Management of non‐healable or maintenance wounds with topical povidone iodine

Abstract

Although complete healing may appear to be the logical goal for most patients and clinicians, some wounds do not have the potential to heal due to a number of factors such as inadequate vasculature, coexisting medical conditions and medications that prohibit the healing process. Local management of wounds that are considered to have poor potential for healing remains elusive. The purpose of this article is to review the evidence that supports the use of topical antiseptic agents in non‐healable wounds. Retrospective chart audit was conducted to evaluate the use of povidone iodine in the management of wounds that were deemed to have poor healing potential.

Introduction

Chronic wounds are common with approximately 50% of home care clients receiving nursing services related to wound care. However, chronic wounds are often complex, recalcitrant to healing and may persist for months or years due to underlying disease processes or complications. The exact mechanisms that contribute to poor wound healing remain elusive but likely involve interplay of systemic and local factors. Although complete healing may appear to be the logical goal for most patients and clinicians, some wounds do not have the potential to heal due to a number of factors such as inadequate vasculature, coexisting medical conditions and medications that prohibit the healing process 1, 2. By determining the potential for healing, a proposed framework (Table 1) describes the primary focus of care and categorises wounds into healable, maintenance or non‐healable (Table 1).

Table 1.

Healable, maintenance and non‐healable wounds

Wound prognosis	Can the cause be treated?	Proposed criteria with examples of key determinants	Goal/objective
Healable	Yes, the cause has been corrected or compensated with treatment. For example, a patient who had undergone a bypass surgery to improve arterial supply to promote healing of an arterial ulcer	Coexisting medical conditions and drugs that do not prevent healing	• Promote wound healing • For example, venous ulcers: 30% smaller by week 4 to heal by week 12
Maintenance	No, poor treatment adherence or lack of appropriate resources. For example, a patient with venous stasis disease and does not wear compression (e.g. stockings)	Coexisting medical conditions and drugs that may stall healing; e.g. hyperglycaemia	• Prevent further skin deterioration or breakdown trauma and wound infection. • Promote patient adherence • Advocate for patients to acquire appropriate resources • Optimise pain and other symptom(s) management
Non‐healable: palliative or malignant	No, a cause that is not treatable. For example, there is widespread metastasis, including the skin, advanced stages of cutaneous malignant conditions and chronic osteomyelitis	Coexisting medical conditions that would prevent normal healing, such as: advanced terminal diseases, malignant conditions, inadequate perfusion, malnutrition with low albumin (<20 mg/dl) or negative protein balance, significant anaemia (Hgb < 80 g/dl) or high‐dose immunosuppressive drugs	• Prevent further skin deterioration or breakdown, trauma, and wound infection • Promote comfort • Optimise pain and other symptoms management

Woo 2011^©.

While maintaining that, the wound moisture is crucial to promote healing, prevailing opinions of clinical experts highlighted the importance of keeping wound dry and preventing infection when healing is not considered to be a realistic outcome 2. Local management of wounds that are considered to have poor potential for healing remains elusive. The purpose of this article is to review the evidence that supports the use of topical antiseptic agents in non‐healable wounds. Retrospective chart audit was conducted to evaluate the use of povidone iodine in the management of wounds that were deemed to have poor healing potential.

Chronic wounds are invariably colonised by microorganisms constituting a complex ecology. Patients with compromised host defence and non‐healable wounds are particularly susceptible to wound infection 3. With the emergence of bacteria that are resistant to commonly used antibiotics, the use of topical antimicrobial agents has become a sensible option for local wound care. However, with the advent of a plethora of topical antimicrobial agents that have been developed in the last decades, clinicians are often confused with when and what antimicrobial agents to use in non‐healable wounds. These wounds are best treated with antiseptics where healing is not immediately achievable (uncontrolled deep infection) or where bacterial burden is more of a concern than tissue toxicity (maintenance or non‐healable wounds Figure 1).

Figure 1.

Wound care approaches to healable and non‐healable wounds.

What is povidone iodine?

