Topical Safety

Wound Healing and Irrigation

Ultimately, the real life topical use of sodium hypochlorite solution to reduce microbial flora involves a risk/benefit balance. The potential for adverse effects must be drawn from the studies discussed and weighed against effectiveness. The topical safety is most important since this is the normal route of administration.

It is a generalization, but a reaction often observed is that potential users may associate the odor of chlorine, its bleaching action and environmental use to conclude that sodium hypochlorite is harsh and irritating. The results of the tests discussed here belie this conclusion. If we return to Dakin and Carrel, they established effectiveness in vitro and went on to invent a method for treating the skin and large traumatic wounds for a period of days with multiple treatments per day. Their method resulted in the preservation of lives and limbs. A variety of tests show little topical toxicity. Sometimes this may be difficult to conclude from some inconclusive and ill-conceived in vitro studies. Many in vitro studies try to extrapolate from cellular models what will happen in use. These tests try to be predictive, but information from use ultimately reveals the true effects.

The human patch testing to predict sensitization and irritation have had good track records. A human irritation and sensitization test using the concentration of sodium hypochlorite in the Alcavis product, ExSept (1,100 ppm) has been conducted.

Long history of use, and published and unpublished studies, have established that buffered sodium hypochlorite solutions do not inhibit would healing and are essentially non-irritating. Studies have also shown that any irritating properties that sodium hypochlorite solutions may have are less pronounced than those exhibited by other ingredients, such as phenol and povidone-iodine (now classified as Category I under the First Aid Antiseptic TFM and in the Health-Care Antiseptic Products TFM in 1994).

As noted previously, while examining the acute dermal toxicity of sodium hypochlorite solution, both Gnemi [26] and Clementi [27] also looked for signs of skin irritation. Gnemi found no evidence of dermal reaction on intact rat skin after a 24-hour exposure to 1.1% sodium hypochlorite. Clementi noted that 4 weeks of exposure to 0.11% sodium hypochlorite solution did not produce significant irritant effect on either intact or abraded rabbit skin.

Gnemi [36] also examined the acute eye irritation effects of sodium hypochlorite. The study was conducted by administering 0.1ml or 0.11% sodium hypochlorite solution to the eyes of rabbits. No reactions were noted during the 72-hour observation period. The author concluded that 0.11% sodium hypochlorite was not irritating to the eye.

They examined inflammatory responses from subcutaneous exposure to sodium hypochlorite in guinea pigs [19]. In these studies, open-ended tubes containing 0.9-8.4% sodium hypochlorite solution was placed under the skin of guinea pigs. After 7 and 14 days, there was no significant difference in inflammatory response between any of the sites treated with sodium hypochlorite, and the negative control sites treated with saline solution.

Cotter et al. [10] studied the effect of 0.1 and 0.5% buffered sodium hypochlorite solutions on the viability of basal cells of guinea pig skin. The basal cells of the skin were exposed to the 0.5% solution and showed no reduction in viability after 1 week, but showed a 15% decrease in viability after 2 weeks. The cells exposed to the 0.1% solution showed no loss in viability after 2 weeks. Cotter concluded that both 0.1 and 0.5% solutions would be well-tolerated by patients.

Billhimer [37] conducted a human primary irritation patch test in a clinical examination of the irritation potential of sodium hypochlorite. In this study, each test subject was exposed to three consecutive 24-hour applications of 0.11% sodium hypochlorite solution with observations taken after each application. Only transient, slight to moderate irritation was observed during the study.

Mian et al. [38] conducted a comparative clinical study of topical antiseptics for treatment of burn patients. Burn patients were treated with either a 1% silver sulfadiazine cream (a standard treatment) or a 0.05-0.11% sodium hypochlorite solution. The patients treated with sodium hypochlorite solution tolerated their treatment with less pain, had a lower incidence of dermatitis, and showed faster wound healing than those treated with silver sulfadiazine cream.

