In 2014, 29.1 million Americans, or 9.3% of the US population, were estimated to have diabetes mellitus.1 Approximately 25% of individuals with diabetes will develop a lower extremity ulcer in their lifetime.2 A diabetic foot ulcer (DFU) is an open wound, commonly located on the bottom or plantar surface of the foot, seen in individuals with type 1 or 2 diabetes, and most often develops from repetitive trauma in the presence of insensate feet.3 A 45% mortality within 5 years is reported for individuals with a DFU.4,5
A DFU is a “potentially deadly and costly complication of diabetes.”6 Diabetic foot ulcers and resulting limb complications account for US $17 billion per year, which is more than the costs associated with treating each of the five most common cancers (breast, colon, lung, prostate, and leukemia).7 A DFU is a burden to patients that impacts their physical and mental health and economic stability.
The estimated annual incidence rate of DFUs ranges from 2% and 4% in developed countries. The prevalence may be higher in developing countries related to socioeconomic differences and inconsistent standards of wound care.8 In a randomized controlled trial of 325 patients, Litzelman et al9 found that an intervention including observation, education on best practices for foot care and footwear, and ongoing self-care management led to a significant reduction in DFUs.
Complications of a DFU can include chronicity, reulceration, osteomyelitis, and amputation. Complications can be reduced when interdisciplinary foot care teams care for these individuals.10 For example, a longitudinal observational study was conducted to identify clinical outcomes of 83 individuals with diabetes who were cared for by an interdisciplinary team. Of the 83 individuals, three had to have a toe amputated, and one required a below-knee amputation,8 indicating successful reduction of amputation in the majority of cases when an interdisciplinary team approach is used.
Amputations can be reduced by 50% if providers used multidisciplinary foot care teams and immediate access to these teams.10 A recent root-cause analysis was done in 13 London hospitals to ascertain if patients were accessing providers early enough to prevent amputations. The researchers found that only 50% of patients having amputations had been seen by multidisciplinary foot care teams. Patients and providers have a need for knowledge on what to assess and the availability of resources if a problem is identified. It is critical that patients with active foot ulcers are referred to multidisciplinary teams for assessment within 24 hours when possible.11 In another Swedish clinical trial by Larsson and Apelqvist,12 researchers showed that, after an 11-year follow-up, a multidisciplinary team approach to foot care reduced amputations in patients with diabetes by 78%.
Effective modalities for treating DFUs include standard wound care, total contact casts (TCCs), and human amniotic allograft (HAA). Few studies have compared standard wound care and a TCC with human bioengineered dressings and a TCC.13,14
Standard wound care. Standard wound care typically consists of assessment, debridement, cleansing, topical treatment, and a protective dressing. For this study, standard wound care was defined as usual wound care provided at the discretion of the wound care professionals. Providers selected dressings based principally on the basis of exudate control, comfort, and cost according to recommendations given by the International Working Group on the Diabetic Foot.15
Human Amniotic Allograft Membrane. The HAA is a biologic wound covering derived from the amnion membrane, the innermost layer of the placenta that surrounds and protects the fetus. It includes amino acids, nutrients, and growth factors that facilitate growth. The HAA can assist in wound healing by allowing cell migration into area tissues, which promotes repair and modulates inflammation and pain, and may reduce infection.16
A prospective multicenter study by Zelen et al13 compared the effectiveness of healing using a dehydrated human amnion/chorion membrane (dHACM) allograft, a living cell-based bilayered product (LCBP), or standard care for treatment of chronic lower-extremity diabetic ulcers. Sixty participants were enrolled and randomized into three equal treatment groups of 20 participants each for weekly care. Complete healing occurred by week 4 in 85% (17/20) of those who received dHACM, 35% (7/20) of participants who received LCBP, and 30% (6/20) of patients receiving standard wound care. The dHACM had significantly higher rates of complete healing within 4 weeks compared with wounds treated with LCBP (P = .001) or standard care (P = .001). After 6 weeks of treatment, participants treated with dHACM continued to have the highest rates of complete healing at 95% (19/20) versus 45% (9/20) with LCBP and 35% (7/20) for participants treated with standard care (P = .0006 and .0001, respectively). More randomized controlled studies need to be done on the effects of allografts.