Povidone iodine (10% PVP‐I) is one of the most extensively used broad‐spectrum topical antiseptics that is an aqueous solution. As an iodophor, PVP‐I is produced by attaching free iodine to the carrier pyrrolidone, a water‐soluble polymer of high colloidal and osmotic pressure 4. Free iodine that is released from the PVP molecules exerts its antimicrobial property by combining irreversibly with tyrosine residues of proteins, disrupting the formation of hydrogen bonding in amino acids and nucleotides, oxidising sulfhydryl (−SH) groups that are essential building blocks of many proteins including important enzymes, and reacting with sites of unsaturated fatty acids 4, 5. These oxidative reactions produce deleterious effects on mitosis and normal cellular metabolism and will ultimately lead to cell death. In vitro, PVP‐I has been demonstrated to be active against a broad spectrum of pathogens including gram‐positive and gram‐negative bacteria, spores forming fungi, protozoa and viruses 6, 7. Giacometti and colleagues 8 confirmed that 10% PVP‐I could also inhibit the growth of Methicillin‐susceptible Staphylococcus aureus (MSSA), Methicillin‐resistant S. aureus (MRSA) and pseudomonas aeruginosa at concentrations of 1000 and 10 000 ug/ml after 30 and 15 min of exposure, respectively. Due to its effectiveness, varying strength of PVP‐I has been used for many years as topical antiseptics on intact skin prior to surgical procedures and vascular catheter insertion as well as on oral mucosa to reduce the number of bacteria (bioburden) 9, 10.

PVP‐I and its action

Although the antimicrobial profile of PVP‐I is appealing for treating chronic wounds, the cytotoxic effect of PVP‐I is, nevertheless, non‐selective. In vitro, PVP‐I is toxic to human fibroblasts even when diluted to a low concentration 11, 12. Balin 13 reported that at a concentration of 0·01% PVP‐I, human fibroblast exponential growth rate was drastically affected increasing the population doubling time from 35 to 53 hours. With increasing concentration, fibroblast mitotic activity was totally obliterated in the presence of a higher 0·1% of PVP‐I. At the end of 7 days, none of the fibroblast remained viable in the presence of 1% PVP‐I. To benchmark the toxicity level, Wilson 14 compared PVP‐I (10%) with other commonly used wound cleansers. Saline solution was non‐toxic and the toxicity index against human dermal fibroblasts was 0 and keratinocytes was 10. In contrast, the toxicity index versus saline for PVP‐I (10%) was 1000 for human dermal fibroblast and 100 000 for keratinocytes 5, 12. PVP‐I (10%) was 1000 times more toxic to dermal fibroblasts than saline solution. However, one of the major challenges to the validity of in vivo toxicity studies is the lack of control over oxygen tension while the cells are incubated. Other cellular activities can also be altered by PVP‐I. After exposed to high concentration of PVP‐I (10%), increased free radical formation and impaired antioxidant defence system including both glutathione and superoxide dismutase activities were observed in erythrocytes, rendering these cells vulnerable to oxidative injury 15. There is evidence that polymorphonuclear leukocyte chemotaxis is diminished following exposure to PVP‐I. Many investigators and clinicians have speculated that this in vitro toxicity may not be totally applicable to in vivo use because of dilution of the antiseptic agent by wound exudation and antiseptics inactivation by organic materials.

PVP‐I and wound management

What is the available evidence on the benefits in toxicity of PVP‐I in vivo for the treatment of chronic wounds? In a randomised study of spinal cord injury patients with pressure ulcers (PU, n = 27), 84% of the PUs treated with hydrogel achieved epithelialisation compared with only 54% treated with gauze and PVP‐I. (P = 0·04) 16. The authors concluded that re epithelialisation and keratinocytes migration were deterred by the toxic effect of PVP‐I. However, the results did not demonstrate any significant difference in the rate of healing (cm²/days) between the two groups.

