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Managing chronic/stalled arterial, venous and pressure ulcers with collagen and oxidised regenerated cellulose dressings

Author(s)

Emilio Galea
Assistant Director of Nursing, Nursing Education Department
Nursing Administration Mafraq Hospital PO Box 2951 Abu Dhabi UAE

Contents
Published:
Last updated: July 2014
Revision: 1.1

Abstract

One of the main challenges faced by clinicians when dealing with wound care is to be able to ‘jump start’ the chronic and stalled wounds that are stuck in the inflammatory stage. One of the reasons for stalled wounds is elevated proteases levels. Although matrix metalloproteases have an important role in the inflammatory stage of wound healing, they become destructive to the wound matrix in a prolonged inflammatory stage.

Collagen / oxidised regenerated cellulose dressings are intended for the effective reduction of protease activity and the protection of growth factors. They also change the wound microenvironment by binding and inactivating gelatinases in wound exudates. The dressing has also been stated as decreasing elastase and plasmin activity during treatment to enable better results in wound healing.

Several studies have been published regarding the use of the collagen ORC dressing in diabetic ulcers, however there is seemingly less evidence regarding the use of this treatment when used in arterial, venous and pressure ulcers. In view of this, a systematic search was conducted to find evidence for the use of collagen ORC dressing in these ulcers. Pubmed, Cochrane, Cinahl and TRIP were utilised to provide a comprehensive list of articles regarding the subject matter.

The main aim of this article was to provide clinicians with enough high level evidence to assist in decision making when choosing to utilise a collagen ORC dressing in venous, arterial and pressure ulcers. The search did not provide any evidence regarding use in arterial ulcers and only provided 3 high level evidenced articles for venous and pressure ulcers. Although evidence is available regarding the use of collagen ORC in lower limb ulcers, there is a requirement for further studies to provide a sounder scientific basis for clinical practice.  


Introduction

During the past 40 years wound management has evolved immensely and many wound therapies have been created to cope with non-healing, chronic and stalled wounds. However, it has been debated that many of these dressing choices are based more on clinician experience rather than scientific evidence, probably because of conflicting conclusions of high-level studies [1][2].  

Wound healing is dependent on the equilibrium between removal of damaged tissue and new tissue formation - this is regulated by growth factors and proteases which are intended to control normal wound repair [3].  Stalled wounds have been described in literature as those wounds that are not healing in the regular pattern, where there is an increase in senescent cells that are less responsive to cellular signalling, decreased growth factors, as well as other diminished cellular responses [4][5]. Cell migration is impaired and there is also insufficient angiogenesis while an imbalance in matrix metalloproteases (MMPs) leads to tissue destruction [6], [7].  26 classes of MMPs have been identified and they are classified according to their substrate specificity and structural similarities [8]. MMPs are capable of degrading collagen and other components of the extracellular matrix and have an important role in the inflammatory stage of wound healing – however, in a prolonged inflammatory stage, they become destructive to the wound matrix [9]. There are cases where the protease activity in chronic/stalled wounds has been reported to be in excess of one hundred times more than that found in acute wounds [10].

Collagen provides platelet aggregation, haemostasis and chemotaxis of macrophages, granulocytes and fibroblasts during wound healing [11]. It is also suggested that collagen matrices, when placed in the wound micro-environment, may provide a building block for tissue growth when endogenous collagen is disrupted by the proteolytic wound environment [12]. Furthermore, oxidised regenerated cellulose (ORC) was added with collagen in a wound dressing to enable binding of the elevated levels of proteases [13].  The ratio of collagen to ORC is around 55:45 – this composition allows for utilisation of the wound healing properties of both materials intended for effective reduction of protease activity, protection of growth factors and also changes the wound micro-environment by binding and inactivating gelatinases in wound exudates [8], [14], [15].  The collagen ORC dressing has also been stated as decreasing elastase and plasmin activities during treatment to enable better results in wound healing [16].

Several studies have been published regarding the use of the collagen ORC dressing in diabetic ulcers and a systematic review has also been conducted [17]. It was however noted that there is seemingly less evidence regarding the use of this modality when used in arterial, venous and pressure ulcers. In view of this, a systematic search was conducted to find the evidence for the use of collagen ORC dressing in these ulcers with the research question set up as: “How effective is the use of collagen and oxidised regenerated cellulose in reducing healing time in chronic arterial, venous and pressure ulcers?”