The HAA used in the current study is similar to dHACM and has been studied in a few randomized controlled clinical trials; it is commonly used in conjunction with total contact casting. A study with 46 participants compared a group of participants using topical platelet-derived growth factor with a placebo hydrogel product along with windowed TCC in treating DFUs. Thirty-eight of the participants either healed or completed 16 weeks of therapy, and eight participants did not complete the study. Study results showed that 12 of 23 individuals (52%) in the experimental group healed before 16 weeks compared with 13 of 23 (57%) in the control group, which was not a significant finding. Of the eight participants who completed the study, five developed cast burns, and three patients required amputation.14
Total Contact Casting. A recent consensus statement on the use of offloading in management of DFUs concluded that adequate offloading increases the likelihood of DFU healing and should be considered part of the standard of care.17 Total contact casting is a method of offloading plantar ulcers that involve the epidermis, dermis, or subcutaneous tissue without infection or decreased or absent sensation.
Total contact casts are a cornerstone in the treatment of DFUs and are recommended in multiple clinical guidelines. They are considered the criterion standard for a DFU based on proven efficacy in multiple randomized clinical trials, showing an overall average healing rate of 89.5% of ulcers, with a mean healing time of 33.5 days.18–24
A very important aspect of treating DFUs is reduction of pressure and shear forces on the foot. Designed to redistribute pressure, TCCs protect the insensate areas on the feet and promote healing while allowing the individual to remain mobile. Although various methods of offloading are available, TCCs have been used in the management of plantar neuropathic DFUs over the past three decades.25
As with any intervention, complications can occur. The average rate of complications using a TCC is estimated to be 20%, with the most common being superficial abrasions and fungal infections. Despite these complications, the ulcers tend to heal, and treatment is not delayed.2 More serious complications can include life-threatening infections from cellulitis or sepsis. A contraindication to TCC is untreated infection or osteomyelitis or severe peripheral arterial disease.26–29 Providers should implement TCC with caution for ulcers that are deep or with a large amount of drainage and in individuals who are blind, ataxic, or morbidly obese.17
Most complications can be ameliorated with careful cast application and close patient follow-up at frequent intervals over the casting period.2,26 Wu et al30 reported that significantly fewer signs of infection were observed in patients who used a TCC. Despite this knowledge and wide availability, TCC use remains limited.14,31
Research on DFUs Treated with a TCC. The Cochrane database reviewed seven randomized controlled trials of individuals treated with a nonremovable cast compared with those treated with removable pressure-relieving devices. They reported that in five of the seven studies there was a statistically significant increase in healed ulcers in individuals treated with a nonremovable cast.24
A 2014 study by Fife et al6 evaluated the use of offloading for DFUs and identified a discrepancy between evidence and practice. The chart review included a total of 11,784 patients with more than 25,000 DFUs seen between January 2007 and January 2013. Only 2.2% of patients had documented information on offloading. The most frequent offloading option was the removable shoe (36.8%) followed by TCC (16.0%). There were significantly more amputations in the first year of treatment (5.2% vs 2.2%, P = .001) in patients who did not use TCC offloading compared with patients using TCC offloading. Healing rates were slightly higher for those treated with the TCC (39.4% vs 37.2%) as compared with those not treated with the TCC. Rates of infection were significantly higher for the non-TCC-treated DFUs versus those treated with the TCC (P = 2.1 × 10-10). In a retrospective study with more than 25,000 individuals with a DFU, all of whom were eligible to be treated with a TCC, an estimated 96% of the individuals were not.6 Fife et al6 also reported more amputations for non-TCC-treated DFU versus those treated with TCC (non-TCC, 5.2%; TCC, 2.2%).
The purpose of this study was to compare two different methods of treating DFUs. This prospective, randomized study provides evidence about the effectiveness of human bioengineered dressings when used with TCC, as compared with standard wound care and TCC.
