EUROPEAN TISSUE REPAIR SOCIETY

PHYSICAL FORCES IV

EFFECT OF NONCONTACT NORMOTHERMIC WOUND THERAPY (NNWT) ON THE HEALING OF DIABETIC NEUROPATHIC FOOT ULCERS: RESULTS OF A SINGLE CENTRE RANDOMISED STUDY INVOLVING FORTY-NINE PATIENTS

DIABETIC foot ulceration is a significant cause of morbidity and it is the most common reason for hospital admission in diabetic patients. Each year between two and three percent of diabetic patients will develop foot ulcers, and up to 15% of diabetic patients will develop chronic foot ulcers during their lifetimes.¹

In those who require lower limb amputation 70 to 90% of these will be preceded by a foot ulcer.1 The majority of ulcers occur in the diabetic foot because of repetitive stress on insensitive feet (diabetic neuropathy). Ulceration of the neuropathic foot develops at the sites of high mechanical pressure on the plantar surface of the toes, over the metatarsal heads and on the plantar surface of the hallux.

The understanding of the physiology and pathophysiology of wound healing has improved substantially during the last twenty years, and, as a result, advanced treatments are starting to become available to the clinician. Synthetic dressings that improve the wound environment, biological skin substitutes that provide cell therapy and growth factors that stimulate wound healing have been shown to improve the healing of neuropathic ulcers in the diabetic foot.² The following report describes our experience with a device designed to maintain wounds and surrounding tissues at normothermia (37°C±1).

A medical device consisting of a wound cover that serves as the primary wound dressing and a heating element or warming card with a power supply provides NNWT. The wound cover is a chamber made up of two layers of high moisture vapour-permeable polyurethane film supported by and attached to a doughnut-shaped open-cell foam pad which is coated with a medical grade adhesive. The central transparent window portion of the wound cover is a two-layered pocket that houses the warming card. The window is positioned directly over the wound and allows for visualisation of the wound when the warming card is not inserted in the pocket. The warming card is the heating element. It is a flat, thin, reusable, resistant heater that connects to the power supply. The warming card does not come in contact with the skin as it remains suspended approximately 1 cm from the wound bed by the wound cover. The power supply is the control unit and automatically maintains the temperature of the heating element at 38°C. The cordless power supply contains a rechargeable battery, measures 15 cm x 10 cm, is 1.5 cm thick and weighs approximately 400 grams.

The purpose of this study was to assess the effectiveness of NNWT for the healing of diabetic neuropathic foot ulcers. The primary efficacy endpoint was the proportion of patients with complete wound healing by week 12.

Eligible patients between the ages of 38 and 78 (with a mean age 59) were entered into the study after an institutional review board-approved informed consent was obtained. All study participants were treated in an outpatient clinical environment with home care (visiting nurse) between appointments. Enrolled patients were randomly assigned to receive either NNWT or standard care (control) according to a computer-generated randomisation schedule. In patients with more than one ulcer, the ulcer with the longest history of non-healing was selected as the target ulcer. Fifty-seven percent of patients were female, 43% were insulin-dependent and 96% had Type 2 diabetes mellitus. The mean ulcer area was 320 mm², 78% reported having the ulcer open for less than one year and 23% had a history of non-healing for 1–3 years. Seventytwo percent of the ulcers were in the forefoot area. There were no significant differences between the control and NNWT treatment groups in patient demographics, baseline ulcer size nor ulcer duration. The patients were followed for 12 weeks for analysis of efficacy endpoints.

Fifty patients were randomised for the trial and 49 were treated; for statistical analysis, 49 patients who met inclusion and exclusion criteria were evaluated, with 25 patients randomised to NNWT and 24 patients to standard care (Control). One patient who was randomised to NNWT was lost to follow up after the initial evaluation (Day 0 visit) and did not receive treatment. All wounds were diabetic neuropathic foot ulcers defined as follows: An ulcer on the plantar surface of the foot in a patient with a diagnosis of Type 1 or Type 2 diabetes mellitus. The target ulcer must be secondary to peripheral neuropathy in a patient with adequate arterial circulation (ankle brachial pressure index (ABPI) >0.7 and palpable pulses). The ulcer must extend through the dermis and into subcutaneous tissue (granulation tissue may be present) but without exposure of muscle, tendon, bone or joint capsule. Exclusion criteria were as follows: clinical signs of infection, osteomyelitis, cellulitis, uncontrolled diabetes and any other clinically significant medical conditions that would impair wound healing inclusive of renal, hepatic, haematological, neurological, or immunological disease. Patients taking corticosteroids, immunosuppressive agents, radiation, or chemotherapy within one month prior to entry into the study were also excluded.

