Goldina Ikezuagu Erowele, PharmD
Clinical Pharmacy Specialist
Formulary Management & Pharmacoeconomics Services
Harris County Hospital District
Ruth Ebiasah, PharmD, MS
Clinical Pharmacy Specialist,
Palliative Care & Oncology
Holy Cross Hospital
Silver Spring, Maryland
FACULTY DISCLOSURE STATEMENTS:
Drs. Erowele and Ebiasah have no actual or potential conflicts of interest in relation to this activity.
U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.
In 2007, the National Pressure Ulcer Advisory Panel (NPUAP) redefined pressure ulcer as a localized injury to the skin and/or underlying tissue, usually over a bony prominence, as a result of pressure alone or in combination with shear or friction.1 The earliest documentation of pressure ulcers was made by Hippocrates in 400 BC. Paget, in his clinical lectures on bedsores in 1873, said that pressure ulcers sometimes erupt from beneath intact skin. Pressure ulcers are a significant clinical, quality-of-life, economic, regulatory, and legal problem for providers and patients alike.2 Pressure sores are a serious and common occurrence in older people, and they will continue to be a major health care concern as the population ages.
The prevalence of pressure ulcers has been described extensively in various health care settings, including long-term care facilities, acute- and critical-care settings, and general surgical settings. In the United States, prevalence is estimated to be 1.3 million to 3 million.3 Ranges in prevalence rates vary widely depending on the health care setting. According to the NPUAP, rates range from 10% to 18% in general acute care, 2.3% to 28% in long-term care, and 0% to 29% in home care.4 Other reported data have indicated rates of 3% to 14% in hospital settings.5
Pressure ulcers are a major cause of morbidity and mortality in older people and are the most common care problem among nursing home residents, with prevalence estimated at 2.6% to 24%.1,6 In one longitudinal study, 17% of patients admitted to nursing homes had pressure sores at the time of admission.7 Among patients who did not have a pressure ulcer at admission, the risk of developing one after admission was 13% in the first year postadmission and 21% by the second year.2,5 Additionally, it has been reported that the risk of developing a pressure ulcer following surgery is five times greater in patients older than 70 years of age than in those younger than 60 years.8
The development of pressure ulcers is directly associated with the tissue's tolerance to pressure, as well as the intensity and duration of this pressure.9Risk factors for the development of pressure ulcers are classified as intrinsic or extrinsic
Intrinsic factors are those that internally influence the integrity of the skin. These factors include, but are not limited to, the following:
Immobility: All bed-bound patients are at risk for developing pressure ulcers. Limited activity, an immobilized body part, or total inability to move or ambulate is a central, underlying risk factor for the development of pressure ulcers.
Advanced Age: Patients older than 75 years appear to be at greatest risk, possibly due to age-related changes in the skin.11 Skin undergoes physical, structural, physiologic, and immunologic changes with increasing age. These changes may cause decreased barrier function, increased susceptibility to shearing forces, and decreased vascularity.
Impaired Sensory Perception: Conditions resulting in loss of sensation, pain perception, or level of consciousness (e.g., Parkinson's disease, Alzheimer's disease, diabetes mellitus, stroke, spinal-cord injury) may reduce mobility and cause loss of motor control, resulting in abnormal shear forces and friction on skin.9 Additionally, medications that impair sensory perception or level of consciousness (e.g., sedative-hypnotics, narcotic analgesics) can contribute to the development of pressure ulcers.
Poor Nutritional Status: Poor dietary intake and dehydration may contribute to the development of hypoalbuminemia, anemia, or vitamin or mineral deficiency (e.g., vitamin C, zinc), leading to impaired wound healing.9
Comorbidities: Any disease that results in diminished or altered tissue perfusion (e.g., ischemic heart disease, peripheral vascular disease, renal insufficiency, or hypotension) can contribute to the development of pressure ulcers.
Incontinence: Fecal or urinary incontinence can result in prolonged moisture and bacterial contamination. This promotes the breakdown of skin and facilitates the development of pressure sores. Moisture from incontinence may increase the risk of pressure ulcer fivefold.8
Extrinsic factors are related to the degree of external forces that are applied to the skin surrounding the potential wound site.9 These include pressure, frictional force, and shearing force.
