Abstract
The aim of this study was to observe both the clinical signs and symptoms of wounds at risk of infection, that is critically colonised (biofilm infected) and antimicrobial‐performance of an ionic silver alginate/carboxymethylcellulose (SACMC) dressing, in comparison with a non silver calcium alginate fibre (AF) dressing, on chronic venous leg and pressure ulcers. Thirty‐six patients with venous or pressure ulcers, considered clinically to be critically colonised (biofilm infected), were randomly chosen to receive either an SACMC dressing or a non silver calcium AF dressing. The efficacy of each wound dressing was evaluated over a 4‐week period. The primary study endpoints were prevention of infection and progression to wound healing. The SACMC group showed a statistically significant (P = 0·017) improvement to healing as indicated by a reduction in the surface area of the wound, over the 4‐week study period, compared with AF controls. In conclusion, the SACMC dressing showed a greater ability to prevent wounds progressing to infection when compared with the AF control dressing. In addition, the results of this study also showed an improvement in wound healing for SACMC when compared with a non silver dressing.
Keywords: Pressure ulcer, Silver, Venous ulcer, Wound healing, Wound infection, Biofilm
INTRODUCTION
The number of microorganisms colonising a wound, that is ‘microbial bioburden’, is considered to increase the risk of a wound becoming infected 1, 2, 3, 4. That is, in terms of quantitative microbiology, the higher the number, the higher is the risk. In addition to microbial numbers, the microbial diversity of the wound also contributes significantly to delayed wound healing and increased risk of infection 4, 5.
Recently, it has been suggested that a ‘critical colonised’, or more specifically a biofilm‐infected, wound is a chronic wound and therefore is at risk of infection 5, 6. Although this has not been definitively documented in repeated controlled clinical trials, there are indications that by adopting a strategy to reduce the bioburden to a point where the host can manage the bioburden, progression to healing is enhanced 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. An ‘at risk’ wound may not generate visible host reactions or obvious clinical signs of infection 17, 18, 19. Some have aligned this state with critical colonisation (biofilm infected) that currently is considered more of a clinical concept than a microbiological one, given the paucity of microbiological data. A number of clinical markers have been collated 20, 21 to diagnose an infected wound but these are yet to be validated. These include continuous pain, erythema, altered levels of exudate production, newly formed yellow/slough, discolouration of granulation tissue, friable granulation tissue that bleeds easily and odour 20, 22.
Infections are recognised as a concern to wound healing as these complicate standard protocols of care for effective wound management and have serious health implications for the patient (20). Factors known to increase the risk of occurrence of an infection include the microenvironment of the wound, the patient's underlying health, the wound's underlying pathology, and as mentioned previously, the microbial bioburden, the types of microorganisms in the wound 1, 2, 3 and most importantly, the presence of a biofilm 17, 23.
Antimicrobials that aim to reduce or prevent an increase in the wound bioburden, and also reduce the microbial diversity in the wound may help to lower the incidence of infection, and therefore improve wound healing (7). In the last decade, many different antimicrobial barrier dressings have been used to help manage the wound bioburden, within the dressing, in particular, dressings incorporating ionic silver 8, 9, 10.
Silver‐containing antimicrobial barrier wound dressings have to be efficacious against a broad spectrum of microorganisms and must be able to make available and maintain an optimised and sustained level of ionic silver within the wound dressing to be effective. One dressing which shows these characteristics is a silver alginate/carboxymethylcellulose (SACMC) dressing (8). However, few studies have been reported that have evaluated the clinical efficacy of a silver‐containing wound dressing in comparison with a dressing containing no ionic silver.
The aim of this clinical study was to assess signs and symptoms of infection and healing and provide an observational report on whether an SACMC dressing, through its antimicrobial barrier action on microbes within the dressing, could help manage and reduce an ‘at risk’ (critically colonised or more specifically biofilm infected) wound from becoming infected compared with a commercially available, conventional, non silver calcium alginate fibre (AF) dressing when used in the management of both pressure and venous ulcers.