Patients in both groups received standard care treatment for diabetic foot ulcers. Initial aggressive sharp debridement (heavy debridement) of the ulcer was performed at the initial evaluation day 0. Heavy debridement includes removal of necrotic tissue, elimination of undermining and wound margins excised to healthy bleeding tissue. At each weekly follow-up visit light debridement was performed to remove callus surrounding the ulcer, eliminate undermining and to expose the wound margins. Hydrotherapy or other pressurised mechanical methods of wound debridement were not performed. Chemical or enzymatic debridement ointments were not used at any time throughout the study.

All patients were fitted with a therapeutic healing sandal with customised Plastizote‚ inserts (cut out in the area over the ulcer) to accommodate the wound cover and redistribute pressure away from the ulcer. Patients were instructed to avoid bearing weight on the affected foot and were given crutches and a wheelchair.

Upon randomisation, after debridement and prior to treatment, patients were evaluated (baseline, Day 0). Baseline evaluation consisted of a clinical wound assessment including overall wound condition, erythema, oedema, wound margins (undermining), amount of granulation and exudate (type and amount). The size of the wound was determined by computerized planimetry of surface tracings made with an acetate transparent film. The wounds were photographed after debridement and prior to dressing application. At each weekly evaluation the wound was assessed for closure (healing). Wound healing was defined as full (100%) epithelialisation of the wound with absence of drainage. After light debridement, the wound was traced, photographed and clinically graded. Clinical assessment included signs of infection, cutaneous undermining, amount of granulation and amount of drainage. Wound evaluations were performed by one of the two primary investigators who were aware of the treatment regimen (open label).

A record was maintained of the patient’s fasting blood sugar and the diary was checked to verify that radiant heat therapy was applied for one hour, three times daily. Concurrent medication use was updated and both inter-current and adverse events were recorded.

Analysis was carried out on an intention-to-treat basis using SAS software (version 6.10 for Windows) Comparisons between treatment groups for demographics and baseline ulcer characteristics were performed using the Fisher exact test or c2 analyses. Frequency of wound healing between the two treatment groups was compared using a two-tailed Fisher exact test and time to wound closure was computed using a survival analysis by the Kaplan-Meier life- table method.

The application of noncontact normothermic wound therapy was not associated with pain or discomfort. The most common adverse event was skin maceration of the periwound area in the NNWT group. Slight to moderate skin maceration was observed in 10 of the 25 patients but did not result in the discontinuation of therapy.

Treatment with NNWT had a greater mean percent wound closure than control-treated ulcers at each evaluation point (Table 1). When compared with control treatment at the 4, 6, 10 and 12-week time points, the rate of healing in wounds treated with NNWT was 1.8 (p = 0.039), 2.6 (p = 0.044), 2.9 (p = 0.019) and 3.2 (p = 0.011) times faster respectively. The number of days needed for 50% reduction in ulcer area was 25 for the NNWT-treated wounds and 43 for controls (p = 0.031).

The greater effectiveness of NNWT over controls could also be observed by survival analysis using the Kaplan- Meier life table method (Figure 1). A significantly greater proportion of patients in the NNWT treatment group had healed at week 8 (56% vs. 29%, p = 0.04), at week 10 (60% vs. 33%, p = 0.02) and at week 12 (72% vs. 38% p = 0.008). As determined by Cox proportional hazard regression analysis, the average patient treated with NNWT had a 43% better chance for wound healing per unit time than a patient in the control group (p <0.05; 95% confidence interval, 2.014–2.319).