Pressure: Pressure, the most important extrinsic factor, is created when the external surface against the skin and a person's skeleton compress soft tissue sufficiently to halt circulation.8,9,12 The normal capillary filling pressure is 20 mmHg to 30 mmHg; the pressure required to compress capillaries and interrupt circulation is generally considered to be 32 mmHg.10 A patient lying on a hospital mattress can generate a pressure of 45 mmHg to 75 mmHg over such bony prominences as the sacrum, greater trochanters, and heels, where pressure ulcers commonly form.8 If this pressure is sustained for more than 2 hours and exceeds capillary filling pressure within the deep tissue, a pressure sore may result.8
Frictional Force: Frictional forces act to pull on the skin while the weight of the body moves in the opposite direction. This may occur when a patient is repositioned in bed or transferred from bed to a wheelchair.
Shearing Force: Shearing forces are exerted when gravity causes the body to slide while in a fixed position, as when a patient is positioned with the head of the bed in a raised position, generally at greater than a 30° angle.8,9
Since numerous risk factors exist for pressure ulcer, prediction-assessment tools are widely used to stratify patients' risk. There is insufficient evidence for one scale being superior to others. Currently, the Braden and Norton scales are the most widely used prediction tools for pressure ulcer.13,14 The Braden Scale, developed to foster early identification, comprises six sub-scales that rate sensory perception, skin moisture, activity, mobility, friction and shear, and nutritional status. The Braden Scale is performed upon admission, at least quarterly in long-term care facilities, after a major change in clinical status, or after return from the hospital. When the Braden Scale score is 16 or less, prevention protocols should be implemented. The Norton Scale rates physical and mental activity, mobility, and incontinence on a scale of 1 to 4. A score of 14 or less means that the patient is at risk.
The skin consists of three major layers: the epidermis (outermost layer), the dermis (connective tissue containing nerves, blood vessels, and lymphatics), and the subcutaneous layer (containing adipose tissue).9 Skin repair and regeneration are a natural bodily process involving several complex steps. These steps, which may overlap, are categorized as the inflammatory phase, the proliferative phase, and the remodeling phase.
Following hemostasis at the site of injury, the beginning of the inflammatory phase is marked by initiation of an inflammatory response and attraction of neutrophils to the area by degranulating platelets. Transforming growth factor (TGF) beta, tumor necrosis factor (TNF) alpha, and fibroblast cells are released from the damaged blood vessels, and these attract inflammatory cells to the wound site.15 Responding neutrophils and macrophages synthesize additional growth and inflammatory factors and continue the breakdown and cleansing process.
The proliferative phase is characterized by the creation of an extracellular matrix and basement membrane degradation, in addition to the formation of new vasculature. This phase may last for up to 4 weeks in a clean, uncontaminated wound.9
After the third week, the remodeling phase begins; this phase can last for years after the initial injury. The tissue undergoes extensive remodeling as collagen and elastin are added and degraded by fibroblasts. The wound tissue's maximal tensile strength (approximately 80% of the tensile strength of the original tissue) is achieved by the 12th week, and the process of healing is complete.9
The aggravating event in pressure sores is purported to be an unrelieved external force—such as a mattress, wheelchair pad, or bed rail—or traumatic forces that may be present, including frictional and shearing forces. These forces cause circulatory interruption, resulting in ischemia and subsequent inflammation and tissue anoxia. Tissue anoxia leads to cell death, necrosis, and ulceration.
STAGES OF PRESSURE ULCER
Clinical assessment of pressure ulcer should be initiated by determining whether a patient is at risk and performing an examination for early signs of pressure-sore formation at the anatomical sites where such sores are most commonly encountered.8 Pressure ulcers usually occur on the lower part of the body, predominantly the sacral region and heels. Other sites include the elbows, ankles, trochanters, ischia, knees, scapulas, shoulders, and occiput.9
Pressure ulcers are staged according to one of four categories. In February 2007, the NPUAP redefined these categories and added stages for deep-tissue injury and unstageable pressure ulcers.1
Suspected Deep-Tissue Injury: This is a maroon or purplish localized area of discolored, intact skin or a blood-filled blister that is caused by damage of the underlying soft tissue by pressure or shear. The affected region may be preceded by tissue that is painful, firm, mushy, boggy, warm, or cool compared with the adjacent tissue. It may be hard to detect deep-tissue injury in patients with dark skin. Evolution may involve a thin blister over a dark wound bed. The wound may evolve further and become covered in thin eschar. Even with optimal treatment, evolution may be rapid and expose additional layers of tissue.