Method

Pubmed, Cochrane, Cinahl and TRIP were utilised to provide a comprehensive list of articles regarding the subject matter. An initial search on Scopus suggested that the results being achieved were much broader than the other databases and therefore disregarded. A search was also conducted using Google Scholar to scan if there are other articles available that might have been overseen. No search restrictions were implemented in order to be able to find all possible work on the subject matter. The research question was divided utilising the PICO concept [18] (Table 1).
Table 1

Patient/Population

and/or Problem  

Intervention 

Comparison/Control

      (if applicable) 

Outcomes

(or effects) 

chronic ulcers 

collagen and oxidised regenerated cellulose 

 

reducing healing time 

Key words, search strategies and search results are shown in Table 2.  
Table 2:

# 

Search Term 

Pubmed

(all fields – no limits) 

Cochrane

(title, abstract, keywords – no limits) 

Cinahl

(Boolean phrase – no limits) 

Totals 

Concept 1 (P) 

“Chronic ulcer” 

398 

21 

27 

446 

“Chronic ulcers” 

615 

66 

112 

793 

“Chronic wound” 

827 

74 

541 

1442 

“Chronic wounds” 

2043 

211 

1147 

3401 

“Pressure Sore” 

804 

104 

1164 

2072 

“Pressure Sores” 

1946 

299 

1076 

3321 

“Decubitus Ulcer” 

865 

43 

120 

1028 

“Decubitus Ulcers” 

917 

73 

238 

1228 

“Bed sore” 

43 

20 

21 

84 

10 

“Bed Sores” 

128 

24 

56 

208 

11 

“Leg Ulcer” 

7705 

578 

2513 

10796 

12 

“Leg Ulcers” 

3837 

869 

1383 

6089 

13 

“Arterial Ulcer” 

23 

12 

11 

46 

14 

“Arterial Ulcers” 

82 

20 

36 

138 

15 

“Venous Ulcer” 

457 

128 

1535 

2120 

16 

“Venous Ulcers”  

1021 

315 

409 

1745 

17 

#1 or #2 or #3 or #4 or #5  

or #6 or #7 or #8 or #9

or #10 or #11 or #12 or #13

or #14 or #15 or #16  

16445 

1895 

7473 

25813 

Concept 2 (I)  

18  

“Collagen and Oxidised Regenerated cellulose” 

11 

10 

29 

19 

“Collagen and Oxidized Regenerated cellulose” 

44 

11 

56 

20 

“Collagen/Oxidised Regenerated cellulose” 

14 

21 

“Collagen/Oxidized Regenerated cellulose” 

18 

22 

Promogran 

23 

24 

28 

75 

23 

#18 or #19 or #20 or #21 or #22 

65 

31 

43 

139 

Concept 3 (O)  

24 

Reduce* 

1331503 

102538 

115071 

1549112 

25 

Decrease* 

1488047 

96536 

89721 

167304 

26 

Minimize* 

71357 

2952 

8968 

83277 

27 

Minimise*  

7492 

6144 

1441 

15077 

28 

Heal* 

2482527 

179283 

940962 

3602772 

29 

#24 or #25 or #26 or #27 or #28 or #29  

4751164 

295181 

106969 

5153314 

Combined concept search  

 

 

Pubmed 

Cochrane 

Cinahl 

 

30 

#17 and #23 and #29 

21 

18 

17 

56 

MESH Search  

Search Term 

Pubmed 

Cochrane 

Totals 

Collagen 

146 

1638 

1784 

Cellulose, oxidized 

38 

39 

Wound healing 

3826 

3830 

#1 and #2 and #3 

29 

35 

TRIP  

Population  

Intervention  

Outcome  

Ulcer* 

Promogran 

Heal* 

Total found : 5

NB – search with different terminology in “Intervention” did not render additional varied results  

Total number of hits: 96; Total number of different articles found: 66

Additional databases:

Databases of on-going research:

NB –  - Search conducted utilizing concept 2 terminology.

