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Treatment of Chronic Skin Ulcers in Individuals with Anemia of Chronic Disease Using Recombinant Human Erythropoietin (EPO): A Review of Four Cases
Chronic skin ulcers result in significant economic costs to the healthcare system and negatively impact the quality of life of those individuals who live with skin breakdown. Recent literature suggests that many chronic wounds persist because of inflammatory processes that alter the wound environment.
Analysis of wound fluid taken from healing and chronic wounds revealed that chronic wounds have elevated levels of inflammatory mediators and degradative enzymes that interfere with the healing process.1 Healing wounds are characterized by high mitogenic potential, rapid cellular migration, balanced inflammatory cytokines, low proteases, and good cellular response to growth factors. Chronic wounds, however, are characterized by poor mitogenic potential and cell migration, high proteases and inflammatory cytokines, and senescent cells unresponsive to growth factors.2
Chronic skin ulcers experienced by patients who have low concentrations of circulating hemoglobin (<100 g/L) may be difficult to heal because of impairment in tissue oxygenation. Various types of anemias have differing underlying causes, including nutrient deficiencies (eg, iron deficiency anemia) and anemia as the result of chronic disease. Iron deficiency anemia results from inadequate intake, absorption, or utilization of iron and/or acute or chronic blood loss3,4 and is characterized by low hemoglobin and other hematological changes with microcytic, hypochromic red blood cells. Levels of stored iron, as indicated by low serum ferritin values, are low.
Anemia of chronic disease (ACD) is characterized by low hemoglobin concentrations and other hematological changes with normocytic, normochromic red blood cells. In ACD, red blood cell production is impaired and red blood cell life span may be shortened. Anemia of chronic disease is also characterized by a normal or elevated serum ferritin level. Generally, ACD is not an iron-deficiency anemia and is refractory to an iron-enhanced diet, iron replacement therapy (either oral or intravenous), and transfusion. In fact, iron supplementation and transfusion are generally contraindicated in ACD because of the risk of iatrogenic hemochromatosis. Anemia of chronic disease occurs in individuals with a chronic inflammatory process such as arthritis, chronic renal failure, or chronic skin ulcers. It is thought to be the result of impaired responsiveness of erythroid progenitor cells due to persistent elevated levels of circulating inflammatory cytokines that are known to occur in patients with chronic inflammatory conditions such as rheumatoid arthritis. Anemia of chronic disease may be associated with chronic skin ulcers.5
The hormone erythropoietin (EPO) plays a crucial role in the regulation of hematopoiesis and induces the proliferation, maturation, and differentiation of erythroid (red blood cell) precursors. It has a direct hemodynamic and vasoactive effect. Erythropoietin therapy can correct the anemia of chronic disease, but it cannot correct the anemia due to iron deficiency. Erythropoietin enhances cell phagocytosis and reduces macrophage activation; therefore, modulating the inflammatory process. The anti-inflammatory effects of EPO may be able to reverse the chronic inflammatory condition believed to underlie chronic skin ulcers. By interfering with the chronic inflammatory process, EPO may help reduce inflammatory cytokines and degradative enzymes that interfere with many wound healing processes and limit new tissue growth. Erythropoietin’s effects on the wound healing process include not only restoring the normal wound environment but also (recently found) interacting with vascular endothelial growth factor (VEGF). Together, EPO and VEGF stimulate endothelial cell mitosis and motility important in new vessel growth and wound healing.6 Additionally, EPO demonstrates beneficial neurotrophic and neuroprotective functions, which may ameliorate neurological damage following spinal cord and brain injury.7
Recombinant human erythropoietin (rHuEPO) is commercially available and has been used for some time to treat ACD related to chronic kidney failure. However, despite the numerous documented effects of EPO on cellular and physiological events known to be important in the healing process and the management of ACD, few clinical studies investigating the use of EPO to promote the healing of chronic wounds have been initiated. In 1992, Turba et al8 reported that five patients with ACD related to Stage IV pressure ulcers were treated successfully. In this study, mean hemoglobin increased from 88 g/L to 124 g/L with 4 weeks of treatment (considered to be statically significant [P <0.001]). The authors did not comment on the effect on pressure ulcer healing. In a single case report of a 22-year-old man with sickle cell disease and a chronic leg ulcer, treatment with EPO resulted in the rapid and complete healing of the chronic leg ulcer, further improvement in hematological parameters, and relief from chronic pain.9
The sites of the current study are the Regional Spinal Cord Injury Program and the Chronic Wound Management Clinic. Spinal cord injured patients are at high risk of developing pressure ulcers, many of which become associated with ACD. These ulcers are challenging to heal, despite the fact that interdisciplinary efforts have been successful in addressing most of the factors contributing to these ulcers. Pressure redistribution, nutritional support, management of incontinence, and good local wound care are key components of the program. In an attempt to reverse ACD, several patients were treated with subcutaneous EPO. A retrospective chart review was conducted to assess the effect of this treatment.
