressure sores is common, debili- tating, and refractory to the usual hematinic agents such as iron and folic acid.’ It is the anemia of chronic disease in that the serum iron and total iron-binding capacity are de- pressed. the serum ferritin is increased. and there is reticu- locytopenia.‘,3 Although patients with this anemia usually do not complain of fatigue or shortness of breath. probably because they are bedfast, they often require blood transfu- sions in preparation for reconstructive surgery or in the immediate postoperative period.
Recently, recombinant human erythropoietin (rHuEP0) has become available for the treatment of anemia. Prelimi- nary reports of improvement in the anemia of chronic renal failure,4 acquired immunodeficiency syndrome,5 and rheu- matoid arthritis6 prompted us to explore the use of rHuEP0 in patients with pressure sores awaiting or recover- ing from reconstructive surgery. Our experience with five patients is summarized in this report.
METHODS
The subjects of this report were paraplegic or quadriple- gic patients admitted to our hospital and rehabilitation insti- tute for management of grade IV pressure sores, Patients had hemoglobin values of lOg/dL or less, hypoferremia, relative reticulocytopenia, decreased total iron-binding ca- pacity, and normal-to-increased serum ferritin levels (ta-
From the Diwion ofPlasticand ReconstructivcSurge~. the DepxtmentsofPhysi-
cal Medicine and Rehabditauon and Surgery. and the Division of Hematology/On-
cology. the Department of Medicine. Northwcstcrn Memorial Hospital and the Reha-
bditation Institute of Chicago. Submitted for publication Januar) XX. 1991. Accepted in rewed form June I I.
1991.
No commercial party havmgadirect or indirect mterest in thesubject mattcrofthis
article has conferred or will confer a hen&it on the authors or on any organization
with which the authors are associated.
Reprint requests to David Green. PhD. MD. 3-1 E Superior St. Room 1407.
Chicago, IL 606 I I. C! 1992 by the American Congress of Rehabilitation Medicine and the American
Academy of Physical Medicine and Rehabilitation
0003-9993/97/7306-0019$3.00/O
ble). Erythropoietina was given in various doses, subcutane- ously and three times a week. The highest hemoglobin concentration observed after therapy (usually after 4 weeks of erythropoietin) was compared with the immediate pre- treatment value using paired-sample T-tests. with values less than .05 (two-tailed) considered significant.
CASE REPORTS
Case 1. A 77-year-old woman with T7 paraplegia of 1 I years’ duration was admitted for a left ischial flap reconstruction of a grade IV pressure sore. Admission hemoglobin was 8.6g/dL. with 2% reticulocytes. She was given 2U of packed red blood cells (RBC) intraoperatively, and her postoperative hemoglobin was 10.6g/dL. However, duringthe next month the hemoglobin gradu- ally declined to 8.8g/dL. with a reticulocyte count of 2% despite the daily administration of iron. Serum albumin was 2.7g/dL. Subcutaneous doses of 8.OOOU rHuEP0 were begun three times a week. After 4 weeks of treatment (fig 1). the hemoglobin was 1 1.7g/dL with 4.8% reticulocytes. The rHuEP0 was then de- creased to 4.OOOU weekly, and her hemoglobin remained in the normal range during 5 weeks of follow-up.
Case 2. A 34-year-old man had C6 complete quadriplegia for 2 years. He was admitted for treatment of a large grade IV left trochanteric pressure sore. After surgical debridement. his hemo- globin decreased from 9.2g/dL to 7.4g/dL. with a reticulocyte count of only 0.3%. He was given 7U of packed RBCs. raising his hemoglobin to 10.6g/dL. His serum albumin was 2.9g/dL. Three days later he was started on rHuEP0 in a dose of8,OOOU subcuta- neously three times a week. During the next 2 months. his hcmo- globin increased to 15.3g/dL (fig I). with 4. I%, reticulocytcs; an extensive flap reconstruction was performed. The rHuEP0 was continued. the surgical site showed excellent healing, and he was discharged with a hemoglobin of 13.9g/dL. with a prescription to continue on rHuEP0 once a week.