METHODS AND MATERIALS
Protocol overview
Between October 2005 and August 2006, a total of 36 subjects (36 wounds) participated in a randomised, prospective, open label, multicentre, multinational study. These included two in Belgium (24 subjects) and one in the Netherlands (12 subjects). An equal number of subjects were randomised to the two arms of the study (SACMC interventional and AF control) via a computer‐generated randomisation system. The study was approved by the Ethics Committees of the three participating study centres and conducted in accordance with appropriate regulatory guidelines, including Good Clinical Practices and the 1964 Declaration of Helsinki and its various amendments. Informed consent in writing was obtained for all study subjects.
The primary study endpoints were preventing wounds from developing an infection and progression of wounds to healing (using wound surface area as the maker) when SACMC or AF dressings were applied, for up to 4 weeks.
Wound dressings
The SACMC dressing is a highly absorbent, sterile, non woven dressing composed of a high glucuronic acid calcium alginate, carboxymethylcellulose and an ionic silver generating compound (silver sodium hydrogen zirconium phosphate). The SACMC dressing makes silver ions available and forms a gel on contact with wound fluid. The silver ions provide a sustained availability of antimicrobial activity at the wound dressing interface against a broad spectrum of microorganisms frequently associated with delayed wound healing and infection.
The AF dressing (Kaltostat, ConvaTec Ltd, Deeside, UK) is also a marketed dressing. It is a highly absorbent fibrous pad composed of mixed calcium and sodium salts of alginic acid in the ratio of 80:20. In the presence of exudate or other body fluids containing sodium ions, the fibres absorb liquid and swell to form a gel‐like material.
Selection and description of subjects
The inclusion criteria for patients enrolled in this study can be seen in Table 1. Specifically, these included patients over the age of 18, with a chronic wound suitable for treatment (more than 2 cm in one dimension and no larger than 20 cm for pressure ulcers or more than 5 cm in one dimension and no larger than 20 cm for venous leg ulcers), at risk of infection (determined by the target wound assessment criteria) and moderate to heavily exuding.
Table 1.
Signs and symptoms of critical colonisation/risk of local infection
| Continuous pain |
| Erythema |
| Warmth |
| Moderate to serious exudates |
| >50% of wound is yellow/slough |
| Discolouration of granulation tissue |
| Friable granulation tissue that bleeds easily |
| Pocketing at wound base |
| Foul odour |
| Necrotic plaque on target wound |
In addition to the above inclusion criteria a wound was considered to be at risk of infection when at least two of the following criteria and/or symptoms, without obvious clinical signs of infection, were presented (the wound assessment criteria). The wound assessment criteria for assessing the signs and symptoms of an at risk or biofilm‐infected wound included continuous wound pain, presence of erythema, oedema, warmth, moderate to heavy exudate levels, slough (at least 50% of the total wound surface area), discoloured granulation tissue, friable granulation tissue, pocketing at wound base, foul odour or necrotic plaque in the wound (hard, black, dry leathery eschar). These signs and symptoms of an at risk (critically colonised), or more specifically a ‘biofilm infected’, wound were synthesised from a number of clinical and research‐based sources 3, 19, 22.
The exclusion criteria used in this study included: target wounds that showed signs of general or systemic infection (fever, lymphangitis), wounds requiring immediate systemic treatment with antibiotics, patients already treated with systemic antibiotics, patients known to have the presence of a disease or medical condition that may affect the wound healing process, patients who had systemic corticosteroid, immunosuppressive, radiation or chemotherapy, a very poor life expectancy and any physical or medical state considered to have an effect on healing.
The evaluation of the wound was based on a modified ASEPSIS index (24). The modification consisted of prolonging the evaluation period from the original ASEPSIS scoring period to 4 weeks. The modified ASEPSIS index was applied to this study as a clinical tool to assess performance of all wound dressings in ‘at risk’ or biofilm‐infected wounds. In addition to the above criteria, wounds considered likely to become infected were also clinically judged not to require treatment with systemic antibiotics, yet showed at least one other sign or symptom of an ‘at risk’ or biofilm‐infected wound which included moderate to heavy exudate production.
Further information about the demographic data and pre‐existing medical conditions of the study population can be found in 2, 3.
Table 2.