METHODS AND MATERIALS
This study was conducted in a university-affiliated rural Midwestern wound care clinic. The clinic employs two wound care physicians and three nurse practitioners who specialize in wound care with ready access to vascular, internal medicine, and infectious disease colleagues. Institutional review board approval was obtained from the university and the medical center review boards.
The HAA used in this study (AmnioExcel; Integra Lifesciences, Plainsboro, New Jersey) is a wound cover that is dehydrated during processing and is provided in various geometric sizes; it is marketed as a human cell/tissue product.
The TCC used in this study (TCC-EZ; Derma Sciences Inc, Plainsboro, New Jersey) is easy to apply with a one-piece, roll-on, lightweight casting consisting of a fiberglass shell that closely conforms to the leg and foot shape. The fiberglass shell is placed over protective padding applied to the leg and foot and can usually be applied in less than 10 minutes. A bar is located on the bottom of the cast for offloading. This TCC creates a “natural healing chamber” around the foot and lower leg.32
Adults 18 years or older with a diagnosis of type 1 or 2 diabetes and a DFU located on the plantar surface larger than 0.5 cm2 in area were invited to participate in the study if they had not demonstrated a 50% reduction in wound area following 4 weeks of standard treatment. Patient DFUs were graded by the primary care providers using the University of Texas diabetic wound classification system.33 Periodic reminders were sent by the researchers to clinic primary care providers to refer patients meeting the criteria.
Participants had to be assessed as cognitively intact by wound clinic primary care providers to participate in the study. Other inclusion criteria were: random blood glucose of 450 mg/dL or less, a hemoglobin A1c (HbA1c) of 15% or lower drawn within the 4 weeks prior to study enrollment, and evidence of adequate perfusion to the subject’s foot as established with an ankle-brachial index of between 0.7 and 1.2. Participants were excluded if they had gangrene on any area of the affected foot or evidence of infection not currently being treated as determined by their primary care provider.
Participants who met study inclusion criteria and agreed to participate in the study signed written consents for study procedures. Then they were randomly assigned to a treatment group by a research assistant who drew a sealed envelope from a box containing an equal number of envelopes for each treatment group. Following random assignment to treatment group, participants had blood work drawn for an HbA1c if they had not already within the previous 4 weeks. The ulcer area was cleansed, and a full assessment of the foot and ulcer area was done. Group A treatment consisted of TCC and a skin substitute (HAA), whereas group B treatment included TCC and standard wound care. A walking boot was used to cover the cast for protection.
Participants returned to the wound clinic 3 or 4 days following the first visit for ulcer assessment (including drainage, ulcer size, cast sizing, treatment, and other factors) and reapplication of the TCC. Thereafter, ulcer assessment and treatment and TCC reapplication occurred weekly. Participants were followed up by wound clinic providers weekly for up to 12 weeks, or 1 week beyond any complete closure occurring earlier than 12 weeks. Upon closure of the ulcer or at the end of the 12 weeks of treatment, HbA1c was recorded, and participants completed a researcher-designed questionnaire with content validity established by the researchers with expertise in nursing and lower leg and foot ulcers. The questionnaire contained six demographic items and a 12-item satisfaction questionnaire related to the TCC. Participants whose DFU closed wore the TCC for 2 weeks posthealing and then were fitted for proper footwear. All participants were provided with postulcer instructions regarding complications and offloading and prescription for therapeutic shoes and/or orthotics. Participants returned to the wound clinic 90 days after closure or 90 days after the 12 weeks of study participation for a follow-up visit.
Descriptive statistics were used to analyze demographic data; t and χ2 tests were used for comparison purposes.
The following research questions were addressed:
- What is the difference in time to closure for DFUs treated with TCC and HAA compared with those treated with TCC and standard wound care?
- Is there a relationship between HbA1c and time to closure for DFUs treated with TCC and HAA compared with those treated with TCC and standard wound care?
- What is the 90-day recurrence of DFUs?
- What is the participants’ reported satisfaction using TCC?
- What are the adverse effects of using TCC and HAA?