Methods
To review the effect of 6 weeks of EPO 75 IU/kg administered subcutaneously three times weekly in resolving refractory anemia of chronic disease and healing Stage IV pressure ulcers, a retrospective chart review of four patients treated in 2003 who received EPO in the course of regular clinical care was conducted. All patients selected for treatment had spinal cord injuries and a hemoglobin ≤100 g/L with hematology parameters consistent with ACD. All had one or more Stage IV pressure ulcers. Patient demographic data and medical histories were extracted from the charts. All treatment parameters were reviewed. Staff comments on participation in therapy were reviewed. Where available, hemoglobin, ferritin, and ulcer parameters also were extracted from the charts (regrettably, documentation at times was absent). Rectangular surface area was calculated from extracted length and width measures.
General treatments. All patients received physiotherapy and occupational therapy assessments. Pressure redistribution (ie, seating assessment) was a key focus and integrated into interventions. Dietitian consults were obtained and nutritional deficiencies were addressed. Bowel routines were established to prevent fecal soiling of the ulcers and continence management strategies were implemented. All ulcers were aggressively sharply debrided. All undermined areas in one ulcer were deroofed. Ulcer bacterial loads were managed with topical antimicrobial dressings and/or systemic antibiotics when clinically indicated. A hydrofiber (Aquacel, ConvaTec, Princeton, NJ or alginate packing (Kaltostat, ConvaTec, Princeton, NJ) was used in all ulcers and covered with absorptive adhesive foam cover dressings. Where possible, dressings were changed every 2 to 3 days. Comorbid conditions (eg, diabetes) were medically managed. All patients received rHuEPO 75 IU/kg subcutaneously three times weekly for 6 weeks. Iron supplementation with oral ferrous gluconate (as indicated by ferritin levels) was administered.
Results
Four patients, all men, with a mean age of 59 years (± 19), were treated. Three were treated as inpatients and the fourth was treated as an outpatient. The clinical decision to implement rHuEPO therapy in each case had been reached when standard therapy had failed to produce significant improvement and the patient was deemed to have ACD. Data were extracted and summarized from patient charts (see Table 1). Ulcer dimensions reported are for the largest ulcer if multiple ulcers were present. Initial assessment values reported predate the initiation of EPO treatment and the final value reported is after 6 weeks of treatment. The elapsed time between initial and final values is 6 to 8 weeks. Serum parameters such as ferritin and albumin are at the discretion of the admitting physician and, at the time, were not always requested.
Case Histories
Case 1. Mr. A is a 60-year-old man who developed paraplegia in 2003 secondary to a spinal cord abscess from C2 to T3 that resulted from a septic discitis. His history included diabetes mellitus type 2 with complications (retinopathy, neuropathy, and nephropathy). Before his discitis, he developed a left foot ulcer complicated by osteomyelitis that was thought to be the source of his discitis, ultimately resulting in a left forefoot amputation. He developed a neurogenic bladder and bowel secondary to his spinal cord injury.
On admission to the rehabilitation program, Mr. A had two pressure ulcers, a right heel ulcer (Stage III) and a sacral ulcer (Stage IV) that measured 7.6 cm x 3.8 cm x 1.0 cm with no undermining. Initial hemoglobin was 93 g/L and rose to 114g/L after treatment with rHuEPO. Ferritin was greater than the upper limit of detection, indicating significant iron overload. He received no iron supplementation and his ferritin dropped to 518 g/L by the time he was discharged. Also by discharge, the heel ulcer had resolved and the sacral ulcer had diminished to 3.0 cm x 1.5 cm x 0.1 cm. The sacral ulcer was completely healed by his first follow-up visit to the outpatient clinic.