Demographic data
| SACMC | AF | |
|---|---|---|
| Male (n) | 6·0 | 4·0 |
| Female (n) | 12·0 | 14·0 |
| Median age (years) | 79·9 | 77·0 |
| Mean age (years ± SD) | 73·4 ± 16·2 | 73·5 ± 12·1 |
| Minimum age (years) | 39·6 | 40·1 |
| Maximum age (years) | 94·0 | 85·3 |
| BMI (weight/sqrt length) ± SD | 30·5 ± 11·1 | 27·1 ± 5·7 |
Table 3.
Pre‐existing medical conditions in study population
| SACMC | AF | |||
|---|---|---|---|---|
| n | % | n | % | |
| History of leg ulcer | 9 | 50·0 | 6 | 33·3 |
| History of pressure ulcer | 2 | 11·1 | 4 | 22·2 |
| Diabetes | 6 | 33·3 | 4 | 22·2 |
| Hypertension | 6 | 33·3 | 5 | 27·8 |
| Lower limb arteriopathy | 0 | 0·0 | 1 | 5·6 |
Study treatments and assessments
Subjects who met the inclusion criteria were enrolled in this study and were randomised to either treatment groups through sequential allocation of a study number. The randomisation was balanced per centre. Based on the modified ASEPSIS index, the scoring period and treatment were prolonged to 4 weeks with either SACMC or AF wound dressings. The wound site was inspected on five occasions, that is one time before treatment with the SACMC and AF dressing and at every weekly patient visit for up to 4 weeks. The wound index score was obtained based on the findings of serious exudates, erythema, purulent exudates and separation of deep tissue. Medical evaluations included: amount of wound closure, reduction in wound area during treatment, condition of surrounding skin, assessment of complete debridement of the wound and wound pain intensity.
Endpoints evaluated at enrolment and subsequent weekly assessments of all wounds were: progress of wounds towards or away from infection (based on the signs and symptoms of ‘critically colonised’ or at risk of an infection in Table 1); wound deterioration and progress of wounds towards or away from healing (assessed by semi‐quantitative evaluation and by change in wound area from baseline). Wound healing was evaluated semi‐quantitatively by assigning weights to each non healing or healing component. Deterioration = −1, stagnation = 0, improvement = 1 and healed = 2. Mean scores for the SACMC or AF wound dressings were then derived from the totals. Missing to follow up was scored as zero.
Wound surface calculation and planimetric analysis were carried out using tracings taken by the investigators visiting each patient. Photographs were also taken as a potential back‐up for wound surface analysis, in case the accuracy of individual tracing could not be sufficiently obtained.
Statistical analysis
Comparability in baseline characteristics for the treatment groups was verified by using Student's t‐test for continuous variables (e.g. age, body weight, number of wounds and duration of wound). A Chi‐square test was used to compare baseline characteristics for categorical variables (e.g. gender and concomitant diseases). Comparability in wound characteristics was verified by using a Student's t‐test for continuous variables (e.g. wound size and wound pain intensity) and Chi‐square test for categorical variables (e.g. presence of erythema, warmth and wound pocketing).
RESULTS
Study population characteristics
The demographic data for the two cohorts in this study were similar (Table 2). There were comparable number of males and females in each study group, and there were no statistical differences in mean age, different age categories (e.g. <70, 70–80 and >80) or body mass index (BMI) between the study groups. There was also no statistical difference observed between the study groups (treatment and control) in relation to location of ulcers either on the left leg, right leg or sacrum and there was no statistically significant differences in the distribution of pre‐existing medical conditions at the study baseline (Table 3).
Of the 36 wounds included in the study, 12 were pressure ulcers and 24 were venous leg ulcers. The wounds were evenly distributed by type, but there was a difference in mean wound surface area between the two groups at baseline (20·1 cm2 for the SACMC versus 14·2 cm2 for the AF group). The mean duration of ulcers in the SACMC group was also greater than the mean duration of ulcers in the AF study group (15·5 months versus 10·2 months). Both study groups had comparable distributions in physical wound conditions at study baseline, and there were no statistically significant differences at baseline between the groups for any of the 10 criteria used to assess whether wounds were likely to become infected (Table 4).
Table 4.
