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A case study to demonstrate the role of proteases in wound healing

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Adam Derbyshire, BSc (Hons), DNp.

District Nurse, De Parys Medical Centre, Bedford Primary Care Trust

Wound healing is undoubtedly a complex process. For simplicity, however, it is commonly divided into four distinct but overlapping phases:

Wound healing is undoubtedly a complex process. For simplicity, however, it is commonly divided into four distinct but overlapping phases:

- The vascular response - temporary wound closure through the formation of a clot comprising thrombocytes and fibrin, commonly called the coagulation cascade

- The inflammatory response - a normal response to injury characterised by localised heat, swelling and functional disturbance. Due to the increased permeability of the capillary membranes, exudate is produced. This is made up of neutrophils initially, and then macrophages that cleanse the wound and release growth factors such as platelet-derived growth factor, transforming growth factor-a and tumour necrosing factor-a. They also produce cytokines and proteases

- Proliferation - new connective tissue fills the wound, decreasing its size through granulation (facilitated by a collagen matrix through which angiogenesis occurs), contraction (contraction of fibroblasts at the wound margins bringing them together) and epithelialisation (the growth of new epithelial cells across the wound)

- Maturation - the development of scar tissue through the reorganisation of collagen fibres (Flanagan, 1999). Figure 1 shows the approximate length of time taken by each stage.

The role of proteases in wound healing
Proteases are enzymes present in wound exudate. In acute wounds they maintain the balance between tissue synthesis and degradation by regulating gene expression and enzyme activation and inhibition. If this regulation is defective, as in many chronic wounds, the increase in proteolytic activity will cause healing problems.

Matrix metalloproteinases (MMPs), particularly collagenase, denature collagen molecules. They have been found in high concentrations in the exudate of chronic wounds. Therefore their production requires inhibition in order to move from the inflammatory phase to proliferation.

Promogran is a relatively new product (developed by Johnson & Johnson) and is the first of its type. Its action is to reduce the level of proteolytic enzymes by trapping and inhibiting their activity. The dressing's mode of action is detailed in Box 1. The following case study, written by district nurse Adam Derbyshire, outlines its use and effectiveness in the clinical area, for those new to the product.

Case study - Patient profile
Forty-seven-year-old Laura Barker presented to the district nursing service on March 27, 2003, after discharge from hospital the previous day, with a large exudating ulcer (8cm long by 7cm wide by 1.5cm deep) on the lower left calf. Her calf area appeared swollen and was dark in colour; it had a sponge-like texture and was hot to touch.

Ms Barker had a history of epilepsy, and the wound had been caused during a seizure. She smoked heavily, which meant there was a possibility of compromised circulation at the ulcer site. She appeared dishevelled, with poor personal hygiene and awareness. This was reflected in the condition of Ms Barker's flat, even though family members visited and cleaned for her. Ms Barker's weight was approximately 95kg and her height 1.68m, giving an body mass index of 33.659 (over 30 is considered obese) (Arterburn and Hitchcock-Noel, 2001).

The patient had been commenced on flucloxacillin 500mg four times a day, amoxycillin 500mg three times a day and metronidazole 400g three times a day to try to reduce the infection in the leg.

Initial assessment
The discharge letter from the hospital described the wound as being 8cm by 8cm in size and the surrounding skin as being hot and oedematous, which continued around the circumference of the leg. The dressing regimen established in the hospital was a film dressing applied to the macerated skin, a silver dressing applied to the wound bed, a hydrogel, and a hydrocolloid dressing to secure.

Hospital staff had been unable to perform a Doppler ultrasound because of pain in the limb and the district nursing service was asked to make a full assessment of the leg after the oedema and pain had subsided. When the district nurses assessed the patient, the level of pain and oedema were such that Doppler ultrasound was still not an option.

The silver dressing was continued during the first week home post-discharge to help facilitate infection reduction (White, 2003). At the beginning of the second week, a zinc bandage was applied. A crepe bandage was applied during both weeks to keep the dressings in place. The wound was extensive and the level of 'strike through' of exudate meant that the dressing would need to be changed on alternate days.

On April 11 2003, 16 days since the first district nurse visit, the wound was considered clean enough to begin healing. The wound bed was now free of yellow slough. Inflammation had reduced since the completion of the multi-antibiotics course. The overall appearance of the wound indicated that the wound was not infected and the decision was taken to apply a Promogran dressing.

Wound assessment
Examination revealed an ulcer measuring 8cm by 7cm, with numerous indentations and crevices. There was also a 1cm by 1.5cm opening on the top right aspect of the wound, which appeared very deep and painful. Thus overall the wound was 57.5cm2.

Treatment
On the day of the district nursing assessment (April 11), following photography (Photos 1 and 2) and wound mapping, the wound was cleaned with normal saline and two Promogran 123cm dressings were shredded and applied to the surface in a double layer because of the level of exudate. Gauze was applied over the dressing and secured with a crepe bandage. The dressing was to be changed twice weekly.