Stage I: This stage consists of intact skin with nonblanchable redness of a localized region, usually over a bony prominence. Dark skin may not have visible blanching, but its color may differ from the surrounding area. The area may be painful, firm, soft, warm, or cool compared with the adjacent tissue. It may be difficult to detect this stage in patients with darkly pigmented skin. This stage may be a heralding sign of risk.
Stage II: This stage involves partial-thickness tissue loss and presents as a shallow, open ulcer with a reddish-pink wound bed without slough. This stage of ulcer may also present as an intact or open/ruptured serum-filled blister. It may present as a shiny or dry shallow ulcer without slough or bruising (bruising signifies suspected deep-tissue injury). This stage should not be used to describe skin tears, tape burns, perineal dermatitis, excoriation, or maceration.
Stage III: This stage is characterized by full-thickness tissue loss. Subcutaneous fat may be visible, but bone, muscle, and tendon are not exposed. Slough may be present, but the depth of tissue loss is not obscured. Undermining and tunneling may be involved. The depth of an ulcer of this stage varies by anatomical location: Since the ear, the bridge of the nose, the occiput, and the malleolus do not have subcutaneous tissue, stage III ulcers in these locations can be shallow; areas of significant adiposity, in contrast, can develop ulcers of this stage that are quite deep. Bone and tendon are not visible or directly palpable.
Stage IV: Stage IV comprises full-thickness tissue loss with exposed bone, muscle, or tendon. Slough or eschar may be found on some areas of the wound bed. Undermining and tunneling often are involved. The depth of an ulcer of this stage varies by anatomical location, as described in stage III above. Stage IV ulcers can extend into the muscle or supporting structures (e.g., tendon, fascia, or joint capsule), rendering osteomyelitis a possibility. Exposed bone and tendon are visible or directly palpable.
Unstageable: Unstageable pressure sores involve full-thickness tissue loss, and the base of the ulcer is covered by slough (yellow, tan, brown, green, or gray), eschar (brown, tan, or black), or both, in the wound bed. Until enough of the slough or eschar is removed to expose the base of the wound, the true depth and stage of the ulcer cannot be determined. Stable (dry, intact, and adherent, with no erythema or fluctuance) eschar on the heels should not be removed.
THERAPEUTIC TREATMENT OPTIONS
Nonpharmacologic treatments include reduction of tissue pressure, frequent repositioning, and the use of surfaces that are protective and supportive.16Frequent repositioning (and selection of proper position) is extremely important. Bed-bound patients should be turned a minimum of every 2 hours, and they should be elevated as minimally as possible to avoid the shear forces on tissues that result from sliding down the bed. Lifting devices or bed linen should be used to reposition patients, rather than pulling or pushing the patient (which causes friction and shear forces). Patients placed in chairs should be repositioned every hour, and they should be encouraged to change position on their own every 30 minutes. Protective padding includes pillows or foam wedges that can placed between the knees, ankles, and heels when patients are lying on their sides; pillows, foam, and heel protectors can be used when patients are supine. Support surfaces under bed-bound patients can be changed to reduce pressure.
A change from standard mattresses is necessary when patients are unable to reposition themselves and periodic repositioning care is unavailable. Special mattresses are indicated for patients with stage I ulcers who develop hyperemia on static surfaces and for patients with stage III or IV ulcers. Air-fluidized or high-air-loss mattresses contain silicone-coated beads that liquefy when air is pumped through the bed. Advantages include cooling and reduction of moisture on surfaces. These mattresses are indicated for patients with nonhealing stage III and IV sores or numerous truncal ulcers.
PHARMACOLOGIC TREATMENT OPTIONS
The yearly cost of preventing and treating pressure ulcers is astronomically high, proving the dictum of preventive therapy being beneficial not only for the patient, but also for the economics of the health care system.17 Conservative treatment of pressure sores includes appropriate wound care, debridement of necrotic tissue, optimization of nutrition, release of pressure, and minimization of muscle spasticity in order to provide the patient with the best opportunity to heal by secondary intention. Stage I and II pressure sores are treated conservatively. Some patients with stage III and IV pressure ulcers must be treated conservatively because of coexisting medical problems.18
Therapeutic measures for a pressure sore should be appropriate to its stage and should be consistent with the patient's therapeutic goals. Many therapeutic interventions follow the same principles as preventive interventions. In one study, independent predictors of healing included pressure ulcer size, older age, and receiving rehabilitation services.19 Both immobility and incontinence were associated with poor healing of pressure ulcer.