During his stay, Mr. A had recurrent periods of sepsis and required transfer back to acute care on one occasion. Once he started the EPO, he had no further episodes, a chronic urinary tract infection resolved, and staff commented on his increased energy and ability to participate in his rehabilitation program.
Case 2. Mr. B is a 66-year-old man with longstanding paraplegia secondary to a motor vehicle accident in 1978. He has poorly controlled type 2 diabetes and he smokes. His peripheral neuropathy and peripheral vascular disease ultimately led to a left below-knee amputation in 1998. He has diabetic nephropathy and commenced dialysis within 6 months of discharge from the rehab program in 2003. He has a neurogenic bowel and bladder and at one point had undergone a colostomy in attempt to assist in closure of his chronic ulcers. He has had recurrent pressure ulcers with a myocutaneous flap closure in 1995, subsequent breakdown, and a repeat flap procedure in 2002. At the time of his admission to the rehabilitation program, this flap had dehisced.
On recent admission, four areas were open along the flap edges and the flap was completely undermined. The largest opening was over the left ischial tuberosity and measured 3.0 cm x 1.5 cm x 1.5 cm with circumferential undermining of 3.0 cm to 7.5 cm. He also had multiple areas of Stage II ulceration and drainage was copious and seropurulent.
Initially, Mr. B’s hemoglobin was 86 g/L with the characteristic profile of ACD, and his serum albumin only 17 g/L. By discharge, his hemoglobin had risen to 105 g/L on EPO and iron supplementation and his albumin was 25 g/L on intensive dietary intervention. Also by discharge, all areas of Stage II ulceration had closed. The ischial tuberosity ulcer had dimensions of 2.0 cm x 2.0 cm with a depth of only 0.5 cm and no undermining. The initial plan was to discharge him to a nursing home but with his significant improvement Mr. B was better able to participate in his rehabilitation program and achieved his goal of discharge to home with home care assistance.
Case 3. Mr. C is a 33-year-old man who fell from a ladder in 1995 and suffered a spinal cord injury resulting in T9 paraplegia and a concurrent closed head injury. Because this was a workplace injury, he had extensive extra funding through the Work Place Safety and Insurance Board of Ontario (WSIB). He was labeled a difficult patient related to his multiple risk-taking behaviors and had exhausted the good will of most of his caregivers. He had undergone a spinal fusion but ultimately the hardware was removed secondary to chronic infection. He suffered a cerebrovascular accident in 2003 that left him with additional right-sided weakness. He had a dislocated hip with ongoing pain and flexion contractures of the knees. Multiple attempts at flap closure to resolve chronic problems with recurrent pressure ulcers had failed. He is an ongoing smoker.
Initially, Mr. C was seen in the outpatient chronic wound management clinic; subsequently, he was admitted to the Short-Term Assessment and Planning program in Complex Continuing Care. On admission, he had five large pressure ulcers over all his bony prominences. The smallest ulcer (over the right greater trochanter) measured 3.3 cm x 3.2 cm x 2.0 cm and was undermined 6 cm in the 9 o’clock direction. The largest was the sacral ulcer which measured 11.0 cm x 10.0 cm x 3.0 cm with undermining of 2.8 cm from 11 to 8 o’clock. All ulcers were Stage IV, undermined, positive for methicillin-resistant Staphylococcus aureus (MRSA) and drainage was copious and seropurulent. On admission, Mr. C’s hemoglobin was 78 g/L and ferritin was 223 g/L. Serum albumin was low (27 g/L).
Mr. C’s ulcers were successfully decolonized with topical antisepsis using betadine in combination with a course of oral cotrimoxazole and rifampin and debrided. Mr. C also received nutritional intervention, a seating assessment, and chronic pain management intervention. Discharge planning was coordinated with his WSIB case worker and included modifications to his home, provision of a low-air-loss bed, and liaison with his family physician and local pharmacist. His defeatist approach shifted to active participation in his care. By discharge, all ulcers had shown a decrease in size and the amount of undermining. The sacral ulcer measured 10.0 cm x 9.5 cm x 2.1 cm with no undermining (this ulcer closed completely within 6 months of discharge). His hemoglobin had come up to 110 g/L on the EPO and all remaining ulcers continue to improve.
Case 4. Mr. D was a 78-year-old man in good general health except for coronary artery disease and hypertension before the repair of an abdominal aortic aneurysm. Intraoperatively, he suffered from critical ischemia to the spinal cord and became an incomplete paraplegic. Postoperatively, he developed a large sacral decubitus ulcer.
