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Treating Recalcitrant Diabetic Wounds with Hyaluronic Acid: A Review of Patients
The characteristic wound in the patient with diabetes is the foot ulcer, which is estimated to affect up to 15% of all people with diabetes during their lifetime.1 The cost of diabetic foot ulcers is high; the length of hospitalization for such patients is 59% longer than for diabetic patients without foot ulcers,2 and approximately 85% of all amputations follow foot ulceration.3 People with diabetes also suffer from venous disease and leg ulceration, presenting a clinical picture similar to that seen in the general population.4,5
While dressings remain the mainstay of wound treatments, they have no "active" wound healing properties. Despite major recent advances in wound treatment technology, a high prevalence of chronic wounds exists, underscoring a need for topical agents that can actively promote wound healing. Treatments have been developed to better address the needs of the wound - eg, vacuum-assisted closure (VAC) and added growth factors and cells to enhance healing.6 These therapies have met with mixed success in the clinic7,8; none, as yet, has been definitively proven to be cost-effective.
A molecule widely found in connective tissues and known to be integral to the repair process9,10 is the polymeric carbohydrate hyaluronic acid (HA), also known as hyaluronan. Hyaluronic acid is a naturally occurring, non-immunogenic, biodegradable polysaccharide. The umbilical cord, synovial fluid, vitreous humor in the eye, and rooster combs are particularly rich in hyaluronic acid. Hyaluronic acid has been shown to enhance angiogenesis11 and the phagocytic responses of macrophages.12,13 Hyaluronic acid in gel form has been used successfully for many years in ophthalmology and in the treatment of connective tissue disease, inflamed joint conditions,14 and rheumatoid arthritis. In wound healing, HA is involved in the early response to injury, acting with fibrin to support the influx of fibroblasts and endothelial cells into the wound site and the subsequent formation of granulation tissue.15 The topical application of HA has been shown to be effective in the treatment of chronic wounds.16 However, natural HA is difficult to sterilize and handle. It is rapidly broken down in vivo, particularly when applied to wounds. To overcome these problems, HA has been esterified with benzyl alcohol to form a soft, white fleece and rope that can be easily manipulated (ie, cut to shape and inserted into the wound) and that degrades slowly to provide a sustained release of HA to the wound. This HA ester, or HYAFF® (Fidia Advanced Biotechnology, Padova, Italy), has been incorporated into Hyalofill® by ConvaTec Ltd. (Princeton, NJ) and is available in fleece, sheet, and rope forms.
Preliminary clinical data on the use of HA ester in nonhealing and difficult-to-heal wounds has been encouraging.17-19 Using a known healing rate from historical data on standardized treatments as a reference,20 Sheehan's group was able to identify patients whose ulcers had become static - ie, showed no signs of progress to healing for over 4 weeks - and who responded to management with HA ester (see Table 1). Hyaluronic acid is available in both sheet and ribbon forms for flat, open wounds and for cavities/sinuses. Clinical performance aspects of HA ester use include the following observations7,8,21-23:
* Hyaluronic acid in ribbon form is effective in the treatment of sinuses where, owing to its biodegradability, it does not need to be removed from the wound.15
* Hyaluronic acid is effective in the treatment of indolent diabetic foot ulcers and can be used as a limb preservation measure to avoid amputation.8,21,23
* In moderate and heavily exuding wounds, the use of a hydrofiber secondary dressing provides for optimal exudate control and HA efficacy.7
* Hyaluronic acid has been shown to stimulate healing, even in immunocompromised patients.7,21,22
More specifically, HA stimulates the wound and facilitates the development of a well vascularized dermal bed.11,24 Hyaluronic acid ester has been used before grafting with autologous keratinocytes.25 The HA ester is used as a "primer" for 2 to 3 weeks before grafting to stimulate the wound bed before the cells are applied. Research by Navsaria26 showed that on full-thickness wounds, the "take" rates of grafted keratinocytes are significantly improved if the wound is pretreated with HA ester.
At Guy's Hospital, London, and the Meadowbrook Foot and Ankle Center, New York, HA ester has been used on various wounds.7,8,27,28 The most dramatic results have been noted when it is used for recalcitrant ulcer beds and wounds that are slow to heal and appear "stuck" in the inflammatory stage of healing.