Heggers et al. [39] conducted both in vivo and in vitro examinations of the effects of sodium hypochlorite on wound healing. The in vivo portion of this investigation consisted of making full-thickness incisions in rats, and then examining the effect of 0.25 and 0.025% sodium hypochlorite solutions on these wounds. The rats were sacrificed after 3, 7 and 14 days of treatment and examined. The wounds treated with sodium hypochlorite showed little or no difference from those treated with the saline controls. The cells exposed to 0.25% solution demonstrated cell death and disruption; the cells exposed to 0.025% solution remained viable, but exhibited some cellular damage; and the cells exposed to 0.0125 showed no adverse effects. This study clearly illustrated that in vitro results do not always correlate well with in vivo results. This theoretical extension of the direct in vitro effect of sodium hypochlorite on fibroblast cells to an effect on wound healing clearly cannot be derived from this study.

Cooper et al. [40] examined the in vitro effects of three topical antiseptics on fibroblasts and keratinocytes. The test solutions were 0.125% sodium hypochlo-rite, 0.5% povidone-iodine, and 0.25% acetic acid. The cells were exposed to various dilutions of the antiseptic solutions. Toxicity to the fibroblasts was measured by a test system that recorded the rate of thymidine incorporation and the rate of neutral red uptake. Toxicity to the keratinocytes was measured by the rate of neutral red uptake. With this test system, sodium hypochlorite was toxic only at the highest concentration. Sodium hypochlorite was shown, in this test, to be the least toxic to fibroblasts and keratinocytes of the three tested antiseptic solutions.

Spangberg et al. [41] examined the in vitro toxicity and antimicrobial effectiveness of seven commonly used dental endodontic antiseptic solutions. The antiseptics tested were sodium hypochlorite, chlorhexidine, three different iodine compounds, parachlorophenol and formocresol. The toxicity was measured by exposing tissue cultures of HeLa cells to various concentrations of the solutions. The antimicrobial effectiveness was determined by mixing the antiseptic solutions with various microorganisms in the presence of calf serum. All of the compounds tested proved to be toxic to the tissue culture cells at concentrations below the effective antimicrobial concentration.

Lineaweaver et al. [14] examined the effects of four topical antiseptics on wound healing by both in vivo and in vitro methods. The antiseptics were 0.5% sodium hypochlorite, 1.0% povidone-iodine, 0.25% acetic acid, and 3.0% hydrogen peroxide. In the in vivo portion of this study, 4-cm incisions were made on the backs of rats, and these wounds were irrigated with each one of the antiseptic solutions three times a day, for 4 days. After a given treatment, its effect on wound healing was measured by two testing methods: the tensile strength of the wound and determination of the rate of wound epithelialization. All of the solutions, except hydrogen peroxide, showed some inhibition of the wound healing process. The in vitro portion of the study consisted of treating cultured human fibroblasts with various dilutions of the four antimicrobial solutions. After 24 hours of exposure, all of the solutions were toxic to the fibroblasts at full strength. Sodium hypochlorite was toxic, as defined in this study, at 0.025%, but not at 0.005%. Non-toxic levels of other solutions tested were at 0.001% for povidone-iodine, 0.0025% for acetic acid, and 0.003% for hydrogen peroxide. Lineaweaver also examined the bactericidal effectiveness of the four test solutions. While all four were found to be effective as antimicrobials, only sodium hypochlorite and povidone-iodine were antimicrobial at concentrations that were not toxic to the fibroblasts after direct application to the cells.

In addition, in an in vitro study by Kozol et al. [15], the effect of sodium hypochlorite solution on neutrophil migration was used as an assay. Sodium hypochlorite solutions, down to a concentration of 0.00025%, inhibited greater than 90% of neutrophil function.

The studies by Lineaweaver and Kozol provided the suggestion that sodium hypochlorite, along with other topical antimicrobials (some of which are category I under the First Aid Antiseptic TFM), showed in vitro effects and may cause some adverse effects on wounds and wound healing. However, this evidence must be weighed together with some other relevant information and conclusions cannot be drawn from differing assay techniques extended to rationalize effects on wound healing. From the clinical information accumulated over the years, it may be reasonably assumed that these studies place too much emphasis on in vitro methods. Carrel's early clinical work with sodium hypochlorite solutions was strongly criticized by a Dr. Almoroth Wright, who based his criticisms on results from in vitro experiments. Carrel replied that, 'experiments must be made under the real clinical conditions of the treatment, if sound conclusions are to be reached' [2]. History tells us that Carrel was right. As it turns out, the treatment developed by Wright, highly regarded on the basis of his in vitro observations, was unsuccessful in practice.