  1. MetaRegister of Controlled Trials (UK)

  2. UK Clinical Research Network Study Portfolio

  3. ClinicalTrials.gov

  4. Open grey

 

A set methodology was used in how the search was conducted utilising published guidelines [19]. Both singular and plural forms of terms were utilised where an exact phrase was used, e.g. “chronic ulcer” and “chronic ulcers”. Where singular words were utilised, truncation was used to avoid missing any slight variation in the search term, e.g. reduce* to include reduces, reduced, reducing, etc. Using shorter term e.g. reduc# yielded a vast number of terms which were not relevant to search.

Synonyms and different terminology were also utilised to maximise search e.g. ‘decrease’ instead of ‘reduce’ and using the term ‘bed sore’ and ‘decubitus ulcer’ for the term ‘pressure ulcer’. The trade name of the dressing was utilised in concept 2 to ensure that both articles utilising generic and brand name of the product were caught. Using the term protease-modulating matrix did not provide different results from the other terms. Difference in spelling, e.g. English and American spelling ensured that articles completed in different countries and/or for different journals were identified.

Controlled vocabulary was used to perform a more complete search, i.e. Medical Subject Headings (MeSH). Boolean: ‘OR’ connector was utilized to broaden the search while ‘AND’ connector was utilized to narrow the search. The ‘explode’ function was deemed unnecessary for the results found.

Inclusion and Exclusion criteria

A total of 96 articles were identified from the different databases after the search was completed (30 were duplicate, thus the end total of different titles was 66). Out of these, the articles that included data suitable to answer the research question were identified.

Evidence collected was sorted in order to identify any irrelevant work. The elimination strategy included: (a) articles whose title suggests irrelevance to subject matter were excluded (e.g. diabetic ulcer). If a doubt still existed after review of the title, the abstract was looked into to identify relevance. If any doubt was still present after looking at the title and abstract, the article as a whole was looked over to confirm if it should be included or eliminated. Irrelevance of articles found may be summarised as: main topic different from research query, e.g.:  skin substitutes; sequential therapy and/or therapy used in conjunction with other modality e.g. silver (cannot determine if effect only due to modality in the query); focus on different treatment modalities apart from collagen ORC e.g. foams, alginates, hydrocolloids; acute wounds; diabetic wounds; surgical wounds; haemostatic properties. (b) Furthermore, lower level of evidence [20], [21], e.g. opinion papers, were also excluded.

Inclusion was limited to studies that were considered as relevant, i.e. discussed the particular modality, that is, collagen ORC, modality was used as management of chronic arterial, venous or pressure ulcers and studies that were considered as a higher level of evidence.  

3 studies were finally identified as evidence that would facilitate answering the research query. 2 articles were regarding venous leg ulcers and 1 was about pressure ulcer management.

Venous ulcers

In the first randomised controlled prospective open-label multicentre comparative two-arm parallel-group study [22], seventy-three patients with stagnating venous leg ulcers which had to be free of infection and of at least 30 days duration were recruited. The target wound had to be ≥2cm but ≤10cm in any one dimension. They were divided into two cohorts where thirty-seven were randomly allocated in cohort 1 to collagen ORC and thirty-six in cohort 2 to non-adherent silicone dressing.  Eleven venous leg ulcers healed in the control group (31%) and 15 in the collagen ORC group (41%) (p=0.373). Healing was considered to be achieved if the target ulcer was completely re-epithelialised. Overall, 15 venous leg ulcers healed or improved (≥ 50% reduction in size) in the control group (42%) and 23 in the collagen ORC group (62%) (p=0.079). Surface area decreased, on average, by 36.5±11.4% (median decrease: 44.6%) in cohort 2 group and by 54.4+10.9% (median decrease: 82.4%) in cohort 1 (p<0.001). A ≤20% surface area reduction was observed in 15 patients in cohort 1 and in seven in the cohort 2 (42% versus 19%; p=0.034). Although the study’s aim was not to show efficacy of healing rate, results did suggest that the collagen ORC provided better results in comparison to the non-adherent dressing. Justification for choosing the non-adherent dressing as comparison was that it has been shown that it is appropriate management of this type of ulcer and the non-adherent dressings avoid damage to the venous leg ulcer bed and reduce the risk of skin sensitivity. One of the weaknesses listed was the inability to conduct a double-blind trial.

