The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay
The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay
Foot complications are major causes of hospital admissions for diabetes, and they often demand surgical procedures and prolonged length of stay. Indeed, diabetic foot complications are major global public health problems in that these foot lesions and amputations represent the most important of all long-term problems associated with the disease of diabetes and have medical, social, and economic implications. Three great pathologies come together in the diabetic foot: neuropathy, ischemia, and infection. Their combined impact is so great that it causes more amputations than any other lower limb disease. As diabetic foot problems quickly reach the point of no return, it is vital to diagnose them early and provide rapid and intensive treatment. Furthermore, it is important to achieve early recognition of the at-risk foot so as to institute prompt preventive measures.The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay. The late sequelae of diabetic peripheral neuropathy are recognized to be foot ulceration and Charcot’s neuroarthropathy. It has been the fact that the risk of developing foot ulceration as a result of end-stage complications of neuropathy and vascular disease in diabetes is much greater than the other end-stage sequelae of diabetes, namely, retinopathy and nephropathy. The prevalence of foot ulceration in the general diabetic population is 4–10%, being lower in young and the highest in older patients. The lifetime risk for foot ulcers in diabetic patients is about 15%. Rothman’s model of causation defines a combination of neuropathy, trauma, and foot deformity to be the commonest pathways to foot ulceration and faulty healing may eventually lead to amputation. Foot ulceration and amputation affect the quality of life for patients and create an economic burden for both the patient and the health care system. Therefore, efforts to identify the patient who is at risk for foot ulceration, prevention, and appropriate treatment must, of necessity, become a major priority for healthcare providers. Peripheral neuropathy and vascular disease alone do not cause foot ulceration.
Diabetic foot ulcer (DFU) is the most costly and devastating complication of diabetes mellitus, which affect 15% of diabetic patients during their lifetime. Based on National Institute for Health and Clinical Excellence strategies, early effective management of DFU can reduce the severity of complications such as preventable amputations and possible mortality, and also can improve overall quality of life. The management of DFU should be optimized by using a multidisciplinary team, due to a holistic approach to wound management is required. Based on studies, blood sugar control, wound debridement, advanced dressings and offloading modalities should always be a part of DFU management. Furthermore, surgery to heal chronic ulcer and prevent recurrence should be considered as an essential component of management in some cases. Also, hyperbaric oxygen therapy, electrical stimulation, negative pressure wound therapy, bio-engineered skin and growth factors could be used as adjunct therapies for rapid healing of DFU. So, it’s suggested that with appropriate patient education encourages them to regular foot care in order to prevent DFU and its complications.The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay.
Core tip: Diabetic foot ulcer (DFU) is the most common complication of diabetes mellitus that usually fail to heal, and leading to lower limb amputation. Early effective management of DFU as follows: education, blood sugar control, wound debridement, advanced dressing, offloading, advance therapies and in some cases surgery, can reduce the severity of complications, and also can improve overall quality of life of patients especially by using a multidisciplinary team approach.
INTRODUCTION
Diabetes mellitus (DM) is one of the main problems in health systems and a global public health threat that has increased dramatically over the past 2 decades[1,2]. According to epidemiological studies, the number of patients with DM increased from about 30 million cases in 1985, 177 million in 2000, 285 million in 2010, and estimated if the situation continues, more than 360 million people by 2030 will have DM[3,4].
Patients with DM are prone to multiple complications such as diabetic foot ulcer (DFU). DFU is a common complication of DM that has shown an increasing trend over previous decades[5-7]. In total, it is estimated that 15% of patients with diabetes will suffer from DFU during their lifetime[8]. Although accurate figures are difficult to obtain for the prevalence of DFU, the prevalence of this complication ranges from 4%-27%[9-11].