During the study, approximately 270 potential participants were screened for inclusion. The study sample consisted of a total of 13 adults (males = 11, females = 2; Table). Group A had seven participants (male = 6, female = 1), and group B had six (male = 5, female = 1). The mean age of group A was 58.5 years (range, 44-78 years; SD, 12.96 years), whereas the mean for group B was slightly younger at 55.17 years (range, 30-77 years; SD, 18.32 years). Most participants had type 2 diabetes mellitus (A = 4, B = 4), whereas the remainder had type 1 (A = 3, B = 2). Participants had a variety of comorbid conditions; peripheral neuropathy was the most common (69.2%), followed by hypertension (58.3%), peripheral vascular disease (53.8%), and coronary artery disease and renal disease (both 46.2%).
Difference in Time to Closure
The majority of participants experienced wound closure during the course of the study (92.3%), with one participant in each group not achieving wound closure, both of whom had Charcot foot. One participant in each group was diagnosed with an infection in the DFU during the study, and both of these participants had Charcot foot as well. The impact of Charcot foot and infection rates were not analyzed because of limited data.
At the study outset, mean ulcer surface area (length × width in cm2) was larger for group B (2.78 cm2) compared with group A (1.54 cm2). Group A had a longer mean time to closure (29.50 days) compared with group B (26.20 days). Of interest, the outlier with the longest healing time in group A had multiple comorbidities, including advanced age and type 1 diabetes.
HbA1c and Diabetic Foot Ulcer Closure
Group A had a higher mean HbA1c at study onset (9.63%) compared with group B (8.47%) and higher mean HbA1c at study closure for group A (8.82%) compared with group B (6.20% [data available for only one subject]). Although the higher HbA1c in group A may have made a difference in healing, given the small sample and limited HbA1c data, conclusions about the relationship between HbA1c and DFU closure could not be determined.
Recurrence of Diabetic Foot Ulcers
The 90-day recurrence rates were different for the two groups, with only one recurrence for group A (14.29%) and five recurring ulcers in group B (83.33%). Although significance cannot be established because of the sample size, there was a definite trend toward significance that merits further investigation with HAA.
Wound drainage was monitored at every visit. The majority of participants in group B had no drainage (83.3%) or a small amount (16.7%) compared with group A participants, where 42.9% had moderate drainage, 28.6% had a small amount, and 28.6% had none.
Participant Satisfaction with TCC
Overall, participants reported satisfaction with TCC, with 70% reporting that they did not mind wearing the cast. Participants reported that the cast was neither hot (60%) nor cold (80%), and that the cast was not tight (80%) or itchy (100%). Overall, 70% reported the cast to be comfortable and not painful, and 90% of participants reported that they would be willing to wear the cast again.
Although participants in group B (standard wound care and TCC) had a larger mean ulcer surface area at study outset and a shorter time to closure, this must be interpreted cautiously. Regarding surface area, the smaller surface area of group A (HAA and TCC) may have contributed to a lower rate of recurrence. Another possible explanation could be that participants in group A had a significantly higher HbA1c and presence of or treated infection at study outset and conclusion than did group B participants; however, poststudy HbA1c data were not consistently available because providers were reluctant to obtain postclosure HbA1cs outside normal diabetic protocols. It is known that elevated blood glucose levels are a detriment to healing. It should be noted that preexisting infection was an exclusion criterion for the study, and no other indicators of infection or inflammation were documented during the study that could explain the longer closure time for group A. Infection is very common in this population; however, patients who had infection were not included in the analysis in either group (one from each group). Another factor that may have affected time to closure was that group A had more participants overall diagnosed with hypertension and coronary artery disease. Further study with a larger sample is highly recommended.
Regarding wound drainage, which sometimes is an indicator of infection, the majority of participants in group B had no drainage (83.3%) or a small amount (16.7%) compared with group A participants: 42.9% had moderate drainage, 28.6% had a small amount, and 28.6% had none. It is possible that the amount of drainage in one participant in group A was reflective of an inflammatory and/or infectious condition in the DFU, although the individual was screened for presence of infection prior to cast application and met study inclusion criteria.