On admission, Mr. D’s ulcer measured 6.4 cm x 4.0 cm x 3.5 cm and was undermined 5.0 cm from 6 to 12 o’clock. The ulcer base was sloughy and drainage was heavy and serous. His admission hemoglobin was 94 g/L but rose to 111 g/L with 6 weeks of EPO and iron supplementation. As hemoglobin levels improved, Mr. D took a more active role in his rehabilitation. One month before discharge, his ulcer was surgically deroofed to remove all undermining; the final dimensions were 10.0 cm x 5.0 cm x 2.0 cm but all edges were attached with no undermining. He was discharged home on topical negative pressure therapy. He was followed in the outpatient clinic and his ulcer went on to close within 2 months.
Summary data. Mean initial hemoglobin for these 4 patients was 88 g/L (± 7.4). After 6 weeks of rHuEPO injections, the mean hemoglobin of these patients rose to 110 g/L (± 3.7) (see Figure 1). Mean surface area of the largest ulcer decreased from 42.3 cm2 (± 40.2) to 38.4 cm2 (± 44.3) over 6 weeks of treatment despite the fact that the patient in Case 4 showed a significant increase in surface area as a result of a surgical deroofing performed to eliminate all undermining. All patients showed a decrease in the depth of the target ulcer from 2.3 cm (± 1.2) to 1.2 cm (± 1.0) (see Figure 2). Data were not analyzed for statistical significance because the sample size was too small.
Discussion
All patients experienced an improvement in hemoglobin with 6 weeks of treatment with rHuEPO. In the study reported by Turba et al,8 a comparable increase in mean hemoglobin from 88 g/L (± 1.0) to 124 g/L (± 1.6) was observed with 4 weeks of treatment. No previous studies report on change in ulcer status. In the current study, ulcer status improved for all patients — ulcer depth diminished, wound surface areas decreased, and wound bed appearance and the extent of undermining improved in all ulcers. Some patients showed increased ability to fight recurrent infections and all patients felt more energetic and better able to participate in their rehabilitation activities.
No adverse effects were observed. The use of rHuEPO has been discontinued in some dialysis units because of problems with pure red cell aplasia resulting in anemia resistant to further supplementation,10 a consequence of the development of autoantibodies to the rHuEPO.11 Discontinuing the rHuEPO and treating the patient with immunosuppressive agents resolves the problem. To date, long-term use in pressure ulcer patients has not been tried, so it is unclear if these patients also would develop autoantibodies. In this retrospective review, all patients received only 6 weeks of therapy and no clinical evidence for the development of autoantibodies was seen. In each case, 6 weeks of treatment was sufficient to bring the hemoglobin level up into a more suitable range.
The staff remarked that once rHuEPO was started improvements in the ulcer appearance were noted at each dressing change. One can speculate that this resulted from more than just increased oxygen delivery to the tissues through improved hemoglobin and may be the result of interaction with and stimulation of intrinsic growth factors.
This study was hampered by inconsistent chart documentation; while outpatient charts are complete, sequential ulcer dimensions were not always documented on the inpatient chart. However, values were recorded by the consultation team before and after the initiation of 6 weeks of EPO therapy. In addition, some hematologic parameters, such as ferritin, were not always monitored or could not be found on the chart. Charting practice has changed as a result of the chart review.
The results achieved are promising enough to suggest that a prospective study is warranted. Such a study would carefully collect all hematologic factors as well as use validated tools for determining ulcer size and appearance. In addition, collecting wound fluid before, during, and after treatment is recommended to determine the effect on chronic inflammatory mediators.
Once an effect size is determined, a randomized double-blind controlled trial could be designed. Research into effects at the molecular level may be useful.
Treatment is expensive. Six weeks of therapy as outlined costs approximately $6,000 (Canadian). If efficacy can be shown, pharmaco-economic models could determine cost-effectiveness.
Clinically, the two case series suggest that patients with ACD and a pressure ulcer might benefit from 4 to 6 weeks of subcutaneous injections of rHuEPO.
Conclusion
Human recombinant erythropoietin shows promise in resolving the refractory ACD associated with Stage IV pressure ulcers. Further study is suggested. The results of this study also may suggest that rHuEPO acts as a growth factor either alone or in conjunction with intrinsic factors in the wound. Studies of its role at the molecular level are indicated.
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