To date, DFU is considered as a major source of morbidity and a leading cause of hospitalization in patients with diabetes[1,5,12,13]. It is estimated that approximately 20% of hospital admissions among patients with DM are the result of DFU[14]. Indeed, DFU can lead to infection, gangrene, amputation, and even death if necessary care is not provided[14]. On the other hand, once DFU has developed, there is an increased risk of ulcer progression that may ultimately lead to amputation. Overall, the rate of lower limb amputation in patients with DM is 15 times higher than patients without diabetes[8]. It is estimated that approximately 50%-70% of all lower limb amputations are due to DFU[8]. In addition, it is reported that every 30 s one leg is amputated due to DFU in worldwide[9]. Furthermore, DFU is responsible for substantial emotional and physical distress as well as productivity and financial losses that lower the quality of life[15]. The previous literature indicates that healing of a single ulcer costs approximately $$17500 (1998 United States Dollars). In cases where lower extremity amputation is required, health care is even more expensive at $30000-33500[16].The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay. These costs do not represent the total economic burden, because indirect costs related to losses of productivity, preventive efforts, rehabilitation, and home care should be considered. When all this is considered, 7%-20% of the total expenditure on diabetes in North America and Europe might be attributable to DFU[17].
ETIOLOGY OF DFU
Recent studies have indicated multiple risk factors associated with the development of DFU[18-21]. These risk factors are as follows: gender (male), duration of diabetes longer than 10 years, advanced age of patients, high Body Mass Index, and other comorbidities such as retinopathy, diabetic peripheral neuropathy, peripheral vascular disease, glycated hemoglobin level (HbA1C), foot deformity, high plantar pressure, infections, and inappropriate foot self-care habits]1,12,20-22] (Figure (Figure11).
The risk factors for diabetic foot ulcer. Ulcers may be distinguished by general or systemic considerations vs those localized to the foot and its pathology. (Data adapted from Frykberg et al[18]).
Although the literature has identified a number of diabetes related risk factors that contribute to lower-extremity ulceration and amputation, to date most DFU has been caused by ischemic, neuropathic or combined neuroischemic abnormalities[6,17] (Figure (Figure2).2). The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay. Pure ischemic ulcers probably represent only 10% of DFU and 90% are caused by neuropathy, alone or with ischemia. In recent years, the incidence of neuroischemic problems has increased and neuroischemic ulcers are the most common ulcers seen in most United Kingdom diabetic foot clinics now[23].
Etiology of diabetic foot ulcer. (Data adapted from Boulton et al[17]).
In total, the most common pathway to develop foot problems in patients with diabetes is peripheral sensori-motor and autonomic neuropathy that leads to high foot pressure, foot deformities, and gait instability, which increases the risks of developing ulcers[24-26]. Today, numerous investigations have shown that elevated plantar pressures are associated with foot ulceration[27-29]. Additionally, it has been demonstrated that foot defor-mities and gait instability increases plantar pressure, which can result in foot ulceration[24,30].
MANGMENT OF DFU
Unfortunately, often patients are in denial of their disease and fail to take ownership of their illness along with the necessary steps to prevent complication and to deal with the many challenges associated with the management of DFU. However, numerous studies have shown that proper management of DFU can greatly reduce, delay, or prevent complications such as infection, gangrene, amputation, and even death[6,31,32].
The primary management goals for DFU are to obtain wound closure as expeditiously as possible[33,34]. As diabetes is a multi-organ systemic disease, all comor-bidities that affect wound healing must be managed by a multidisciplinary team for optimal outcomes with DFU[35-38]. Based on National Institute for Health and Clinical Excellence strategies, the management of DFU should be done immediately with a multidisciplinary team that consists of a general practitioner, a nurse, an educator, an orthotic specialist, a podiatrist, and consultations with other specialists such as vascular surgeons, infectious disease specialists, dermatologists, endocrinologists, dieticians, and orthopedic specialists[39]. Today, numerous studies have shown that a multi-disciplinary team can reduce amputation rates, lower costs, and leads to better quality of life for patients with DFU[39-41]. The American Diabetes Association has concluded that a preventive care team, defined as a multidisciplinary team, can decrease the risks associated with DFU and amputation by 50%-85%[42]. It’s suggested that with applying this approach take appropriate strategies for management of DFU to consequently reduce the severity of complications, improve overall quality of life, and increase the life expectancy of patients[36]. In this article, we review available evidence on the management of DFU as follows: education, blood sugar control, wound debridement, advanced dressing, offloading, surgery, and advanced therapies that are used clinically. The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay.