Wound fluids may contain tissue growth factors that facilitate re-epithelialization. Thus, healing of pressure ulcers is promoted by dressings that maintain a moist wound environment while keeping the surrounding intact skin dry.20 The goal is to keep the ulcer bed moist to retain tissue growth factors while allowing some evaporation and inflow of oxygen to keep surrounding skin dry, facilitate autolytic debridement, and establish a barrier to infection.9,12,18 A moist wound environment is achieved by loosely packing the wound with saline-moistened gauze that is not allowed to dry (occlusive dressings are equally effective and reduce the nursing time required for wound care). Several types of dressings are available commercially; there are no clear recommendations for use of one type of dressing versus another, but individual circumstances may favor one form of dressing over another.21
Transparent films provide an effective barrier for retaining moisture; they are good secondary dressings when combined with another product for full-thickness wounds, and they may be used alone for partial-thickness wounds. Hydrocolloids generally are effective for retaining moisture and are useful for promoting autolytic debridement; they come in a variety of sizes and shapes for use on different parts of the body. A comparison study of transparent absorbent acrylic dressings and hydrocolloid dressings in the management of stage II and shallow stage III pressure sores demonstrated that the transparent film dressing improved the ability to assess the ulcer as well as patient comfort, although time to wound closure was nearly identical between the two groups.22
Hydrogels, which are designed to maintain a moist wound bed, and can be used for deep wounds with little exudate. Both alginates and foams are highly absorptive and are useful for wounds with significant exudate.9,23 A study of 110 elderly (mean age 83.5 years) patients in a geriatric hospital ward with stage III or IV pressure ulcers found that sequential use of a calcium alginate dressing for 4 weeks followed by a hydrocolloid dressing for 4 weeks was preferable to a hydrocolloid dressing alone for 8 weeks (control condition). In this study, the mean absolute surface area reduction (SAR) was significantly larger in the sequential-treatment group than in the group that had just the hydrocolloid dressing (7.6 cm2 vs. 3.1 cm2 at week 8). Similarly, at week 8, significantly more patients in the sequential-therapy group had a 40% SAR (75% vs. 59% for controls).24 Iodine-solution wet gauze comes in a variety of forms and provides broad-spectrum antimicrobial coverage in the setting of a moist wound environment.18 Further information about the various dressings used to treat pressure ulcers is given in TABLE 2.9,10,15-17
Poor nutritional status or dehydration can weaken the skin and make a person more vulnerable to developing pressure ulcers. Nutritional screening must be a part of the evaluation of any patient with pressure sores. Dietary consultation is recommended for patients who are malnourished, and an evaluation of swallowing ability should be considered.
Nutritional interventions to prevent or treat pressure ulcers include providing additional nutrition and dietary supplements and encouraging adequate dietary intake by the patient. High-calorie foods and supplements should be used to prevent malnutrition.12,18 If oral dietary intake is impractical, enteral or parenteral feeding—if compatible with the patient's wishes—should be considered to achieve a positive nitrogen balance (≈30-35 calories/kg/day and 1.25 g-1.5 g protein/kg/day). Zinc supplementation supports wound healing, and replacement at a dose of 50 mg tid may be useful. Supplemental vitamin C (1 g/day) may be administered if intake is insufficient and deficiency is present, although data supporting its effectiveness in accelerating healing have been inconsistent.25 A 2003 Cochrane review of four trials found that although there is some evidence that nutritional interventions may be able to reduce the occurrence of pressure ulcers, more evidence is needed to identify effective dietary interventions.26
Topical Growth Factors
Growth factors have been found in vivo and in vitro to show promise for tissue repair.27 Several growth factors, including TGF, epidermal growth factor, platelet-derived growth factor, fibroblast growth factor, interleukin-1 and interleukin-2, and TNF, have been shown to mediate the healing process in acute wounds.28
To date, no growth factor has received FDA-approved labeling for such use. Topical recombinant human BB platelet-derived growth factor (rPDGF-BB) has been found to stimulate the migration of neutrophils, macrophages, and fibroblasts into wounds; hasten the accumulation of glycosaminoglycans and fibronectin; and enhance collagen production.29 The commercially available rPDGFBB becaplermin has been the most extensively studied for wound healing in humans.