Hyaluronic acid ester is indicated for all wound types, provided the wound is clean without slough or dry, black, necrotic tissue. It is not intended for use on patients with known sensitivity to the dressing or its components.
Certain wounds may have a better response if VAC therapy is implemented before the application of HA ester.29 Examples of this include heavily exuding, chronic infected, and large, deep open wounds.
Guidelines for Applying HA Ester
Application. Clinicians using HA ester in wound care should perform the following steps:
* Cleanse the wound site, rinse well, and dry the surrounding skin.
* Position the HA ester onto the surface of the wound.
* Insert the rope form into the cavity or sinus.
Cover the wound with a sterile secondary dressing held in place with surgical tape or a bandage as appropriate. The secondary dressing chosen will vary according to the level of exudate - ie, for a lightly or moderately exuding wound, an alginate or hydrocolloid will be sufficient; in highly exuding wounds, a dressing that can manage large quantities of exudate (such as Aquacel® Hydrofiber® dressing, ConvaTec, Princeton, NJ) is essential. Hydrofiber dressings can be used on top of HA ester to increase exudate absorption.
Because HA ester is biodegradable, the rope form need not be removed from the cavity.
Interval between dressing changes. The interval between dressing changes will depend entirely upon the state of the wound. Heavily exuding wounds may need daily changes initially, but as healing progresses and the amount of exudate decreases, the interval between changes may be extended from 3 to 5 days.6 Because HA ester has no significant exudate handling properties other than requiring a moist environment, the choice of secondary dressing becomes paramount. The case histories that follow used a hydrofiber dressing to provide a moist environment that optimizes the delivery of HA.
Length of use. Hyaluronic acid ester is only necessary until a visible change in the wound bed is evident - generally 2 weeks or four to five applications are appropriate to "jump start" a wound, after which moist wound healing products can be used. Use of the rope form is advised until the sinus is closed.
Case Studies
The following case studies illustrate the use of HA on difficult-to-manage wounds with static wound beds. In this context, these individual case studies, conducted by the authors, are intended to provide supplementary clinical evidence30 to that obtained from the controlled clinical trial.18
Case 1.
History. A 64-year-old man with a history of insulin-dependent diabetes mellitus, peripheral vascular disease, hypertension, coronary artery disease, benign prostate hypertrophy, and cataracts was referred to the clinic by a vascular surgeon. He had undergone bilateral arterial graft reconstruction but continued to have poor circulation in his legs. The left second toe was amputated following complications from an ingrown toenail on the adjacent first toe that led to osteomyelitis.
At presentation, three ulcers were found: the stump of the exposed second metatarsal head and two necrotic dorsal ulcers, with a sinus tract distally exiting the stump of the second digit amputation (see Figures 1 and 2). Symptoms of advanced cellulitis required immediate admission, as the patient was at risk of losing the foot. Wound cultures were positive for Staphylococcus aureus and Candida albicans. The clinical challenge in this case was to manage a diabetic ulcer on a foot with subcutaneous tissue (cellulitic) infection.
Treatment and outcome. Surgical debridement of the second metatarsal head ulcer and necrotic soft tissue structures was performed, as well as debridement of the dorsal wounds. Because they were malodorous, wounds initially were covered with a hydrofiber dressing and Carboflex® odor control dressing (ConvaTec, Princeton, NJ). Intravenous culture directed antibiotics and oral itraconazole were implemented for infection management.
After 3 weeks, the patient was discharged from hospital and treated on an outpatient basis. Intravenous antibiotics and antifungals were changed to the oral forms to continue treatment outside hospital and the ulcers were debrided as clinically indicated at dressing changes. Once the cellulitis subsided and the amount of exudate decreased, HA ester was introduced as the wound contact layer. At this stage, the wounds were clean, noninfected, and without exposure of bone. A hydrofiber was used as secondary dressing to manage wound exudate and DuoDERM® hydrocolloid dressing (ConvaTec, Princeton, NJ) was applied to retain the HA ester and hydrofiber dressings. Dressings were changed every 3 days. Too weak to walk due to his heart condition, the patient used a wheelchair, so various clinicians were consulted to facilitate rehabilitation. His physiotherapist encouraged him to walk for exercise using a removable walking cast and a cardiovascular exercise regimen was arranged that did not compromise the healing of his foot ulcers.