RESEARCH
In this review article, we searched for articles published between March 1, 1980 and July 28, 2014 in the following five electronic databases: PubMed, Science Direct, Embase, Web of Science, and Scopus, for both English and non-English language articles with the following keywords: “diabetic foot ulcer”, “amputations”, “wound management”, “debridement”, “advanced dressings”, “offloading modalities”, “hyperbaric oxygen therapy”, “electrical stimulation”, “negative pressure wound therapy”, “bio-engineered skin“, “growth factors”, and “foot care” as the medical subject heading (MeSH). Study designs that were included were randomized controlled trials (RCTs), case-control studies, cohort studies, prospective and retrospective uncontrolled studies, cross-sectional studies, and review studies. Case reports and case series were excluded. We searched bibliographies for all retrieved and relevant publications to identify other studies.
Education
It has been shown that up to 50% of DFU cases can be prevented by effective education. In fact, educating patients on foot self-management is considered the cornerstone to prevent DFU[12,43-45].
Patient education programs need to emphasize patient responsibility for their own health and well-being. The ultimate aim of foot care education for people with diabetes is to prevent foot ulcers and amputation.The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay. Currently, a wide range and combinations of patient educational interventions have been evaluated for the prevention of DFU that vary from brief education to intensive education including demonstration and hands-on teaching[46]. Patients with DFU should be educated about risk factors and the importance of foot care, including the need for self-inspection, monitoring foot temperature, appropriate daily foot hygiene, use of proper footwear, and blood sugar control[47]. However, education is better when combined with other care strategies, because previous reviews on patient education has suggested that when these methods were combined with a comprehensive approach, these methods can reduce the frequency and morbidity of the limb threatening complications caused by DFU[48].
Blood sugar control
In patients with DFU, glucose control is the most important metabolic factor. In fact, it is reported inadequate control of blood sugar is the primary cause of DFU[6,49,50].
The best indicator of glucose control over a period of time is HbA1C level. This test measures the average blood sugar concentration over a 90-d span of the average red blood cell in peripheral circulation. The higher the HbA1C level, the more glycosylation of hemoglobin in red blood cells will occur. Studies have shown that blood glucose levels > 11.1 mmol/L (equivalent to > 310 mg/mL or an HbA1C level of > 12) is associated with decreased neutrophil function, including leukocyte chemotaxis[50]. Indeed, a greater elevation of blood glucose level has been associated with a higher potential for suppressing inflammatory responses and decreasing host response to an infection[6]. The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay. Pomposelli et al[51] has indicated that a single blood glucose level > 220 mg/dL on the first postoperative day was a sensitive (87.5%) predictor of postoperative infection. Furthermore, the authors found that patients with blood glucose values > 220 mg/dL had infection rates that were 2.7 times higher than for patients with lower blood glucose values (31.3% vs 11.5%, respectively)[51]. In addition, it’s indicated that a 1% mean reduction in HbA1C was associated with a 25% reduction in micro vascular complications, including neuropathy[47]. Investigations have found that poor glucose control accelerated the manifestation of Peripheral Arterial Disease (PAD). It has been shown that for every 1% increase in HbA1C, there is an increase of 25%-28% in the relative risk of PAD, which is a primary cause of DFU[52]. However, to date, no RCT has been performed to determine whether improved glucose control has benefits after a foot ulcer has developed.