One trial enrolled 124 patients with stage III or IV pressure ulcers who were randomized to receive 100 mcg/g becaplermin gel once daily alternating with placebo gel every 12 hours (n = 31); 300 mcg/g becaplermin gel once daily alternating with placebo gel every 12 hours (n = 32); 100 mcg/g becaplermin gel twice daily (n = 30); or placebo (n = 31).30 Complete healing was significantly more frequent with 100 mcg/g or 300 mcg/g becaplermin once daily than with placebo (P = .005 and P = .008, respectively). A difference was not observed between the becaplermin 100 mcg/g twice-daily group and the placebo group. No sores in placebo recipients healed completely, compared with 3% in patients given becaplermin 100 mcg/g twice daily, 19% in the 300-mcg/g once-daily group, and 23% in the 100 mcg/g once-daily group. Interpretation of the results, however, may be confounded by the negative dose-response effect, a substantially lower rate of healing than observed for other standard treatments, and failure of any ulcers to heal in placebo recipients. Adverse effects were similar in all treatment groups and included skin ulceration, urinary-tract infection, rash, erythema, and fever.
In June 2008, the FDA issued a follow-up "Dear Healthcare Professional" letter regarding an earlier safety review of becaplermin. In March 2008, the FDA had announced that it had received information from a retrospective study and was investigating the possibility of an increased risk of cancer or mortality from cancer in patients with diabetes who used becaplermin, compared to patients who did not use becaplermin. The FDA completed its review of this study and noted an increased risk of mortality from cancer in patients who used three or more tubes of becaplermin gel. As a result, the becaplermin prescribing information was updated to include a new black box warning regarding this finding. It is important to note that while the study showed an increase in mortality from cancer, the number of mortalities was small, there was no overall increase in the incidence of cancer, and the observed malignancies were remote from the ulcer treatment site. The FDA recommends the use of becaplermin only when the potential benefits outweigh the risks.31
Primary treatment of pain is treatment of the pressure sore itself. Options for treatment should include nonsteroidal anti-inflammatories (such as naproxen or ibuprofen) or acetaminophen, which are used for mild-to-moderate pain. Opioids may be necessary during dressing changes and debridement. In cognitively impaired patients, changes in vital signs can be used as an indication of pain. Opioids should be avoided when possible because sedation promotes immobility.
THE PHARMACIST'S ROLE
The cornerstones of therapy for pressure ulcers remain elimination of the source of the pressure or friction and appropriate wound care. Prevention is imperative, because once a pressure ulcer forms, prolonged hospitalization and expensive therapy are distinct possibilities. The pharmacist's role in the prevention of pressure ulcers includes educating patients about the contributing factors and monitoring patient progress to ensure successful healing of the sore when therapies are initiated. Patient education about the proper use of prescribed discharge medications and preventive steps necessary to ensure that the ulcer will not occur again is quite important for reducing the health care burden of pressure ulcers on society.
- National Pressure Ulcer Advisory Panel. Updated staging system. Pressure ulcer stages revised by NPUAP. February 2007. www.npuap.org/pr2.htm. Accessed February 27, 2009.
- Black J, Baharestani M, Cuddigan J, et al. National Pressure Ulcer Advisory Panel's updated pressure ulcer staging system.Urol Nurs. 2007;27:144-150,156.
- Brem H, Lyder C. Protocol for the successful treatment of pressure ulcers. Am J Surg. 2004;188(suppl):9S-17S.
- Cuddigan J, Berlowitz D, Ayello E. Pressure ulcers in America: prevalence, incidence, and implications for the future. Adv Skin Wound Care. 2001;14:208-215.
- Scott JR, Gibran NS, Engrav LH, et al. Incidence and characteristics of hospitalized patients with pressure ulcers: State of Washington, 1987 to 2000. Plast Reconstr Surg. 2006;117:630-634.
- O'Donnell JA, Hofmann MT. Skin and soft tissues. Management of four common infections in the nursing home patient. Geriatrics. 2001;56:33-38,41.
- Brandeis GH, Morris JN, Nash DJ, Lipsitz LA. The epidemiology and natural history of pressure ulcers in elderly nursing home residents. JAMA. 1990;264:2905-2909.
- Papantonio CJ, Wallop JM, Kolodner KB. Sacral ulcers following cardiac surgery: incidence and risk factors. Adv Wound Care. 1994;7:24-36.