Six days later (April 17) photographs were again taken of the wound. Photo 3 shows the level of exudate that had leaked through in three days. Photo 4 shows the wound after it had been cleaned. The small brownish area on the right side of the wound is the dressing that has dried at the wound margin. There was a major improvement since initial application of the dressing (three had now been made). The wound appeared to be a lighter pink colour and was not as deep as previously. The residual dressing was left in place at the edge of the wound for fear of causing further trauma if it was removed. Applying pressure to the small wound produced a large blood clot that revealed a deeper hole. Overall, the swelling around the site was much reduced.

Ten days (April 21) after the start of treatment, the wound was redressed. Nearly the entire wound area was a lighter pink in colour and appeared much shallower. The smaller wound was also much shallower and a single dressing was sufficient to cover the wound.

Three days later (April 24) the district nurses learnt that Ms Barker had had an epileptic seizure and fallen on her leg (see Photo 5). After cleansing, we found that the fall had caused minimal damage to the wound, although the swelling had increased as a result (see Photo 6).

Examination of the smaller wound led to a very large clot of blood being expelled. The larger wound was remapped and found to have improved considerably, being as much as 1cm smaller at the wound edges. The leg was redressed.

At the next dressing appointment on May 1, the district nurses found that the wounds had been redressed at Ms Barker's hospital appointment two hours before their visit and another type of dressing had been applied. This was removed.

The larger wound was cleansed, photographed, mapped once again and Promogran reapplied. It was only 20 days since the initial dressing application but there were clear signs of improvement (see Photo 7). One concern was a purplish discoloration noted around the wound.

At the next visit by the district nurses - five days later on May 6 -

Ms Barker reported that she had had another epileptic seizure and had woken up on the floor. Staff were relieved to find minimal trauma and were able to clean the wound easily (see Photo 8).

Concern was also raised about the swelling around the patient's ankle area, which had not reduced, in spite of the fact that the swelling in the rest of the leg had subsided. The GP was informed but said he was sure there was no fracture to worry about. The purplish discoloration seemed to be fading.

A visit three days later on May 9 revealed that the dressing had built up on the lower aspect of the wound again. The dressing was very hard to remove with saline (see Photo 9) and was left in place. In retrospect, a secondary dressing may have prevented the Promogran dressing from drying out and may have improved the healing rate at this stage.

At the next visit, four days later on May 13, district nurses found the dried dressing had flaked off to reveal newly healed skin underneath (Photo 10).

Thirty-two days after the initial use of Promogran the size of the larger wound had reduced considerably. Wound mapping revealed that its area was now 4cm2 compared with the 57.5cm2 initially reported to us. There was slight oozing from the smaller wound at this visit but there appeared to be no cause for concern.

To aid the subsequent removal of the dressing it was suggested by the manufacturer's wound-care representative that we dampen the dressing with saline before application.

On May 19 the signs of healing had clearly accelerated and the wound was rapidly shrinking (see Photo 11). This was confirmed at the following visit four days later.

Seven weeks after the first application and after the 14th application of the dressing, the wound had healed completely (Photo 12). A dry dressing was applied purely for protection.

Outcome
The Promogran dressing is very easy to tear to the required size and, based on previous experience, applying it in double layers seemed to increase wear time and help reduce exudate levels very swiftly.

We felt that the initial action of Promogran in raising the wound bed to the surface in three weeks was remarkable. The subsequent 10 days of accelerated healing were equally notable. Overall, the healing process took seven weeks and 14 applications of dressing.

Our main problem was that the dressing proved difficult to remove once exudate levels had reduced, increasing the risk of damage to the wound bed on removal. We were thus not able to view the wound to check healing progress at each visit, but had to wait until further visits.

Evaluation
This was a-difficult-to-heal wound and, while the use of Promogran was not planned initially, the positive response convinced us to continue to use the dressing with our patients.

The initial high cost of this dressing was justified in this case by the swiftness of the healing process. Using alternative treatments may have meant the wound would have taken longer to heal and would have required more input from district nurses. In 1998 it was estimated that each individual district nurse visit costs the NHS £23.37 (Morrell et al, 1998). Any reduction in the number of visits that might have been required is a valid cost saving to the trust.

With Promogran it took just seven weeks to heal a wound 57.5cm2, taking it through the four stages of healing from vascular response to maturation. The high levels of exudate present at the start of treatment actively diminished as the protease-modulating dressing reacted to reduce the proteolytic activity within the wound. The healing process was enhanced and the dressing prevented the wound from becoming much more serious.

The patient's name has been changed.

Arterburn, D. Hitchcock-Noel, P. (2001)Endocrine disorders: obesity. Clinical Evidence 5: 412-419.

Flanagan, M. (1999)The physiology of wound healing. In: Miller, M., Glover, D. (eds). Wound Management: Theory and practice. London: Emap Healthcare.

Johnson & Johnson Wound Management. (2002)Promogran: Protease-modulating matrix. (product monograph). Ascot, Berks: Johnson & Johnson Wound Management.

Morrell, C.J., Walters, S.J., Dunn, S. et al. (1998)Cost effectiveness of community leg ulcer clinics: randomised controlled trial. British Medical Journal 316: 7143, 1487-1491.

White, R.J. (ed.). (2003)The Silver Book. Salisbury, Wiltshire: Quay Books.

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