T

he world is facing a major epidemic of diabetes. There are 190 million people with diabetes in the world today. Over the next 22 years, this number is expected to increase 72 percent worldwide to nearly 325 million people. Specifically, in the United States, diabetes is expected to increase 60 percent over the next 22 years, while in Europe diabetes is expected to increase a modest 16 percent. The highest prevalence of diabetes is in the Pima Indians’ community in Arizona where up to 50 percent of the residents have diabetes. There is an increasing number of young people and children with type 2 diabetes especially among ethnic minority groups. This increase in diabetes is mainly attributed to modernization or westernization of the world’s societies¹.

PathophysiologyNeuropathy
       A lack of pain is what leads to many of the lower-limb complications often seen with diabetes. Diabetic neuropathy is a complication associated with diabetes that can lead to foot ulcers. Those at greatest risk of developing foot ulcers include those who have past histories of foot ulcers, those who have undergone amputations, or those with microvascular complications. As early as 1887, it became clear to the medical community that diabetes may play an active role in the causation of perforating ulcers. An article published in Lancet in 1887² stated it was abundantly evident to the author in his clinical observation that the cause of the perforating ulcers was a degeneration of peripheral nerves. Yet there is a paradox in diabetic neuropathy, because some individuals experience severe pain with preserved sensation, while others experience much less pain and loss of sensation, and still others have no symptoms whatsoever.
       Twenty percent of persons with diabetes will develop foot ulcers, and the vast majority of these ulcers are initially due to neuropathy. Neuropathic ulcers are frequently complicated by infection. In a study by Reiber,³ investigators reviewed several cases to determine key component causes that resulted in the diabetic foot ulceration. Investigators found that while a single component cause may be important in the development of ulceration, it would not cause ulceration on its own; however, when combined with other component causes, ulceration would develop. This study showed that the most important component cause of diabetic ulceration was neuropathy, which was present in four out of five subjects (78%). Other causative factors include infection and ischemia. It is mandatory that physicians treating diabetic patients with foot problems determine which components of this etiologic triad (neuropathy, infection, ischemia) are contributing to the foot ulcer in each patient. It is estimated that 80 percent of diabetic ulcers are potentially preventable.
       Neuropathy on examination is usually symmetrical; the symptoms are usually bilateral, but they may be more severe on one side. Most often, however, symptoms are symmetrical. Often, when diabetic neuropathy rapidly progresses, the physician may attribute the symptoms to another cause.

Epidemiology
       Globally, there appears to be a steady increase in major amputations, although there have been some regional differences. Studies in the United Kingdom reported an increase in amputation despite the St. Vincent Declaration to reduce amputations by 50 percent. Likewise, there is no evidence of a decrease in amputations⁴. Sweden, however, has been successful in reducing the number of amputations. All Swedish citizens carry cards with them that contain their medical data. This allows Sweden to have very accurate databases, and together with well-organized diabetes care, this has probably resulted in a fall in the amputation rate⁵.
       The prevalence of foot ulceration in the various studies worldwide is important to consider. For example, in a study from Sweden in 1990, the subjects had a prevalence of foot ulcers of less than one percent and a population aged 15 to 50 with type 1 diabetes. However, in a study from the United Kingdom, 1.4 percent of the patient population in the study had active ulcers, and this study comprised active and a history of ulcers; in other words, 4.8 percent of the population had ulcers previously or during the study. In the developing world, like South Africa, especially in Algeria, 12 percent of the patient population have active ulcers and 6.7 percent were amputees. The US has a high rate of amputation, which is at 8.1 per 1,000 persons with diabetes. More recent data from the San Antonio population base dataset shows the incidence of ulceration to be about 6.8 per 1,000 persons with diabetes per year^6,7.
       A HMO US population retrospective study published in 1999 estimated the outpatient cost of a foot ulcer over two years to be $28,000, which did not include inpatient treatment⁶. Worldwide, particularly in developing countries, diabetes is increasingly common.
       There is an ongoing study on neuropathy to determine why there are differences. In a paper published in Diabetes Care, 1,665 persons with diabetes enrolled in a health management program⁶. This study showed incidence of ulcerations to be 6.8 percent and incidence of amputations to 0.6 percent. This study showed that amputation rates are greater in Mexican Americans.
       According to a study by Reiber, who investigated outpatient foot ulcer episodes in the Veteran’s Administration (VA) in 2001, the rate of foot ulcer episode was very high in VA patients with diabetes⁸.
The US Centers for Disease Control and Prevention (CDC) surveillance system is the largest telephone server in the world, servicing 44 states. According to data obtained from this system, 12 percent of adults with diabetes have a history of foot ulcers. There are limitations to this study, which include that it is based on self reporting. In other words, subjects may or may not even know what a foot ulcer is⁹.
       Certain ethnic groups are considered to be at greater risk of ulceration, including Mexican Americans, Hispanics, and Blacks, while other ethnic groups appear to be at lower risk. The incidence of diabetic foot ulcers is likely to increase. Foot ulceration is a major burden for the economies of developing countries⁹.
       The risk factors for diabetic foot ulcers appear to be well described, although there has been much neglect of psychological aspects of diabetic neuropathic foot complications¹⁰. The important physical factors to look for on clinical examination include neuropathy, peripheral vascular disease, foot deformity, and other microvascular complications. Those patients with known risk factors, including past histories of foot ulceration or amputation, require much more frequent follow up, regular education, and podiatric care in order to reduce the all too high incidence of diabetic foot ulceration in the United States.