- Sewchuk D, Padula C, Osborne E. Prevention and early detection of pressure ulcers in patients undergoing cardiac surgery. AORN J. 2006;84:75-96.
- Livesley NJ, Chow AW. Infected pressure ulcers in elderly individuals. Clin Infect Dis. 2002;35:1390-1396.
- Cannon BC, Cannon JP. Management of pressure ulcers. Am J Health Syst Pharm. 2004;61:1895-1907.
- Arnold MC. Pressure ulcer prevention and management: the current evidence for care. AACN Clin Issues. 2003;14:411-428.
- Norton D. Calculating the risk: reflections on the Norton Scale. Decubitus. 1989;2:24-31.
- Braden B, Bergstrom N. Pressure ulcers in adults: prediction and prevention. Clinical Practice Guideline No. 3. Rockville, MD: Agency for Health Care Policy and Research; May 1992:14-17.
- Mast BA, Schultz GS. Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair Regen. 1996;4:411-420.
- Merck Manuals Online Medical Library. Pressure ulcers. www.merck.com/mmpe/sec10/ch126/ch126a.html#sec10-ch126-ch126a-1091. Accessed January 1, 2009.
- Salcido R, Popescu A. Pressure ulcers and wound care. eMedicine. http://emedicine.medscape.com/article/319284-overview. Accessed January 1, 2009.
- Wilhelmi BJ, Neumeister M. Pressure ulcers, surgical treatment and principles: treatment. eMedicine. http://emedicine.medscape.com/article/1293724-treatment. Accessed January 1, 2009.
- Berlowitz DR, Brandeis GH, Anderson J, et al. Effect of pressure ulcers on the survival of long-term care residents. J Gerontol A Biol Sci Med Sci. 1997;52:M106-M110.
- Bergstrom N, Horn SD, Smout RJ, et al. The National Pressure Ulcer Long-Term Care Study: outcomes of pressure ulcer treatments in long-term care. J Am Geriatr Soc. 2005;53: 1721-1729.
- Graumlich JF, Blough LS, McLaughlin RG, et al. Healing pressure ulcers with collagen or hydrocolloid: a randomized, controlled trial. J Am Geriatr Soc. 2003;51:147-154.
- Brown-Etris M, Milne C, Orsted H, et al. A prospective, randomized, multisite clinical evaluation of a transparent absorbent acrylic dressing and a hydrocolloid dressing in the management of Stage II and shallow Stage III pressure ulcers. Adv Skin Wound Care. 2008;21:169-174.
- ACP Internist. Special focus: pressure ulcers. www.acpinternist.org/archives/2007/07/special.htm. Accessed January 1, 2009.
- Belmin J, Meaume S, Rabus MT, et al. Sequential treatment with calcium alginate dressings and hydrocolloid dressings accelerates pressure ulcer healing in older subjects: a multicenter randomized trial of sequential versus nonsequential treatment with hydrocolloid dressings alone. J Am Geriatr Soc. 2002;50:269-274.
- Royal College of Nursing. The management of pressure ulcers in primary and secondary care: a clinical practice guideline. September 2005. www.nice.org.uk/nicemedia/pdf/CG029fullguideline.pdf. Accessed January 1, 2009.
- Langer G, Knerr A, Kuss O, et al. Nutritional interventions for preventing and treating pressure ulcers. Cochrane Database Syst Rev. 2003;4:CD003216.
- Rothe M, Falanga V. Growth factors: their biology and promise in dermatological diseases and tissue repair. Arch Dermatol. 1989;125:1390-1398.
- Thomas DR. Age-related changes in wound healing. Drugs Aging. 2001;18:607-620.
- Tzeng DY, Deuel TF, Huang JS, Baehner RL. Platelet-derived growth factor promotes human peripheral monocyte activation. Blood. 1985;66:179-183.
- Rees RS, Robson MC, Smiell JM, Perry BH. Becaplermin gel in the treatment of pressure ulcers: a phase II randomized, double-blind, placebo-controlled study. Wound Repair Regen. 1999;7:141-147.
- FDA. Update of safety review follow-up to the March 27, 2008, communication about the ongoing safety review of Regranex (becaplermin). www.fda.gov/cder/drug/early_comm/ becaplermin_update_200806.htm. Accessed January 1, 2009.