Case 3. A 48-year-old man had T8 complete paraplegia of I5 years’ duration. He was admitted with a grade IV left ischial pres- sure sore with underlying osteomyelitis. His serum albumin was 3.0g/dL. He was treated with antibiotics and underwent a flap reconstruction 9 days after entry. His preoperative hemoglobin was 8.?g/dL; 4U of RBCs were given perioperatively, increasing
Arch Phys Med Rehabil Vol73, June 1992
ERYTHROPOIETIN FOR PRESSURE SORE ANEMIA, Turba
Patient
Baseline Characteristics of the Anemia in the Five Patients With Pressure Sores -.____
Hb (g/dl,)/Hematocrit Reticulucyte Serum Iron TIBC (%I (%I wg/mL crg/mL
Ferritin
nfz/mL
0.3 17 I IO IO08 1 .o 28 045
4 8.3/25.2 ‘.I 38 167 550 5 8. 1126.1 1.5 18 132
Normal Range I4.0- I8.0/40-54 O.I-I.0 40- 170 100-400 70-300
Ahhreviation: TIBC‘. total iron binding capacity.
the hemoglobin to 9.5g/dL, postoperatively. During the following month. the wound opened and required additional surgery. Preop- erative hemoglobin was 8.4g/dL. with reticulocytes of I’%. Once again. 4U of RBCs were needed. To stabilize his hemoglobin, rHuEP0 therapy was begun on the first postoperative day in a dose of 8,000U three times a week. His reticulocyte count rose to 2.5% and during a I-month period. the hemoglobin increased to I I .Sg/dL (fig 2), and the surgical wound healed uneventfully.
Case 4. A 27-year-old woman with a 4-year history of T12 complete paraplegia was admitted after falling and fracturing her left femur. She was found to have a grade IV sacral pressure sore and a hemoglobin of 8.8g/dL. Open reduction and internal fixa- tion of the fracture were performed; 5U of RBCs were given perio- peratively. During the month after surgery, her albumin was 3.3g/ dL. and the hemoglobin gradually declined to 8.3g/dL; 1U of RBCs was given before sacral flap reconstruction. Her postopera- tive hemoglobin was 9.2g/dL. A dose of 5,OOOU rHuEP0 was initiated subcutaneously three times a week. During the next 3 weeks, the hemoglobin increased to I lg/dL (tig 2). and the rHuEP0 was decreased to 5,000U weekly. On discharge. her he- moglobin was 12.4g/dL.
Case 5. A 32-year-old man, with TlO paraplegia for IO years, was admitted because of fever and a grade IV left ischial pressure sore. His admission albumin was 2.8g/dL and hemoglobin was 8,4g/dL. He had been treated in the past with ferrous sulfate but was noncompliant in taking this medication, and. therefore, he was begun on iron dextran complex. 2mL intramuscularly and daily. After completion of a 20-day course oftherapy, his hemoglo- bin was unchanged at 8.1 g/dL. and the reticulocyte count was only 1.5%. Doses of rHuEP0 were started at 4,OOOU three times a week. Four days later he underwent debridement and flap recon- struction: 4U of packed RBCs were required intraoperatively. Ten
Hemoglobin 16. ~~----
-6 -4 -2 0 4 6 8
1
10
Fig I-Hemoglobin response of patients 1 and 2 to rHuEP0, begun at week 0. Patient 1 (+ ); patient 2 ( +).
days after starting rHuEP0, the hemoglobin was 8.7g/dL and the reticulocyte count was 2.9%. The rHuEP0 dose was increased to 1 O.OOOU three times a week, and the hemoglobin rose to IO.4g/dL (fig 2). No further transfusions were required, and the surgical flap healed uneventfully.
In summary, all patients had an increase in hemoglobin concen- tration, with values rising from 8.8 -t 1 .Og/dL pretherapy to 12.4 + 1.6g/dL (p < .OO I ) after a median of 4 weeks of treatment. The rHuEP0 was well tolerated. and no adverse effects were observed in any patient.
DISCUSSION
The five patients described in this report had a number of features in common; hemoglobin on admission ranged from 8.2g/dL to 10.1 g/dL, and they had relative reticulocy- topenia, hypoferremia, decreased total iron-binding capac- ity, and normal-to-increased serum ferritin (table). These are characteristics that define the anemia of chronic dis- ease.2.3 In addition, they all required transfusions in the perioperative period. Because they remained anemic after reconstructive surgery, treatment with rHuEP0 was initi- ated.
All patients responded to this treatment with improve- ment in hemoglobin concentration and there were no fur- ther transfusions, even though some patients required addi- tional surgery. Although iron supplementation has been recommended for some patients receiving erythropoietin therapy, it was not given to patients I, 7, 3, and 4 because their ferritin levels were more than SOOng/mL, and patient
hemoglobin (G/dl) 14 /pp- ~----
I
Fig 2-Hemoglobin response of patients 3, 4, and 5 to rHuEP0, begun at week 0. Patient 3 (+); patient 4 ( -t ); and patient 5
( A 1.