Basic Science and Mechanism of Action of Negative Pressure Wound Therapy
       The negative pressure wound therapy (NPWT) device (Vacuum Assisted Closure®, V.A.C.® Therapy, Kinetic Concepts Inc., San Antonio, Texas) consists of a sterile, open-foam cell dressing that is cut to fill a wound defect. The foam is sealed to the wound by an adhesive dressing, and an evacuation tube is applied to the foam. The end of the tube not placed through the foam is attached to a pump outside of the wound, so subatmospheric or negative pressure can be applied uniformly to all tissue within the wound.
       In theory, applied negative pressure will stimulate development of granulation tissue in a previously nonhealing wound leading to epithelization. The proposed process by which the NPWT device accomplishes this is by uniformly drawing the wound edges closed by applying controlled local negative pressure. This pressure removes interstitial fluid, which allows tissue decompression, removes infectious materials, and provides a closed moist wound healing environment. Thus, given the action of NPWT, it is possible that the following mechanisms occur: provision of a moist wound healing environment; improved management of exudate; improved bacterial burden within the wound; increased wound temperature; and physical stimulation of cells.


Moist wound healing (occlusion)
       NPWT applies occlusion to the wound bed, which, theoretically, creates a moist wound healing environment. Advantages of a moist wound bed include promotion of rapid epithelization of acute wounds, enhanced healing of chronic wounds, reduced pain, and reduced chance of infection. The most simple outcome of this is that moisture in the wound bed prevents the epithelium from having to migrate and digest crust. In the moist wound bed, the epithelium has a smoother pathway to reepithelize the surface of the wound. Additionally, in this more aqueous milieu, growth factors are more active, more available, and more easily synthesized within a moist environment compared to a desiccated environment. There may be more available matrix materials as well, and moist wounds maintain their lateral voltage gradient, or so called wound healing potential, more effectively than wounds that are dried¹¹.

Exudate management
       Exudate can be detrimental to wound healing because it contains excess amounts of proteases, primarily matrix metalloproteinases, and lesser amounts or inactivity of their inhibitors.
       In addition to removing fluid that contains an imbalance of matrix metalloproteinases and their inhibitors, there may be other benefits of NPWT in regard to removing fluid. Localized edema occurs in response to tissue injury, and this localized edema then results in an increase in interstitial pressure. This increased interstitial pressure then causes occlusion of the microvasculature and lymphatics. This leads to decreased nutrients and decreased oxygen delivery. A greater accumulation of metabolic waste and increased bacterial colonization leads to a release of protein-degrading enzymes. These protein-degrading enzymes may then cause capillary damage and hypoxia, which lead to a decrease in collagen matrix formation and an oxidative burst. This oxidative burst is important in destroying neutrophils, the presence of which leads to inflammation and a subsequently more proteolytic environment¹². NPWT creates an increase in diffusion gradients, which then facilitates the removal of this excess interstitial fluid and improves some of those parameters.

Infection control
       With regard to the concept that NPWT helps control bacterial burden, one study¹³ involved five pigs with acute wounds that were inoculated with 108 infecting organisms. Investigators applied 125mmHg to some of these wounds and then harvested full-thickness biopsies from each of these wounds every 24 hours for bacterial burden. They found that between Days 4 and 5, NPWT wounds had a decrease in the bacterial load (105), while the control wounds not receiving NPWT continued to have elevated levels of bacteria.
       It has been suggested that the presence of higher bacterial loads within wounds delays healing¹⁴. If a reduction of bacterial burden is achieved with NPWT, the result may have a beneficial effect on healing.

Wound heating
       Chronic wound fluid is inhibitory to cells, and if that fluid is heated, it reverses the inhibitory effect. Some clinicians have used devices, such as Warm-Up® therapy (Augustine Medical, Eden Prairie, Minnesota), to warm wounds, in effect perhaps reversing the chronic wound fluid. A small, randomized trial in 10 patients with diabetic foot ulcers¹⁵ showed better healing compared to a control group when they received Warm-Up therapy. A simpler alternative to raising the temperature of a wound is the use of an occlusive dressing. By using an occlusive dressing, NPWT may also warm the wound and provide this beneficial effect for healing.

Physical stimulation of cells
       In 1892, Julius Wolfe noted that bone changed shape in response to physical stress. Subsequent to that, a German histologist, Richard Thoma, extrapolated Wolfe’s observation to soft tissues and found that the development of blood vessels is governed by dynamic forces acting on their walls as follows: An increase in velocity of blood flow causes dilation of the lumen; an increase in lateral pressure of the vessel walls causes it to thicken; and an increase in end pressure causes formation of new capillaries. This is the law of tension stress,¹⁶ and it postulates that gradual traction on living tissues creates stresses that can stimulate and maintain regeneration or active growth of certain tissue structures. In other words, slow, steady forces metabolically activate tissues.
       When NPWT is applied to patients, the foam in the wound bed collapses, which transmits a negative force to surrounding tissues. This force deforms the extracellular matrix in cells, and by doing this, it capitalizes on this tension stress effect. This results in activating tyrosine kinases, transporting genes, stimulating calcium release, and inducing early growth response genes.
       Through the aforementioned mechanisms, numerous studies suggest that NPWT may improve healing by providing a moist wound healing environment, improving management of exudate, improving bacterial burden within the wound, increasing wound temperature, and physically stimulating cells.