A Closer Look At Combination Therapy For Chronic Wounds

Patricia Kim, DPM, and John M. Giurini, DPM

The advent of advanced treatments has made it possible for chronic wounds to benefit from a wide range of combined modalities. With a closer look at the research and an illuminating case study, these authors examine the efficacy of wound dressings, skin substitutes, hyperbaric oxygen therapy and other therapies.

When it comes to diabetic foot wounds, clinicians may use biologic dressings either independently or in combination with other modalities to facilitate swift resolution of the ulceration. While physicians typically choose treatments based upon patient selection, experience and regional preferences, a wide host of therapeutic modalities are available today. These modalities include silver impregnated dressings, platelet-rich plasma (PRP), bioengineered skin substitutes and hyperbaric oxygen therapy (HBOT).

   All wounds begin as acute wounds that ideally progress through the four typical phases of healing: hemostasis, inflammatory, proliferative and healing. Acute wounds heal in an expected timeframe without any disruption to these processes. Wounds become chronic and fail to heal due to a poor molecular environment that is rife with inflammatory cytokines, proteases and low levels of growth factors. Biologic therapies aim to alter the environment in some way in order to restart the normal healing pathway.

   Chronic wounds affect approximately 6 million people in the United States with lower extremity ulcerations being the most common. Due to an increase in adult obesity, the incidence of diabetic foot ulcers is increasing at a rate of 14 percent per year with 84 percent of that subgroup ultimately undergoing amputation.1 Neuropathy, peripheral vascular disease and pressure are the most common factors causing chronic lower extremity ulcers. Signs of chronic wounds include but are not limited to: increasing wound size, necrosis or nonviable tissue, recurrent breakdown and lack of granulation tissue.2

   Inflammatory phase markers, such as macrophages and polymorphonuclear neutrophils, aid in preparing the wound bed for the proliferative phase. However, their extended presence can cause tissue damage. Bacterial biofilms also act as a deterrent to wound healing. Biofilms are cells that attach to surfaces and are embedded in self-produced extracellular matrix.3 This film shows resistance to antibiotics due to inactivation of antimicrobial agents by extracellular polymeric substances, differentiation of cells into resistant dormant cells and a decreased oxygen gradient.

Investigating The Efficacy Of Silver Dressings

Silver containing dressings have been in use for many years to help manage local infection. Silver has a broad spectrum antibacterial range that includes gram-negative, gram-positive (including methicillin resistant Staphylococcus aureus (MRSA)), aerobic, anaerobic yeast and fungi.4 Silver’s antimicrobial effect is due to its inhibition of DNA replication, interference of the respiratory chain in microbial cytochromes and interference of microbial electron transport system components.

   A study utilizing Aquacel Ag (ConvaTec) showed that the silver impregnated dressings were able to decrease bacterial bioburden without any serious adverse events while continuing to promote wound moisture and exudate management.4 Research also shows that silver dressings can potentiate antibiotic therapy by increasing the susceptibility of bacterial walls within biofilms to antibiotics.3 In addition to its antimicrobial properties, silver also has antiseptic as well as anti-inflammatory properties.

   Peripheral edema often accompanies chronic wounds. This occurs via excessive interstitial hydrostatic pressure, which can compromise skin perfusion. Silver impregnated dressings can decrease edema, thereby improving skin perfusion as well as reducing the pain that patients may experience.

   Silver dressings are relatively inexpensive with multiple varieties. There are few adverse side effects but those include burning at initial application and hardening of dressings over joints.4 This therapy is useful in the clinical setting due to its cost effectiveness, safety and ease of application.

A Closer Look At The Potential Of Medical Honey

Clinicians have historically utilized medical honey for a myriad of ailments but investigators have only recently begun to look at the modality for chronic wounds. Medical honey contains leptospermum honey, which has demonstrated in vitro activity against MRSA.5

   The effectiveness of medical honey is due to its hygroscopic property as well as its low pH. Hygroscopic properties draw moisture out of an environment, thereby dehydrating bacteria whereas other products inhibit or attack the bacterial cell wall or inhibit metabolic pathways. Chronic wounds typically have a pH value >7.3 when colonized by bacteria.5 Honey’s low pH allows acidification of the wound, which inhibits bacteria and speeds wound healing.

   Protease activity is also suppressed as a neutral pH is optimal for proteases to destroy growth factors, protein fibers and fibronectin in the wound matrix. Medical honey also acts as an anti-inflammatory, which decreases wound exudate as well as edema. Nerve endings are sensitized by prostaglandins during the inflammatory phase, which are also decreased due to honey’s anti-inflammatory property.

   Another beneficial effect not often mentioned is malodor, which is commonly present in chronic wounds. Topical medical honey can reduce this unpleasant characteristic. It can be a cost effective treatment method that one can easily use in the clinical setting.

What You Should Know About Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy has been in use for more than 40 years as a wound healing adjunct. With HBOT, a patient goes into a compression chamber under atmospheric pressure greater than one atmosphere absolute of 100 percent oxygen.6 This increased pressure theoretically increases the oxygen level dissolved in the blood, which in turn affects vascular tone and promotes wound healing.

   One would not use HBOT alone but in combination with serial debridements, antibacterials and local dressings. While few well-controlled randomized trials exist documenting the efficacy of HBOT, there is growing evidence that supports HBOT as a successful adjunct in the treatment of chronic diabetic foot ulcers.7 Complications are few but can include oxygen poisoning, claustrophobia or ear/sinus/lung damage.

Emerging Insights On Combining NPWT with Conservative Care

Negative pressure wound therapy is another treatment that one usually uses in combination with antibacterials. The environment created with the apparatus decreases edema by lowering exudate collection. This in turn increases blood flow to the wound bed, allowing the phases of wound healing to continue.