Other clinicians have used PVP‐I in case series (no comparators) to manage vascular prosthetic graft infection 17, post‐nail ablation 18, giant omphaloceles [a protrusion of the intestine and omentum through a hernia in the abdominal wall near the navel 19], odontogenic infection and acute post‐surgical wounds 20 with favourable results. During the study period, Vehmeyer‐Heeman et al. 21 evaluated wound healing in 10 burn patients after split skin graft application. Operated sites were randomly treated with either vaseline gauze or PVP‐I (10%) impregnated vaseline gauze. Analysis of quantitative bacteriology indicated a significant reduction (P < 0·05) in the number of colony forming units (CFU) per gram of tissue between PVP‐I and the vaseline gauze in the third and fourth quarter of the total healing time (4·0 CFU/cm² versus 9·6 and 1·1 versus 4·0). The 50%‐healing‐time was significantly improved in the PVP‐I group (9·4 versus 10·1 days, P = 0·023). The healing time was statistically shortened by almost 1 day but this may not be clinically relevant. Thyroid function tests were within normal range.

In a study of chronic leg ulcers 22, PVP‐I was compared with silver sulfadiazine (SSD) and chlorhexidine digluconate. All patients (n = 51) had at least two distinct ulcers for the comparative evaluation. One of the ulcers was covered with a hydrocolloid dressing alone as a control while the other ulcer was randomly assigned to be treated with 10% PVP‐I, 1% silver SSD or 5% chlorhexidine covered with hydrocolloid. Compared with the hydrocolloid alone control site, healing rate improved by 4–18% and time to healing was reduced by 2–9 weeks using PVP‐I (all P‐values < 0·01). The performance of PVP‐I was superior to both SSD and chlorhexidine. At the end of the study at week 6, punch biopsy was obtained. Results indicated reduced bacterial density (rated on a 5‐point grading scale) in the wounds treated by the three antimicrobials compared to the hydrocolloid alone. Histological specimen demonstrated a decreased number of bacterial organisms identified in the tissue, decreased inflammatory cells around blood vessels and the pockets of neutrophilic vasculitis associated with the tissue response to bacterial damage had almost cleared with the antimicrobials compared to hydrocolloid alone. More importantly, PVP‐I applications did not affect the number of fibroblasts.

Ulcers related to lymphedema are recalcitrant to healing and recurrent infections are common. Daroczy 23 investigated the use of PVP‐I to manage bacterial burden in wounds associated with chronic lymphedema (n = 25). The number and concentration of wound pathogens were confirmed by semi‐quantitative bacteriology and its impact was assessed by common clinical signs including erythema, oedema, leakage of lymph fluid, satellite ulcers, and ulcer size. Within 4 weeks of regular wound care involving tissue debridement, cleansing with diluted PVP‐I and the use of topical PVP‐I ointment, the number of bacterial colonies were significantly reduced (P < 0·001). Local erythema, oedema and satellite lesions were also significantly improved (P < 0·001). To provide further support for the efficacy of PVP‐I in the treatment of wound infection, a group of patients (n = 63) with infected venous stasis ulcers were studied 24. Only superficial ulcers that were less than 5 cm in diameter were recruited. These ulcers were randomly treated with betadine with compression, betadine without compression or systematic antibiotics with compression. At week 12, 82% of the wounds healed with topical betadine and compression in contrast to 85% with systemic antibiotics and compression therapy (no significant difference). In combination with adequate compression, topical antiseptic and systemic antibiotics achieved similar clinical endpoints in patients with bacterial damage associated with venous leg ulcers. There are similar findings demonstrating topical PVP‐I alone was just as effective as the combination of PVP‐I and parenteral antibiotics in the management of post‐appendectomy wound infections 25. All patients (n = 72) received daily antiseptic dressings with PVP‐I 10%, with half of the subjects receiving additional parenteral antibiotics. The additional systemic therapy did not alter the length of hospital stay.

The local wound environment signifies a dynamic ecosystem of regulatory signals/mechanisms generated by living, injured, and necrotic cells, damaged extracellular matrix, microbial bioburden, and varying degrees of angiogenesis and matrix deposition. The effects of reduction of bacterial damage must be weighed against possible toxic effects on the cellular structures responsible for healing. The beneficial and toxic effects of PVP‐I on wound healing remain debatable.

On the basis of the literature review, topical PVP‐I is appropriate to reduce moisture and create an environment that is not conducive for bacterial proliferation in wounds that are not likely to heal. To evaluate the effectiveness of topical PVP‐I in the management of maintenance and non‐healable wounds, a chart review was conducted.