In the second study [23], a prospective trial was performed in 40 patients with chronic venous leg ulcers. Inclusion criteria were: chronic venous insufficiency, leg ulcer present >3 months that was non-responsive to medical treatment, the wound size was within the range of 50 cm2 and 100 cm2, reflux present in the area of the extrafascial cutaneous saphenous veins and/or of the deep conducting veins and/or perforating veins and patients were ready and able to adhere to medical instructions and comply with the scheduled visits. Cohort 1 (n=30) was treated with the collagen ORC dressing while cohort 2 were treated with hydropolymer (polyurethane) or hydrocolloid dressings (n=10). The results showed a favourable clinical response in 76.9% in cohort 1 in respect to 66.7% in cohort 2. Mean value reduction of ulcer area was statistically significant in cohort 1 (P < 0.0005). The wound score (score assessed by granulation, colour, consistency, discharge/exudates) improved in cohort 1 from 2.28 (1.24) (before treatment) increasing to 3.72 (1.57) (after 1 week; P <0.0023) and 4.92 (1.68) (after 2 weeks; P < 0.000027). This study examined the immediate effects of the collagen ORC dressing and was designed as a prospective case comparison study. The authors hypothesised that “the positive effect of the collagen ORC dressing on the microcirculation might be due to its collagen content as well as its ability to reduce the enzyme activity in the wound fluid and rebalance the wound environment”

Pressure Ulcers

A randomised control trial was conducted to evaluate the use of collagen ORC in the management of pressure ulcers in selected patients according to a standardised protocol [24]. In this randomised, prospective, controlled, clinical study in pressure ulcers, 2 cohorts were randomly set up where cohort 1 (n=40) were treated with collagen ORC while cohort 2 (n=40) were given treatment which consisted of daily disinfection and viscose-rayon gauze soaked in white Vaseline. Wounds in both groups were covered with a hydropolymer dressing. Treatment was only initiated when the wound was cleansed (no necrosis and no infection) using surgical debridement and disinfection with PVP-I solution.  All patients with complete healing underwent a 6-month follow-up. Complete healing was achieved in 36 (90%) in cohort 1 compared to 28 (70%) in the control patients. Time required to achieve a clean wound ranged from 1-6 weeks, after which time to complete healing ranged from 2-6 weeks for cohort 1 wounds and 2-8 weeks for cohort 2. The authors concluded that the study demonstrated a greater frequency of complete healing and shorter healing times in collagen ORC treated patients compared to controls. Furthermore, fewer dressings were needed in cohort 1 (6-15) than in cohort 2 (14-52) as well as shorter hospitalisation stays (360 v 1164) which translates to cost effectiveness. It was also suggested that the ease of use experienced with collagen ORC allowed for earlier discharge and home management.

Conclusion

In an article published in 2002 it was suggested that there were in excess of 3000 wound management products available and all manufacturers claim that their products are beneficial in promoting healing [25]. Although wound dressings alone are not responsible for healing wounds, the choice of the most appropriate dressing will most probably facilitate wound progression [25]. The clinician’s role is essential to determine effective wound management and this entails that there should be adequate knowledge of wound care modalities [25]. Choosing the right dressing has to start with an overall patient and wound assessment with the specific treatment goal options identified - only then can the clinician identify ‘‘using the right product on the right wound at the right time” [26]. Unfortunately, systematic reviews available regarding the different wound management products available have failed to provide us with high levels of evidence regarding their clinical efficacy [27], [28].

The main aim of this article was to provide clinicians with enough high level evidence to assist in decision making when choosing to utilise a collagen ORC dressing in venous, arterial and pressure ulcers. The search did not provide any evidence regarding use in arterial ulcers and only provided 3 high evidence level articles for venous and pressure ulcers. Although there is some evidence to support the use of collagen ORC, there is a clear need for further evidence.

The other main concern regarding utilisation of collagen ORC is that its use is very specific, that is, it should be used in wounds where there is an elevated protease level. It is suggested that a point of care test that establishes whether protease levels are genuinely elevated in the wound should be utilised to determine if usage of a collagen/ORC dressing is appropriate or not [29]. The point-of-care protease test would be the optimum solution to lead to ‘informed, cost-effective decisions about which treatment is or is not appropriate’ [30].

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