Number of patients [number (N) and %] with signs and symptoms of a critically colonised ‘at risk’ wound at baseline in the SACMC and AF groups
| SACMC | AF | |||
|---|---|---|---|---|
| N | % | N | % | |
| Clinical signs | ||||
| Continuous pain | 2 | 11·1 | 2 | 11·1 |
| Erythema | 8 | 44·4 | 8 | 44·4 |
| Warmth | 3 | 16·7 | 5 | 27·8 |
| Moderate to high serious exudate | 16 | 88·9 | 17 | 94·4 |
| >50% of wound is yellow/slough | 9 | 50·0 | 9 | 50·0 |
| Discoloured granulation tissue | 6 | 33·6 | 7 | 38·9 |
| Friable granulation tissue | 6 | 33·3 | 8 | 44·4 |
| Pocketing at wound base | 2 | 11·1 | 2 | 11·1 |
| Foul odour | 6 | 33·3 | 8 | 44·4 |
| Necrotic plaque on target wound | 3 | 16·7 | 1 | 5·6 |
Prevention of infection
The average scores for the mASEPSIS index found at pre‐treatment were 5·8 ± 2·8 for the SACMC group and 6·8 ± 4·3 for the AF study group. At 4 weeks follow‐up, these scores had reduced for both treatment groups towards values of 4·3 ± 5·5 and 5·8 ± 4·3, respectively. The difference was statistically significant (P = 0·013) which indicated that the SACMC dressing was more effective than the AF dressing in preventing critically colonised wounds from reaching clinically infected status. After initiation of each patient into the study, the target wound in each patient was examined clinically to assess the wound's physical condition (pre‐treatment). The mean percentage changes for each of the clinical signs over the study period for both study groups are presented in Table 5. The mean percentage clinically observed differences between pre‐treatment and at week 4 are shown in Table 6. At week 4, the SACMC group showed a statistically significant (P = 0·01) improvement in wound healing compared with three in the AF group (P = 0·01).
Table 5.
Pre‐treatment and weekly symptoms of a critically colonised ‘at risk’ of infection percentages for SACMC and AF groups
| Clinical sign | SACMC (%) | AF (%) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Pre‐treatment | Week 1 | Week 2 | Week 3 | Week 4 | Pre‐treatment | Week 1 | Week 2 | Week 3 | Week 4 | |
| Pain | 11·1 | 5·6 | 11 ·8 | 11·8 | 5·9 | 11·1 | 11·1 | 5·6 | 6·3 | 11·8 |
| Erythema | 44·4 | 55·6 | 11·8 | 23·5 | 17·7 | 44·4 | 66·7 | 61·1 | 37·5 | 35·3 |
| Warmth | 16·7 | 11·1 | 0·0 | 11·8 | 0·0 | 27·8 | 11·1 | 27·8 | 6·3 | 23·5 |
| Exudate | 88·9 | 77·8 | 64·7 | 64·7 | 64·7 | 94·4 | 77·8 | 88·9 | 81·3 | 70·6 |
| >50% slough | 50·0 | 33·3 | 29·4 | 17·7 | 29·4 | 50·0 | 50·0 | 55·6 | 37·5 | 29·4 |
| Discolouration | 33·3 | 22·2 | 11·1 | 11·8 | 0·0 | 38·9 | 27·8 | 22·2 | 6·3 | 17·7 |
| Friable tissue | 33·3 | 33·3 | 35·3 | 29·4 | 29·4 | 44·4 | 27·8 | 50·0 | 37·5 | 23·5 |
| Pocketing | 11·1 | 16·7 | 5·9 | 5·9 | 5·9 | 11·1 | 11·1 | 0·0 | 0·0 | 0·0 |
| Foul odour | 33·3 | 16·7 | 11·1 | 23·5 | 23·5 | 44·4 | 33·3 | 38·9 | 25·0 | 5·9 |
| Necrosis | 16·7 | 5·6 | 23·5 | 11·8 | 11·8 | 5·6 | 0·0 | 5·6 | 0·0 | 5·9 |
Table 6.