The wounds responded immediately as evidenced by the development of granulation tissue. They were epithelialized by week 6 of the management regimen and remained 100% healed after 18 months (Figures 3 and 4).
Case 2.
History. A 44-year-old male presented to the clinic with a venous ulcer on the lateral side of the left leg that had been present for almost 5 years. The primary reason for the ulceration had been IV drug use complicated by several episodes of phlebitis and infection. Comorbidities included non-insulin dependent diabetes mellitus, human immunodeficiency virus (HIV) disease, alcoholism, morbid obesity, and hypertension. This patient was noncompliant and had poor control of hyperglycemia and hypertension. The high prevalence of peripheral vascular disease is well recognized in people with diabetes.31 In the pathogenesis of venous ulceration (as opposed to foot ulceration), venous hypertension is a significant factor. In the presence of reduced immune status, in this case through HIV disease, the healing response is impaired. This frequently renders any ulcer of the lower limb difficult to heal. The diagnosis of venous etiology, as in this case, requires an ankle brachial pressure index (ABPI) <1.32 As diabetic arteries are often sclerosed, the pressure index should be interpreted with caution before applying compression bandaging.33
On presentation, the wound was malodorous and exuding heavily, probably due to the significant amount of edema (see Figure 5). The entire ulcer area was tender. Extensive fungal infections were present on the foot. The ulcer had been managed with an Unna boot, the dressing changed weekly, and a plethora of other topical and systemic materials and drugs, including several types of antibiotics, were used.
The wound was surgically debrided, oral antifungal therapy (itraconazole) was prescribed, and the antibiotic treatment regimen discontinued. Topical use of becaplermin gel (Regranex, Ortho-McNeill Pharmaceuticals, Raritan, NJ) was initiated together with a multilayer compression bandaging system, but this treatment modality had to be stopped after the first application because of hyperesthesia in the form of an "extreme burning sensation." The patient had cut off the bandaging to remove the growth factor gel.
The clinical challenge in this case was to manage a difficult-to-heal wound in an immunocompromised patient with diabetes and additional complicating medical conditions.
Treatment and outcome. A combination of HA ester, covered with a hydrofiber dressing, initially was used with an activated carbon odor-control dressing as the third layer to control wound odor. This was combined with sustained compression using the four-layer bandaging scheme. The first dressing change was carried out after 3 days; thereafter, dressing changes were performed weekly.
Granulation tissue developed quickly (see Figure 6), and by week 5 the entire wound was re-epithelialized (see Figure 7). The rapid response motivated the patient to stop his intravenous drug use and become more compliant.
This case illustrates that even in severely immunocompromised patients where the normal wound repair processes are almost certainly impaired, applying appropriate wound care principles and products can heal recalcitrant wounds.
Case 3.
History. A middle-aged woman who had fluctuating blood glucose levels and was noncompliant with her insulin-dependent diabetes presented with hypoglycemia. The patient had full-thickness necrotic heels colonized with methicillin-resistant Staphylococcus aureus (MRSA) which, following surgical debridement, were treated with conventional dressings. Each wound remained clean but after 8 weeks, little progress in healing occurred, and the surrounding skin had become macerated and painful (see Figure 8).
The clinical challenge was to promote healing of recalcitrant heel wounds in a patient with diabetes. Treatment objectives included: a) controlling blood sugar and ensuring compliance of treatment, b) reducing maceration of the surrounding skin, c) promoting granulation tissue formation and epithelialization, and d) preventing secondary complications
. Treatment. After three applications of HA ester (10 days' treatment), both wounds granulated to the surface and new epithelial tissue was evident. The surrounding skin had improved and was less painful (see Figure 9).
Conclusion
The case histories presented on difficult-to-heal diabetic wounds demonstrate the successful use of a new wound application: HA ester. Despite the underlying diabetes-associated pathologies and physiological problems such as fluctuating blood glucose levels, wound healing was achieved where previous regimens had failed. In the case of Patient 1, wounds healed where little had been expected and amputation had been considered to be the most likely course of action. Avoiding amputation can have considerable implications for both the patient and the hospital, including simplified aftercare support for the hospital. For the patient, limb preservation added to quality of life and reduced morbidity. Although these case studies are anecdotal, they indicate that the use of HA ester, as part of an overall strategy of glycemic control, pressure relief, and debridement may play an important role in healing recalcitrant diabetic wounds and preserving limbs.
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