With regard to grading of ulcers, more participants in group B had a Texas grade 1 (83.3%) compared with group A (42.9%), and more participants in group A had a Texas grade 0 (57.1%) compared with group B (16.7%). Using the University of Texas system, ulcers are graded by depth and staged by the presence or absence of infection and ischemia. A grade 0 ulcer is a pre- or postulcerative site that has healed; a grade 1 ulcer is a superficial wound through either the epidermis or the epidermis and dermis, but does not penetrate to tendon, capsule, or bone. Grade 2 wounds penetrate to tendon or capsule, but there is no bone or joint involvement. Grade 3 wounds penetrate to bone or into a joint. Given this study’s sample size, it is not prudent to draw a conclusion about grading and its relation to ulcer healing; further study is needed.
During this study, approximately 270 participants were screened for potential inclusion. The majority of exclusions were related to infection; however, size and location of the ulcer and provider preference for an alternative mode of treatment limited participation as well. Participants who declined to participate had a variety of reasons, some of which included the distance to travel for weekly wound clinic visits, needing a cast on the right foot (which would have prevented them from driving), and patient desire to not wear a cast for social or other mobility reasons. Although travel costs were defrayed for participants, distance was still a factor in study participation.
In this study, protocols called for wearing of a cast until healing occurred, followed by 2 more weeks of wearing the cast, and then diabetic footwear was prescribed, with good healing results. Follow-up for 90 days showed a recurrence rate of 14.29% for group A and 83.33% for group B. A 2003 randomized controlled trial also documented that customized footwear is effective when the individual adheres to the prescribed regimen.34
Small sample size, in addition to homogeneity of the sample, limits the generalizability of these findings. The sample size was limited because of strict inclusion criteria, but also because of delayed referrals from primary care providers; by the time of referral, some patients were already experiencing complications such as infection and osteomyelitis, which in turn excluded them from the study. It is well documented that earlier intervention for DFUs by patients and providers can decrease detrimental consequences of foot ulcers.
Most participants experienced wound closure during the course of the study. Two participants did not achieve closure, both of whom had Charcot foot. Group A, which had a higher mean HbA1c at study outset, experienced a longer mean time to closure compared with group B. In this small sample, 90-day recurrence rates were different for the two groups, with only one recurrence for group A and five recurring ulcers in group B. Even though researchers could not establish significance because of sample size, there was a definite trend toward significance that merits further investigation with HAA and TCC.
Implications for Practice
Individuals with DFUs should receive early referrals to a wound care team equipped to provide care that is comprehensive and sensitive to the needs of these patients. Individuals in this study could only use the study product if there was no osteomyelitis or infection, and numerous individuals presented with infection upon screening. Earlier referral to a wound care team may have allowed for the provision of specific educational interventions, such as wound care management, diabetes management, offloading, and early detection and prevention of complications.
In this study, the cost of the product was not studied because products were provided by the manufacturer. Product costs should be considered when decisions are made about care of wounds. Certainly the cost of an expensive alternative is of value if the wound does not reoccur as frequently, but again, this requires further research.
Offloading during and after ulcer healing is paramount, and follow-up with patients to detect signs of recurrence is essential. Compliance is also influenced when a product is inconvenient for the patient. Some participants were not enrolled in the study for lack of interest in wearing the offloading boot. In this study, 90% of the patients “would wear the cast again,” with 70% reporting it to be comfortable and not painful. This information may be helpful for caregivers to know when prescribing and teaching patients about offloading.
Staff education regarding cast application and ongoing monitoring is necessary to prevent complications. Educating patients and their families regarding prevention, offloading, and preventing recurrence after the ulcer has healed, including blood glucose management and appropriate footwear post-TCC, is also recommended.
Implications for Research
Larger studies are needed. Collaborative research ventures with the participation of multiple facilities may be required to obtain the number of participants needed for a larger-scale study. The researchers also recommend that consideration be given to less strict study inclusion criteria to enhance recruitment.
Early detection of ulcer occurrence, as well as testing of modalities that help heal and prevent ulcer recurrence, along with associated costs, should continue to be research priorities.
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