Percentage differences for signs and symptoms of critically colonised ‘at risk’ wounds between pre‐treatment and week 4 for SACMC and AF groups
| Clinical sign | SACMC | AF | P‐value |
|---|---|---|---|
| Percentage difference weeks 0 and 4 | Percentage difference weeks 0 and 4 | ||
| Continuous pain | 46·9 | −6·3 | <0·01 |
| Erythema | 54·5 | 20·5 | <0·01 |
| Warmth | 100 | 15·5 | <0·01 |
| Moderate to serious exudates | 27·2 | 25·2 | 0·78 |
| >50% of wound is yellow/slough | 41·2 | 41·2 | 1·0 |
| Discolouration of granulation tissue | 100 | 54·5 | <0·01 |
| Friable granulation tissue | 11·7 | 47·1 | <0·01 |
| Pocketing at wound base | 46·9 | 100 | <0·01 |
| Foul odour | 29·4 | 86·7 | <0·01 |
| Necrotic plaque on target wound | 29·3 | −5·4 | <0·01 |
Wound healing
Wound healing was monitored by the investigators during the 4‐week study by performing weekly macroscopic inspection of the wounds to assess the wound closure process. During the assessment, the wounds were clinically classified as healed, improved, stagnated or deteriorated. Deterioration was observed in one of the SACMC patients (1·5%) compared with nine (13%) in the AF study group. This was statistically significant (P = 0·044). Complete wound healing occurred in three wounds in the SACMC study group and in one wound in the AF study group during the 4‐week treatment period. In addition to the descriptive approach of data analysis above, the wound closure results were also evaluated following a weighted wound progress scoring approach. Figure 1 shows the plot of the semi‐quantitative wound healing scores. The weighted wound progress analysis resulted in scores that were consistently higher during the entire 4‐week follow‐up period for the SACMC group compared with the AF group. Although the differences were not statistically significant by individual week, the SACMC group showed a statistical improvement for the 4‐week overall results (P = 0·011) compared with the AF dressing.
Figure 1.
Weighted wound progress analysis outcome for both study groups.
The mean wound surface area of the AF wounds had increased at 4 weeks (18·7 cm2) compared with baseline (14·2 cm2), whereas the mean wound surface area of the SACMC wounds had decreased at 4 weeks (17·7 cm2) compared with baseline (20·1 cm2; Table 7). This result was not statistically significant; however, there was a statistical difference in the overall wound surface area reduction over time observed for the SACMC‐treated wounds (P = 0·017).
Table 7.
Weekly mean wound surface areas over time
| Week | SACMC | AF | ||||
|---|---|---|---|---|---|---|
| Surface (cm2) | Surface (%) | SD | Surface (cm2) | Surface (%) | SD | |
| Pre‐treatment | 20·1 | 100 | 25·4 | 14·2 | 100·0 | 15·1 |
| Follow‐up week 1 | 17·7 | 88·1 | 25·0 | 13·0 | 91·5 | 13·8 |
| Follow‐up week 2 | 22·1 | 110·0 | 32·6 | 12·4 | 87·3 | 14·7 |
| Follow‐up week 3 | 20·8 | 103·5 | 32·9 | 17·4 | 122·5 | 44·6 |
| Follow‐up week 4 | 17·7 | 88·1 | 25·4 | 18·7 | 131·7 | 44·1 |
Safety
Over the 4‐week follow‐up period, one adverse event (AE) was reported in the SACMC group (wound maceration) and five AEs were reported in the AF group (two cases of wound infection, one case of serious sticking of the wound dressing, one case of over‐granulation and one case of rehospitalisation for additional wound care). There were also some comments of ‘mild sticking of the SACMC dressing to the wound’ at dressing change.
DISCUSSION
The use of silver‐containing wound dressings have been cited as a clinically useful tool in the prevention of infection and also in the management of infected wound 23, 25, 26. This study aimed to observe both the clinical and antimicrobial performance of an SACMC dressing, in comparison with a non silver calcium AF dressing, on chronic venous leg and pressure ulcers considered at risk of infection or to be more clinically specific, biofilm infection. All wounds treated in this study were considered to be critically colonised at baseline (using the target wound assessment criteria), and were positive for at least two of the clinical parameters used, indicating that all wounds showed sufficient clinical signs of serious microbial colonisation to justify the conclusion that they were.
