Antiseptics on Wounds: An Area of Controversy

Anna Drosou, MD, Anna Falabella, MD, Robert S. Kirsner, MD

Disclosures

Wounds. 2003;15(5) 

In This Article

Iodine Compounds

Since the first discovery of the natural element iodine in 1811 by the chemist Bernard Courtois, iodine and its compounds have been broadly used for prevention of infection and treatment of wounds.[35] However, molecular iodine can be very toxic for tissues, so formulations composed by combination of iodine with a carrier that decreases iodine availability were developed. Povidone iodine (PVP-I) results from the combination of molecular iodine and polyvinylpyrrolidone. Povidone iodine is available in several forms (solution, cream, ointment, scrub). The scrub form contains detergent and should be used only on intact skin. Cadexomer iodine consists of spherical hydrophilic beads of cadexomer-starch, which contain iodine, is highly absorbent, and releases iodine slowly in the wound area. It is available as an ointment and as a dressing. Numerous studies have been conducted in order to determine the safety and efficacy of iodine compounds on wound healing.

Povidone iodine. Several animal studies have examined the effects of povidone iodine on the bacterial load of wounds ( Table 1 ). These results have not proven the efficacy of povidone iodine; however, the results of numerous clinical trials show that it is effective in reducing the bacterial load of wounds. Rodeheaver, et al.,[36] studied the bactericidal activity of povidone iodine solution in contaminated wounds in Hartley guinea pigs and the potential therapeutic benefit. Although they found that it can significantly reduce bacterial load 10 minutes after the application of the antiseptic, this effect did not persist. Four days after a single PVP-I application, there was no decreased rate of infection or decreased bacteria number. Another study[37] that evaluated contaminated 12-hour old lacerations in a guinea pig model failed to find any decrease of wound bacterial counts after irrigation with PVP-I in comparison to normal saline. However, the authors mention that this may be due to the formation of a proteinaceous wound coagulum and point out that even parenteral antimicrobials are ineffective in preventing infection in animal models if administered alone more than three hours after wounding.

However, most of the human trials performed prove the efficacy of povidone iodine in clinical situations. Georgiade, et al.,[38] applied PVP-I ointment on burn wounds in 50 patients and showed that control of bacterial growth was effective. There was not a control group in this study; however, the control of bacterial growth showed a significant correlation to the frequency of PVP-I application.

Gravett, et al.,[39] studied the effect of one-percent PVP-I solution in the prevention of infection in sutured lacerations in 395 patients. Their data suggest that use of one-percent PVP-I solution prior to suturing reduces the incidence of wound infection.

In a recent study[40] on clinically noninfected venous leg ulcers, the combination of PVP-I with hydrocolloid dressing was shown to reduce bacterial clumps, neutrophilic vasculitis, and phagocytic infiltration and increase the healing rate in comparison to the hydrocolloid dressing alone.

One of the most cited studies is the one conducted by Viljanto[41] in surgical wounds in 294 pediatric patients. He found that a five-percent PVP-I aerosol, which contained some excipients (glycerol, citrate-phosphate buffer, polyoxyethylated nonylphenol), increased the infection rate. In order to explain these results, he used the cellstic method, which consists of placing a cellulose sponge inside a silicone-rubber tube between the wound edges. Wound exudate fills the sponge, and cells migrate into the sponge. He found that the five-percent aerosol caused pronounced leukocyte migration, a five-percent solution without excipients caused slighter inhibition, while the one-percent solution was practically no different to the control (saline). Subsequently, spraying wounds with a one-percent PVP-I solution had no effect on wound healing while it significantly decreased infection rate. Interestingly, povidone iodine has been found to have increased bactericidal activity in lower concentrations.[42]

Conversely, some studies have not confirmed those previously mentioned results. PVP-I soaking was not found to significantly decrease bacterial counts in acute, traumatic, contaminated wounds that required debridement, while saline soaking caused increased counts. PVP-I solution was not found to be an effective substitute to wound cleaning and debridement.[43] However, PVP-I irrigation has been shown to be effective in several other studies,[44,45,46] so it is not obvious if the lack of effect of PVP-I in this study should be attributed to the antiseptic itself or to the method used. In another study with infected chronic pressure ulcers, PVP-I solution was found to reduce bacterial levels but was no more effective than saline.[47]