Arch Phys Med Rehabil Vol73, May 1992
500 ERYTHROPOIETIN FOR PRESSURE SORE ANEMIA, Turba
5 had just received a course of iron dextran. None of the patients developed signs or symptoms of iron deficiency after erythropoietin treatment.
Why does the anemia of chronic disease respond to rHuEP0 therapy? Studies in animals who were made ane- mic by infliction of turpentine abscesses showed that eryth- ropoietin levels were lower than in iron-deficient animals who had a comparable degree of anemia.’ The erythropoie- tin response to hypoxia has also been shown to be less in animals with chronic inflammation than in control ani- mals.8
It is also possible that the bone marrow in subjects with chronic disease may be less responsive to erythropoietin.’ Administration of exogenous erythropoietin may raise lev- els of the hormone enough to overcome resistence of the marrow erythroid precursors. Whatever the mechanism, it is clear from studies of various populations with chronic disease that erythropoietin improves hemoglobin concen- trations in many patients.
The ability to pharmacologically increase hemoglobin in patients with pressure sores has obvious benefits. First, by avoiding transfusion, patients are spared exposure to blood- borne infectious diseases, as well as transfusion reactions and sensitization to foreign antigens. Second, by increasing hemoglobin and oxygen delivery to the tissues,” the healing of pressure sores may be improved. Third, energy level and mental status may be enhanced: this has been reported in patients with chronic renal failure who were treated with rHuEP0.l’ Finally, increased exercise tolerance enables greater participation in rehabilitation programs.
The adverse effects of rHuEP0 include an increase in blood pressure, shunt occlusion, and seizuresI but these generally occur in patients with preexisting hypertension and renal failure. Other side effects, such as myalgias and headache, are mild, rarely limit therapy, and were not ob- served in any of our patients. The current major problem with the use of rHuEP0 is the high cost of treatment. The efforts made by consumers, physicians, government, and third-party payers may be effective in making this new ther- apeutic agent more affordable. In view of the many poten- tial advantages of rHuEP0, randomized controlled trials to rigorously assess its cost-benefit ratio are clearly warranted.
CONCLUSION
In the preliminary studies described in this report, rHuEP0 seemed to be a safe and effective method for the treatment of anemia associated with pressure sores.
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References Esparaz B, Green D. Anemia in the chronically disabled. In: Green D. ed. Medical management of long-term disability, Rockville. MD: Aspen 1990;~~ 197-206. Cash JM, Sears DA. The anemia of chronic disease: Spectrum of associated diseases in a series of unselected hospitalized patients. Am J Med 1989;87:638-44. Lee GR. The anemia of chronic disease. Semin Hematol 1983;20:6 I-80. Watson AJ, Gimenez LF, Cotton S. Walser M. Spivak JL. Treatment ofthe anemia ofchronic renal failure with subcuta- neous recombinant human erythropoietin. Am J Med 1990; 89:432-S. Fischl M, Galpin JE, Levine JD, et al. Recombinant human erythropoietin for patients with AIDS treated with zidovu- dine. N Engl J Med 1990;322: 1488-93. Pincus T. Olsen NJ, Russell IJ, et al. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med 1990;89: 16 1-8. Zucker S. Lysik R. Bone marrow erythropoiesis in anemia of inflammation. J Lab Clin Med 1974;84:620-3 I. Lukens JN. Control oferythropoiesis in rats with adjuvant-in- duced chronic inflammation. Blood 1973;4 1:37-44. Erslev AJ. Wilson J, Caro J. Erythropoietin titers in anemic, nonuremic patients. J Lab Clin Med 1987:109:429-33. Robertson HT, Haley NR, Guthrie M, et al. Recombinant erythropoietin improves exercise capacity in anemic hemodi- alysis patients. Am J Kidney Dis 1990; 15:325-32. Wolcott DL. Marsh JT, La Rue A, Carr C. Nissenson AR. Recombinant human erythropoietin treatment may improve quality of life and cognitive function in chronic hemodialysis patients. Am J Kidney Dis 1989; 14:478-85. Eschbach JW. Abdulhadi MH. Browne JK, et al. Recombi- nant human erythropoietin in anemic patients with end-stage renal disease. Ann Intern Med 1989; I 11:992- 1000.
Supplier Epogen, Amgen Inc.. Amgen Center, Thousand Oaks. CA 91320-1789.
Arch Phys Med Rehabil Vol73, June 1992
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