To measure the ability of a dressing to prevent an ‘at risk’ or biofilm‐associated wound developing into an infection in vivo, we believe that it is necessary to define when a wound is likely to become infected before the wound actually becomes infected. It is also, therefore, necessary to define precisely when a wound becomes infected. However, the clinical reality is that there is no precise definition or diagnostic indicator currently available that will accurately alert the clinician as to when a wound is about to, or has become infected.
Proposed diagnostic methods for critically colonised definitions range from quantitative criteria that define infection by the number of bacteria in a wound (27) to more modern definitions that analyse infection by clinical indicators (19). Infection defined by the number of bacteria has been rejected by many because some pathogens are more virulent than others (i.e. the type of pathogen is also important) and because the number of bacteria may vary across the wound surface (i.e. a single swab or biopsy may not provide an accurate/complete picture of pathogen numbers) (28). Infection and a diagnosis of critically colonised by clinical indicators are also limited because precise guidance is not available about how many indicators are required and to what extent they should be present before a wound is considered to be infected (19). There is also a reoccurring theme in the literature that wounds need treating with systemic antibiotics, if they are definitely infected (29). In this context, therefore by excluding patients with wounds that needed treatment with antibiotics, the researchers prevented patients with wounds that were already infected from being included in the study population. At the same time, the study used a range of at risk (biofilm infected) indicators from the literature 2, 3, 19, 22 and included patients with wounds that were already displaying at least two of these indicators to provide a sample of ulcers which were considered likely to progress to infection. The study authors adopted a pragmatic view that a percent increase or decrease in these 10 indicators would provide an indication of whether wounds were progressing towards or away from infection over the 4‐week study period. In view of a lack of precision in the literature regarding at risk, critically colonised or ‘biofilm infected’ indicators of infection, this approach was deemed to be reasonable.
After 4 weeks of treatment, the SACMC‐treated wounds showed a significant improvement in a greater number of at risk of infection indicator categories than the AF‐treated wounds. Although these improvements were not seen across all the indicator categories, the SACMC wound group also showed significantly less wound deterioration. Wound deterioration is an important sign of sub‐clinical infection as wound deterioration breakdown has been identified as one of the most valid indicators of wound infection based on the four parameters of sensitivity, specificity, discriminatory power and positive predictive value (19). Deterioration of wounds was observed in only 1·5% of assessments in the SACMC subject group compared with 13% in the AF study group.
Wounds that are progressing towards wound healing generally show improvement in healing markers, in particular by progressing to reduced wound size. Wounds managed by the SACMC dressings showed a statistical improvement, when compared with the AF dressing, in healing when measured by both semi‐quantitative (weighted wound progress analysis) and quantitative (change in wound area from baseline) assessments. In addition to improving wound healing using the criterion described herein, the SACMC dressing was better able to prevent a critically colonised wound progressing to a wound infection also using reasonable criteria in defining wound infection.
In conclusion, from the analysis of the data collected in this randomised prospective clinical investigation comparing SACMC and AF wound dressings in the treatment of critically colonised venous leg and pressure ulcers in a study cohort of 36 patients, it was found that a reduction in mASEPSIS index scores was seen in both study groups. SACMC was statistically more effective in preventing critically colonised wounds from becoming infected. In addition to this, the SACMC dressing showed a lower occurrence of wound deterioration and a reduction in wound size than the patients managed with the AF dressing. These findings suggest that the SACMC wound dressing has a stronger tendency to promote natural wound healing when compared to the AF wound dressing.
Limitations
The study was sensitive to different definitions of critical colonisation, biofilm infected and risk of infection. As outlined in the section on Discussion, this is a complex area of wound management, with much ongoing discussion about what signs and symptoms accurately describe a wound at risk, infected with a biofilm, critically colonised and infected, and little clarity is available, that is precise boundaries between non infected and infected wound tissue. As mentioned, the authors adopted a pragmatic methodology to measure the progress of wounds towards or away from infection, given the clinically imprecise level of ‘critical colonisation’ and ‘risk of’ infection definitions in the literature.
The other limitation of the study was the low sample size, which is a consistent feature of many wound dressing trials, partly because of the challenges of patient recruitment (30). However, although there were only 36 patients included in this study, the trial did gather data on 144 patient weeks of treatment.
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