Methods

Participants and setting

The review included all patients who were assessed at the participating wound clinic 3 months prior to this review. Patients' health records were reviewed for wounds that were considered to have poor healing potential as evaluated by the wound care team and requiring the regular use of topical (4) refusal to wear compression therapy for leg ulcers. Patients receiving antibiotic treatment were excluded from the review. All patients were assessed and monitored on a monthly basis for 6 months. Thirty patients were reviewed (17 males and 13 females) including a total number of 42 wounds. The mean age of the patients was 64 years (SD = 14·6). Wound types and locations are summarised in Table 2.

Table 2.

Non‐healable or maintenance wounds by aetiology and location

	Frequency (%)
Wound types
Diabetic foot ulcer	34 (81)
Pressure ulcer	3 (7·1)
Venous leg ulcer	2 (4·8)
Arterial leg ulcer	2 (4·8)
Unknown	1 (2·4)
Wound location
Forefoot	31 (73·8)
Heel	5 (11·9)
Leg	4 (9·5)
Ankle	2 (4·8)

Results

The majority of the wounds reviewed were related to diabetes and located in the forefoot area. Seventy‐eight percent of patients received antibiotics at some stage during the treatment period (mean = 5 months; SD = 1·67 months). Of all the wounds reviewed, 28·6% (n = 12) achieved complete closure plus an additional 45·2% (n = 19) had reduced wound size with topical PVP‐I within 6 months. The surface areas of the wounds were significantly smaller than the initial measurements in this chronic wound cohort of patients as indicated in Table 3 (Wilcoxon signed ranks test, P = 0·011). A total of 31 wounds exhibited improvement as evident by decreases in surface area by a mean percentage of 73·6. Only one patient required systemic antibiotic treatment during the review period. In this patient population, transient burning or stinging had been observed but there were documented cases of contact irritant or allergic dermatitis.

Table 3.

Assessment of wound measurement

	Mean (SD)
Initial wound size (cm2)	4·5 (10·4)
Final wound size (cm2)	3·3 (9·2)
Duration (months)	5·2 (2·7)

Discussion

Increased surface bacterial burden or critical colonisation can be deleterious to wound healing. Bacteria produce endotoxins and exotoxins that are toxic to the cellular wound microenvironment. Over the years, a plethora of antimicrobial dressings have been introduced. This study reviewed management of 42 non‐healing and maintenance wounds using topical PVP‐I for local wound management. Results suggest PVP‐I is appropriate for routine management of non‐healable and maintenance wounds. However, results of this study may not be generalisable because of the small sample size. Potential bias cannot be ruled out due to the lack of randomisation and retrospecitve nature of this study. While topical PVP‐I may appear superior to silver and moist interactive dressings, results must be interpreted with caution. A high proportion of patients who were treated with topical PVP‐I also received systemic antibiotic agents. The observation period was longer for the patients in the PVP‐I group. Several conditions must also be considered prior to using PVP‐I. High concentration of exogenous iodine has shown to reduce thyroid hormone synthesis. Transient hypothyroidsim was found in 20 infants after PVP‐I was applied to open sternal wounds for 7 days following open heart surgery26. Thyrotropin level was significantly higher than baseline in neonates treated with 10% PVP‐I for insertion of percutaneous central venous catheters 27. The extent and impact of transcutaneous absorption of iodine through wounds in adult are not known. Thyroid functions were not monitored in this study. Other rare but serious adverse effects may include reversible kidney failure, convulsions with central nervous system involvement, peritonitis after mediastinal lavage, irritant contact dermatitis and acute allergic reactions. Contact dermatitis may occur when large quantity of solution is used and brought into contact with skin for prolonged period of time 28. In more severe cases, chemical burn has been reported especially when coupled with maceration; friction and pressure have been reported. Pain often described as stinging and burning sensations is not uncommon on application of PVP‐I on wounds. With the advancement in technologies, other formulations of PVP‐I are available in liposome hydrogel (3%), cadexomer‐iodine (0·9% iodine) and admixture of 70% sugar and 3% PVP‐I; these products enhance moist wound healing and may not be appropriate for maintenance and non‐healable wounds.