Debridement
Debridement is the removal of necrotic and senescent tissues as well as foreign and infected materials from a wound, which is considered as the first and the most important therapeutic step leading to wound closure and a decrease in the possibility of limb amputation in patients with DFU[53-56]. Debridement seems to decrease bacterial counts and stimulates production of local growth factors. This method also reduces pressure, evaluates the wound bed, and facilitates wound drainage[32,57].
There are different kinds of debridement including surgical, enzymatic, autolytic, mechanical, and biological[58] (Table (Table1).1). Among these methods, surgical debridement has been shown to be more effective in DFU healing[54,59-62]. Surgical or sharp debridement involves cutting away dead and infected tissues followed by daily application of saline moistened cotton gauze[53]. The main purpose of this type of debridement is to turn a chronic ulcer into an acute one. Surgical debridement should be repeated as often as needed if new necrotic tissue continues to form[63]. It has been reported that regular (weekly) sharp debridement is associated with the rapid healing of ulcers than for less frequent debridement[59,64-66]. In a retrospective cohort study, Wilcox et al[66] indicated that frequent debridement healed more wounds in a shorter time (P < 0.001). In fact, the more frequent the debridement, the better the healing outcome. The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay.
Table 1
Different kind of debridement for patients with diabetic foot ulcer
| Method | Explanation | Advantages | Disadvantages |
| Surgical or Sharp | Callus and all nonviable soft tissues and bone remove from the open wound with a scalpel, tissue nippers, curettes, and curved scissors. Excision of necrotic tissues should extend as deeply and proximally as necessary until healthy, bleeding soft tissues and bone are encountered[59] | Only requires sterile scissors or a scalpel, so is cost-effective[55] | Requires a certain amount of skill to prevent enlarging the wound[55] |
| Mechanical | This method includes wet to dry dressings, high pressure irrigation, pulsed lavage and hydrotherapy[76], and commonly used to clean wounds prior to surgical or sharp debridement[76] | Allows removal of hardened necrosis | It is not discriminating and may remove granulating tissue It may be painful for the patients[55] |
| Autolytic | This method occurs naturally in a healthy, moist wound environment when arterial perfusion and venous drainage are maintained[18] | It’s cost-effective[55] It is suitable for an extremely painful wound[18] | It’s time consuming and may require an equivocal time for treatment[18] |
| Enzymatic | The only formulation available in the United Kingdom contains Streptokinase and Streptodornase (Varidase Topical®Wyeth Laboratories). This enzyme aggressively digests the proteins fibrin, collagen and elastin, which are commonly found in the necrotic exudate of a wound[77,78] | They can be applied directly into the necrotic area[55] | Streptokinase can be systemically absorbed and is therefore contraindicated in patients at risk of an MI It’s expensive[55] |
| Biological | Sterile maggots of the green bottle fly (Lucilia sericata) are placed directly into the affected area and held in place by a close net dressing. The larvae have a ferocious appetite for necrotic material while actively avoiding newly formed healthy tissue[79,80] | They discriminate between the necrotic and the granulating tissue[79] | There may be a reluctance to use this treatment by patients and clinicians It’s expensive[79,80] |
The method of debridement depends on chara-cteristics, preferences, and practitioner level of expertise[54]. When surgical or sharp debridement is not indicated, then other types of debridement could be used.
An older debridement type that is categorized as biological debridement is maggot debridement therapy (MDT), which is also known as maggot therapy or larval therapy. In this method, sterile and live forms of the Lucilia sericata larvae are applied to the wound to achieve debridement, disinfection, and ultimately wound healing[67-69]. Indeed, larvae secrete a powerful autolytic enzyme that liquefies necrotic tissues, stimulates the healing processes, and destroys bacterial biofilms[70-72]. This technique is indicated for open wounds and ulcers that contain gangrenous or necrotic tissues with or without infection[72]. To date, paucity of RCTs show efficacy of this method with DFU; however, some of retrospective[71,73]; and prospective[74] studies have shown MDT as a clinically effective treatment for DFU. These studies reported that MDT can significantly diminish wound odor and bacterial count, including Methicillin-Resistant Staphylococcus Aurous, prevent hospital admission, and decrease the number of outpatient visits among patients with DFU[71,73-75]. The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay.