   Dressings are confined to the vacuum-assisted closure (VAC therapy, KCI) dressing. Concomitant antimicrobial dressings are rarely used with VAC therapy. A recent systematic review showed increased healing of diabetic foot ulcers when combining conservative treatments with VAC therapy.8

What The Literature Reveals About PRP

Continued research is occurring on PRP, which promotes platelet-derived growth factors, vascular endothelial growth factors and cytokines in the hopes that this will stimulate wound healing. The procedure requires a sample of the patient’s blood that spins down in a centrifuge that separates blood into the red blood cell layer, the “buffy coat” (which is the PRP layer) and the plasma-poor layer. One subsequently injects the isolated PRP layer into the area of concern.

   The theory is that tissue healing and microcirculation improve because of the variety of growth factors contained in PRP. Studies show that PRP can restart the healing process in otherwise recalcitrant chronic wounds. In one study, 96.5 percent of wounds had a positive response with area and volume reduction in only two weeks after three treatments.9 Another study showed that in the most common wounds (including pressure ulcers, venous ulcers and diabetic foot ulcers), the use of PRP reduced wound volume, area, undermining and sinus tract/tunneling after 2.8 weeks with 3.2 applications.10

   Adverse effects are few. Since PRP is an autologous substance, allergic reactions are rare and transmissible infections are fewer. Unfortunately, research is limited and most insurance companies do not reimburse for the procedure. Patients are therefore required to pay for this treatment on their own.

How Effective Are Bioengineered Skin Substitutes?

Skin substitutes were initially developed for the treatment of patients with burns and physicians now frequently use them in the treatment of chronic foot wounds. Some of these substitutes derive from allogeneic sources while others are bioengineered in the lab. They accelerate wound healing by providing a moist wound environment, act as a structural support and provide a network of cytokines and growth factors.

   Skin substitutes consist of an epidermal layer and/or a dermal layer embedded into an acellular matrix, which acts as a support structure.11 This combination of angiogenesis, growth factors and cell adhesion properties allows for a shorter wound healing time when clinicians use skin substitutes in conjunction with other conservative treatments. The three-dimensional skin substitute provides a metabolically active, living scaffold that allows for proliferation of the dermal bed.

   Trials have shown that the use of skin substitutes such as Dermagraft (Advanced BioHealing) or Apligraf (Organogenesis) result in a higher incidence of complete wound closure and shorter time to complete wound healing.12 The most promising results of trials involving skin substitutes indicated that the concomitant use of skin substitutes and other modalities of wound treatment, namely debridement, yielded shorter healing time.13

   Skin substitutes are contraindicated in actively infected ulcers or those patients with bovine allergies. Infections are low and systemic toxicity is rare. Patients can receive this treatment in the office setting. It is a simple, non-painful procedure.

Case Study: Combining Skin Substitutes With Weekly Debridement Of A Chronic Wound

A 70-year-old male presented with a diabetic ulceration on the medial aspect of his left heel. The ulceration has been present for nearly two years without evidence of healing. The patient previously received oral antibiotics and local dressing changes consisting of antibiotic ointment. The patient has had diabetes for 18 years and has experienced complications such as peripheral neuropathy as well as peripheral vascular disease. He also suffers from hypertension and coronary artery disease.

   His physical examination showed normal skin color, turgor and temperature. His dorsalis pedis and posterior tibial artery pulses were non-palpable. There was an ulceration on the medial aspect of his left heel that measured approximately 1.0 cm in diameter and 8 mm deep. The ulceration did not undermine nor probe to bone. The base of the ulceration contained yellow, fibrotic tissue.

   Initial treatment consisted of local debridement of the ulcer, an offloading pad and topical dressings using normal saline. We obtained a formal vascular consultation.

   Noninvasive pulse volume recordings showed monophasic waveforms at the level of the dorsalis pedis and posterior tibial arteries. The patient subsequently had angiographic evaluation to help determine whether stent replacement was necessary. The angiogram revealed a totally occluded anterior tibial artery at the trifurcation and a severely diseased and diminutive peroneal artery down to the foot. His posterior tibial artery was widely patent down to the foot with inline flow from the femoral artery. Since the posterior tibial artery was widely patent to the foot and this was a medial heel ulceration, the vascular surgeon determined that stenting of the artery would provide no added benefit.

   We continued to provide local wound care along with an offloading pad. However, after four weeks, no progress had occurred. We subsequently initiated a series of Dermagraft treatments. Weekly visits consisted of debridement of the ulceration down to healthy bleeding tissue. This involved removal of all fibrotic tissue as well as macerated hyperkeratotic tissue around the margins of the ulceration. We applied a 1 cm2 double layer of Dermagraft weekly for five weeks. Dressings remained intact until the next visit and treatment. By week five, the ulceration had reduced to a diameter of 5 to 6 mm and 2 to 3 mm in depth. We applied a sixth application of double layer Dermagraft. At that point, the patient was ready for application of Apligraf in an effort to achieve 100 percent epithelialization.

In Summary

With this myriad of treatment choices, podiatric clinicians have the tools to combat chronic lower extremity ulcers. Depending on patient selection and wound type, one can use biologic therapies independently or in combination with other modalities to optimize the chances of wound closure. The increasing number of chronic foot wounds with poor prognosis demand attention and further research in an attempt to improve outcomes.

   Dr. Kim is the Chief Resident at Beth Israel Deaconess Medical Center in Boston. She is a Clinical Fellow at Harvard Medical School in Boston.

   Dr. Giurini is the Chief of the Division of Podiatric Medicine and Surgery at Beth Israel Deaconess Medical Center. He is an Associate Clinical Professor in Surgery at Harvard Medical School.


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