Cadexomer iodine. The efficacy of cadexomer iodine has been shown in both animal and human models ( Table 2 ). Mertz, et al.,[48] examined the effect of cadexomer iodine dressing on partial-thickness wounds in specific pathogen-free pigs contaminated with or without methicillin-resistant Staphylococcus aureus (MRSA). Applied daily, cadexomer iodine was found to significantly reduce MRSA and total bacteria in the wounds in comparison to no treatment control and vehicle (cadexomer) at all time points studied (1, 2, and 3 days after inoculation). The reduction was most pronounced at day 3.

In an uncontrolled small study series (n = 19), Danielsen, et al.,[49] used cadexomer iodine in ulcers colonized with Pseudomonas aeruginosa and found negative cultures in 65 percent and 75 percent of patients after 1 and 12 weeks of treatment, respectively.

Povidone iodine. Literature regarding the effect of povidone iodine on wound healing in animal wound models is conflicting. Reasons for this discrepancy may be differences in the parameters of wound healing evaluated, the variety of assessment times, iodine concentrations and control groups, and the diversity of animal wound models (partial thickness, full thickness, burn wounds, ischemic wounds, etc.). The type of animal used appears to be of importance, as different animals show different healing responses. Loose-skinned animals (mice, rabbits, guinea pigs) heal mainly through contraction, while the primary mechanism of healing in tight-skinned animals (pigs) is epithelization, and healing in tight-skinned animals more closely resembles the human healing response.[50] It should be emphasized that none of the animal studies examined the effect of povidone iodine in chronic wound models, as an animal model equivalent to human chronic wounds does not exist. Briefly, in some studies povidone iodine was found to cause no inhibition on wound re-epithelization,[51,52] while in others it retarded healing.[53] As far as the tensile strength of the wound is concerned, PVP-I has been reported to cause increase,[54] reduction,[56] have no effect,[55] and cause either reduction or no effect depending on the assessment time.[29] It has also been found to have no effect on collagen[56] and granulation tissue production or nonsignificant reduction.[57] Moreover, it has been shown to increase revascularization.[53] In another study measuring the corneal toxicity of antiseptics, povidone iodine was found to be nontoxic in rabbit corneas.[58]

Clinical studies evaluating the influence of PVP-I in wound healing are numerous. Most of them have shown no decrease of the wound healing rate from the use of povidone iodine. The aforementioned study by Viljanto[41] found no effect on wound healing when a one-percent solution is used. Niedner[59] reviewed the cytotoxicity of PVP-I and concluded that "the normal course of wound healing (suction blister[60]) as well as the disturbed one (Mohs therapy[61] and burns[62]) is not negatively influenced by PVP-I."

Piérard-Franchimont, et al.,[40] examined the effect of PVP-I in combination with hydrocolloid dressing on venous leg ulcers. The control group was treated with compression hydrocolloid dressings alone. Using planimetric evaluation, they showed that the rate of leg ulcer healing was accelerated in the PVP-I-treated group in comparison to control, especially the first four weeks of treatment.

Lee, et al., in a noncontrolled study found reduction of infection and promotion of healing in patients with long-standing (6 months to 16 years) decubitus and stasis ulcerations.[63]

Knutson, et al.,[64] reported their five-year experience and concluded that the combination of sugar and PVP-I enhanced healing of burns, wounds, and ulcers and reduced the requirements for skin grafting, antibiotics, and the hospital costs. However, they do not mention what "standard care" thecontrol group received; neither is it clear if this improvement is due to PVP-I, to sugar, or to the combination.

Mayer, et al.,[9] reviewed the in-vivo studies examining the effects of the various PVP-I formulations on wound healing. They reported five human studies using PVP-I solution, three with PVP-I ointment, and three with PVP-I cream. In all these studies, PVP-I was not found to negatively influence wound healing in comparison to the control group or to other treatments.