ORDER A PLAGIARISM-FREE PAPER NOW
Despite the advantages of debridement, adequate debridement must always precede the application of topical wound healing agents, dressings, or wound closure procedures, which may be expensive.
Offloading
The use of offloading techniques, commonly known as pressure modulation, is considered the most important component for the management of neuropathic ulcers in patients with diabetes[81,82]. Recent studies have provided evidence indicating that proper offloading promotes DFU healing [83-85].
Although many offloading modalities are currently in use (Table (Table2),2), only a few studies describe the frequency and rate of wound healing with some of the methods frequently used clinically. The choice of these methods is determined by patient physical characteristics and abilities to comply with the treatment along with the location and severity of the ulcer[82].
Table 2
Common offloading techniques
| Technique | Casting techniques | Footwear related techniques | Surgical offloading techniques | Other techniques |
| Examples | TCC (Figure (Figure33) | Shoes or half shoes (Figure (Figure77) | ATL | Bed rest |
| iTCC (Figure (Figure55) | Sandals | Liquid silicone injections/tissue augmentation | Crutches/Canes/Wheelchairs | |
| RCW (Figure (Figure44) | Insoles | Callus debridement | Bracing (patella tendon bearing, ankle-foot orthoses) | |
| Scotch-cast boots (Figure (Figure66) | In-shoe orthoses | Metatarsal head resection osteotomy/arthroplasty/os ectomy/ exostectomy | Walkers | |
| Windowed casts | Socks | External fixation | Offloading dressings | |
| Custom splints | Felted foam/padding | |||
| Plugs |
Data adapted from Armstrong et al[82]. TCC: Total contact cast; iTCC: Instant TCC; RCW: Removable cast walkers; ATL: Achilles tendon lengthening.
The most effective offloading technique for the treatment of neuropathic DFU is total contact casts (TCC)[82,86,87]. TCC is minimally padded and molded carefully to the shape of the foot with a heel for walking (Figure (Figure3).3). The cast is designed to relieve pressure from the ulcer and distribute pressure over the entire surface of the foot; thus, protecting the site of the wound[82]. Mueller et al[87] conducted an RCT that showed TCC healed a higher percentage of plantar ulcers at a faster rate when compared with the standard treatment. In addition, a histologic examination of ulcer specimens has shown that patients treated with TCC before debridement had better healing as indicated by angiogenesis with the formation of granulation tissue than for patients treated with debridement alone as indicated by a predominance of inflammatory elements[88]. The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay. The contributory factors to the efficacy of TCC treatment are likely to be due to pressure redistribution and offloading from the ulcer area. In addition, the patient is unable to remove the cast, which thereby forces compliance, reduces activity levels, and consequently improves wound healing[84]. However, the frequency of side effects referred to in the literature and minimal patient acceptance make this approach inappropriate for wide applications[89,90]. Fife et al[91] has shown that TCC is vastly underutilized for DFU wound care in the United States. Based on this study, only 16% of patients with DFU used TCC as their offloading modalities. The main disadvantage of TCC was the need for expertise in its application. Most centers do not have a physician or cast technician available with adequate training or experience to safely apply TCC. In addition, improper cast application can cause skin irritation and in some cases even frank ulceration. Also, the expense of time and materials (the device should be replaced weekly), limitations on daily activities (e.g., bathing), and the potential of a rigid cast to injure the insensate neuropathic foot are considered other disadvantages. Furthermore, TCC does not allow daily assessment of the foot or wound, which is often contraindicative in cases of soft tissue or bone infections[36,32,83]. In some cases, it is suggested to use other kinds of offloading techniques such as a removable cast walker (RCW) or Instant TCC (iTCC). The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers Essay.