Further, Heggars recognized that the in vitro model was insufficient to provide a complete picture of the wound healing process. His study showed a drastic difference in toxicity between in vitro and in vivo models. Therefore, he states that, 'individual tissue culture toxicity assays may be misleading in that the wound milieu consists of a polycellular environment that consists of a mixture of cell types...which all contribute to the wound healing process' [39]. Heggars also recognized that, 'the cellular constituents provide a protective substance or mechanism that neutralizes the toxicity of NaOCl.' Barese and Cuono [17] also recognized the shortcomings of extrapolating results from in vitro experiments to effects in an actual wound. In a letter critical of Kozol's conclusions described above, the authors note the contradiction between sodium hypochlorite's successful clinical use and its reported adverse effects on tissue cell cultures. Like Heggars, they believed that this apparent contradiction could be explained by the difference between real wounds, and Kozol's model, and in their words, 'which bears little similarity to a real wound milieu.' As noted previously, sodium hypochlorite breaks down rapidly once exposed to blood serum, or other components of the wound environment.

Further, Barese and Cuono also questioned the composition of the 'Dakin's solution' tested by Kozol. They noted that the study did not state whether the solution was buffered, or if buffered, what buffer was used. They further noted that unbuffered sodium hypochlorite is less effective, and far more irritating (due to high alkalinity) than the buffered solution. Interestingly, Kozol [42] does not address this issue in his reply, but rather attacks the relevance of sodium hypochlorite's historical use. The Lineaweaver study also fails to detail the composition of the tested sodium hypochlorite solution [14].

It is quite likely that Kozol and Lineaweaver did, in fact, test unbuffered solutions. Many of the references that discuss the formulation of 'Dakin's solution' and 'Modified Dakin's solution,' including the orginal works by Dakin [5] and Carrel and Dehelly [6], Remington's practice of Pharmacy [43, 44], the Modern Drug Encyclopedia [45], as well as others, describe a buffered sodium hypochlorite solution. However, the USP from at least 1937 describes

'Modified Dakin's solution' as a 0.45-0.5% sodium hypochlorite solution, with no reference to any buffering. Therefore, it is possible that Kozol and Lineaweaver actually examined the effects of an unbuffered sodium hypochlo-rite solution instead of properly formulated Dakin's solution. Dakin himself recognized the irritating potential of unbuffered sodium hypochlorite, and developed his formulation accordingly [5]. Further, in a clinical study by Bloomfield (recognized expert in chlorine compounds), unbuffered sodium hypochlorite (also known as Milton solution) demonstrated a higher score for skin irritancy than buffered sodium hypochlorite solutions [13].

The studies discussed above indicated clearly that sodium hypochlorite is not a skin irritant and does not inhibit wound healing. All but one of the in vivo studies of sodium hypochlorite supports this conclusion. The one study to the contrary, the Lineaweaver study, does not specify whether the protocol used a buffered sodium hypochlorite solution, or a more irritating unbuffered solution. A few in vitro studies indicate that sodium hypochlorite may have adverse effects on some cell types; however, these studies fail to account for the significant differences between in vitro conditions, and the environment of an actual wound. Furthermore, even these in vitro studies demonstrate that sodium hypochlorite is no more irritating, and often less irritating, than other antimicrobials. The original Tentative Final Monograph for OTC Topical Antimicrobial Products recognized that a product that 'causes slight irritation or delays wound healing for a relatively short period can be generally recognized as safe and effective if those side effects are offset by a compensating benefit' [28].

A judgment of safety for topical use weighs the results of toxicity testing against effectiveness in reducing microbial flora to prevent infection. Several studies reported some cellular toxicity in wounds. The measure of toxic effects in theses studies as well as the actual description of products tested is open to question. These possible toxic effects were not confirmed in clinical use of studies.

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