Burn wounds are, in many ways, different than the other acute wounds, and they have a higher risk of infection that not only can delay wound healing but also can cause a significant risk for the patient’s life. Steen[65] reviewed the use of PVP-I in the treatment of burns. After reviewing in-vitro animal and human studies, he concluded that PVP-I has concentration-dependent cytotoxicity. The higher the complexity of the system studied (in-vivo > ex-vivo > in-vitro studies) the less detectable the effects are. He did not exclude the possibility that PVP-I may cause slight retardation in wound healing but believed the benefits of the microbicidal effects of PVP-I should not be ignored. Since large areas usually need to be treated in burn patients, risks of systemic toxicity of increased PVP-I absorption were reviewed, as well.

For several more reviews of PVP-I use on wounds, see references 9, 10, 27, 66, and 67.

Cadexomer iodine. In animal models, cadexomer iodine has been reported to increase epidermal regeneration and epithelialization in both partial-thickness and full-thickness wounds.[33,68] However, cadexomer iodine appears to have no effect on granulation tissue formation, neovascularization, or wound contraction.[59]

Cadexomer iodine has also been the subject of many clinical studies. In these studies, cadexomer iodine has been found to be effective and beneficial to wound healing. Nine clinical trials comparing the effects of cadexomer iodine with other treatments on chronic venous ulcers showed enhancement of wound healing. The other treatments that were compared to cadexomer iodine included various "standard treatment" (cleansing with diluted hydrogen peroxide or dilute potassium permanganate baths and covering with either zinc paste dressings or nonadherent dressings, mainly paraffin-impregnated or saline dressings, or saline wet-to-dry compressive dressings, or gentian violet and polymyxin-bacitracin ointment, or support bandaging/stocking and a dry dressing),[69,70,71,72,73,74] dextranomer,[75] and hydrocolloid dressing or paraffin gauze dressings.[76] In one study, no control group was used, since the main purpose of the study was to examine the safety of cadexomer iodine with regard to development of sensitivity.[77] In several studies, the ulcers had been recalcitrant to previous treatments. All studies found cadexomer iodine not only to cause no inhibition on wound healing but to accelerate it. Moreover, observations of reduction of pain, removal of pus, debris, and exudate, and stimulation of granulation tissue formation were made.[71] The reduction of exudate could be considered an expected action of cadexomer iodine, since cadexomer iodine is designed to absorb large quantities of exudate (each gram can absorb 3mL of fluid) and then results in slow release of iodine.

Apelqvist, et al.,[78] examined the effects of cadexomer iodine in cavity foot ulcers in diabetic patients and found no clinical difference in comparison to other treatments (gentamicin solution, streptodornase/streptokinase, or dry saline gauze) but considerable less costs.

In a randomized trial, Moberg, et al.,[79] compared cadexomer iodine (n = 16) with standard treatment (n = 18) in patients with decubitus ulcers. Cadexomer iodine significantly reduced pus, debris, and pain of the ulcers and accelerated the healing rate. After eight weeks of treatment, the ulcer areas were reduced by 76 and 57 percent in the cadoxemer iodine and standard treatment group, respectively. Six ulcers treated with cadexomer iodine were completely healed, while only one with standard treatment was healed.

Summarizing the review of numerous in-vivo studies of iodine compounds the authors can conclude that in humans PVP-I and cadexomer iodine do not have a negative influence on wound healing, while cadexomer iodine causes an acceleration of healing in chronic human wounds. Both can be effective in reducing bacteria number and decreasing infections. Results from animal studies depend on many variables and should be interpreted with cautiousness. Studies of PVP-I have more conflicting results, especially with animal models, and have caused concern on many clinicians. Nevertheless, the results from the studies evaluating cadexomer iodine are clear and leave no doubt that this newer iodine compound is effective without having any negative influence on wound healing rate. Inversely, an acceleration of wound healing has been observed.

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