The most feasible explanation for the improved healing of diabetic foot ulcers treated with NNWT is the result of increased perfusion of blood combined with an increase in oxygen tension due to vasodilatation of cutaneous blood vessels. Although these parameters were not measured in our studies they have been reported in the literature. Rabkin and Hunt showed that local heat increases blood flow and oxygen tension in wounds in a linear fashion.3 A rise of 5.6–22.5 mmHg oxygen tension can be expected per 1^°C rise in skin surface temperature. Enhanced healing of diabetic foot ulcers treated with NNWT could also be associated with the effect of increased warmth on fibroblast growth and proliferation. Using cell culture models it has been shown that increased warmth provided by the NNWT system enhances adult fibroblast proliferation and seems to reduce the inhibitory effect of chronic wound fluid on newborn fibroblast growth.⁴

Infections are a frequent problem in patients with diabetic foot ulcers. Concerns exist that the local warm and moist environment provided by NNWT might increase the incidence of wound infection and even spread rather than control infection. In our limited experience with 25 patients treated with NNWT to date we have not seen increased infection rates. Interestingly, researchers feel that applying heat could be an effective method of treating infected tissues.⁵

Most clinicians are in agreement that the key to healing neuropathic diabetic foot ulcers in patients with adequate arterial circulation is successful off-loading (pressure and shear relief). The application of the NNWT system three times daily for a one-hour interval may improve patient compliance to off-loading instructions.

Normally, the wound cover in patients receiving NNWT is changed once daily. In larger more exudative wounds, skin maceration may occur and the wound cover should be changed more frequently. In this study, the patients who developed skin maceration around the ulcer were instructed to change the wound cover as needed. Of the ten patients who developed skin maceration, nine resolved with BID dressing changes and one resolved with TID dressing changes.

This study was designed to test the effect of NNWT on healing and to compare the effects with those of standard care for diabetic foot ulcers. We felt that it was not necessary to compare NNWT to a sham unit or the wound cover alone (without the warming card) since the therapy was already tested for efficacy and safety in previous studies. ⁶

The results of this study demonstrate that NNWT improves the healing of diabetic neuropathic foot ulcers. Further study in a greater patient population is necessary to evaluate fully the efficacy of this device and to provide additional information on whether local warmth can reduce the incidence of infection.

Contributors

O. Alvarez was involved in planning the study, obtaining funding, analysing data, interpreting the results, and writing the paper; R. Rogers and J. Booker were involved in patient recruitment, co-ordination of the trial, data collection and patient education; M. Patel contributed to study design, patient recruitment, data collection and editing the manuscript.

Acknowledgements

This study was funded by an unrestricted research grant from Augustine Medical Inc. Eden Prairie, MN. The sponsors of the study had no role in study protocol preparation, study design, data collection, data analysis, data interpretation or writing the report.

References

1. Borssen B, Bergenheim T, Lithner F. The epidemiology of foot lesions in diabetic patients aged 15–50 years. Diabetic Med 1990; 7; 438–44.
2. Dinh T, Pham H, Veves A. Emerging Treatments in diabetic wound care. Wounds 2002; 14 (1): 2–10.
3. Rabkin JM, Hunt TK. Local heat increases blood flow and oxygen tension in wounds. Arch Surg 1987; 122: 221–5.
4. Park HY, Shon K, Phillips T. Effect of heat on the inhibitory effect of chronic wound fluid on fibroblasts in vitro. Wounds 1998; 10: 189–92.
5. Lee ES, Caldwell MP, Talarico PJ, Kuskowski MA, Santilli SM. Use of a noncontact radiant heat bandage and staphylococcus aureus dermal infections in an ovine model. Wound Rep and Reg 2000; 8: 562–66.
6. Berman JB, Kloth LC, Dumit-Minkel S, Sutton CH, Papanek PE, Wurzel DJ. ‘Effects of non-heated Warm-Up‚ dressings on skin temperature elevation and healing of full thickness wounds.’ Abstract presented at The Third European Pressure Ulcer Advisory Panel Meeting, Amsterdam, The Netherlands, September 2–5, 1999.

O.M. Alvarez, Ph.D. and M. Patel, MD
University Wound Care Centers and East Tremont
Vascular Health Center, Bronx, NY
R.S. Rogers, RN, MSN and J. Booker, RN, BSN
Visiting Nurse Service of New York, New York, NY

Correspondence to:
Oscar M. Alvarez, Ph.D.
University Wound Care Centers, LLC,
3175 East Tremont Avenue,
Bronx, New York 10461, USA
(e-mail: oalvarez@comcast.net)