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Antiseptics, iodine, povidone iodine and traumatic wound cleansing
WOUND CLEANSING
Antiseptics, iodine, povidone iodine and traumatic wound cleansing Muhammad N Khan General Surgery, North Hampshire Hospital NHS Trust, Basingstoke. Abul H Naqvi General Surgery, St Luke's Hospital Kilkenny, County Kilkenny, Ireland Key words: antiseptic, iodine, povidone, traumatic wound cleansing
Received 19 July 2005, accepted for publication 1 November 2005
Abstract Wound cleansing is an integral part of the management of acute traumatic wounds. There is consensus that it reduces infection rates. However, the choice of cleansing agent remains controversial, especially the use of antiseptics has been questioned. This article reviews the current literature on the use of antiseptics particularly povidine iodine in traumatic wound cleansing and discusses the beneficial and harmful effects of such practice.
account for about 20-25% of the accident and emergency department workload 2. Depending upon the mechanism of injury they can vary from abrasions and contusions to lacerations and avulsions or degloving injuries] Traumatic lacerations occur when the body is subjected to a force that exceeds the strength of skin or the underlying tissues" Due to the presence of devitalised tissue, foreign bodies and bacteria, traumatic wounds often predispose to the development of invasive infection, which may range from cellulites to deep myositis.
Introduction
Wound cleansing
Numerous studies have shown the conflicting results of bactericidal properties, cytotoxicity and suppression of wound healing with the use of antiseptics. Due to the lack of powerful clinical studies, a standardised regimen has yet to be established. The existing evidence regarding the use of povidone iodine is complicated by the mixture of laboratory, human and animal studies. In vitro studies have shown the toxic effects at a cellular level but clinical studies have failed to show statistically significant difference compared with control interventions. With the emergence of antibiotic resistance, there has been a reappraisal of the use of povidone iodine especially in the management of contaminated and infected wounds. Acute wounds are defined as wounds that heal within an expected time frame without complications'. Traumatic wounds are one category of acute wounds that
Wound cleansing forms a critical part of the management of these wounds. It applies to the application of fluid to aid removal of exudate, debris, slough and contaminants'. Any traumatic wound should be considered contaminated at presentation 6 . Thorough cleansing of these wounds has shown to reduce the infection rate 7•8 • The objective of wound cleansing is to remove the organic and inorganic debris and to create optimum local conditions for wound healing". However, unnecessary removal of the exudate may deprive the wound of the necessary repair agents and enzymes responsible for the coordinated sequence of wound healing and will result in drying of the wound, which goes against the principles of moist wound healing'o,,,. Different terms including wound cleansing, wound cleaning and wound irrigation have been used in the literature. Unfortunately these terms have not been standardised in studies and are used interchangeably. Swabbing and irrigation are the usual cleansing techniques but bathing or showering are other options
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described in the hterature. Apart from different techniques used for cleaning and irrigating wounds, there is disparity among the solutions used for cleansing. Different solutions ranging from tap water to normal sahne to antiseptics have been used, all having their own disadvantages and advantages. The assessment and protocol of management, however, seems rituahstic rather than evidence based 12•13 Although there is evidence to suggest that wound cleansing is not always necessari 4, there is no diagnostic test that would allow healthcare professionals to identify the bacterial load in the wound capable of causing wound infection". The situation is further complicated by studies showing that bacterial colonisation of the wound does not necessarily indicate infection and there is no need to remove the bacteria in the absence of clinical signs of infection'6.".
Antiseptics The use of antiseptics, particularly povidone iodine, in the management of acute traumatic wounds has remained a controversial issue over the last two decades. It is also important to realise that the term iodine has sometimes been used to describe all formulations including povidone iodine, cadexomer iodine and others. These preparations have different iodine concentrations and different characteristics of their component parts. This raises the question of whether they should be grouped and studied separately. The term antiseptic was first used by Pringle in 1750'"' An antiseptic is a substance that inhibits the growth and development of micro-organisms causing sepsis in wounds'9. They may be either bactericidal or bacteriostatic. Commonly used antiseptics for wound cleansing include chlorhexidine, iodine compounds, alcohol, benzalkonium chloride and hydrogen peroxide. The use of antiseptics in wound care is controversial. The debate started after Fleming's lecture in 1919 about his work on antiseptics in septic wounds. The use of antiseptics began to decrease in 1929 after the discovery of penicillin. Stringer et al showed that antiseptics confer no benefit as compared to sahne in cleansing wounds'o In vitro experiments by Brennan and Leaper 2' demonstrated antiseptics were detrimental to the production of collagen, impairing epithehal migration and inhibiting microcirculation. Furthermore antiseptics are inactivated by contact with body fluids, blood, and proteins»' However, they need to be in contact long enough to reduce bacterial numbers 23 This evidence led to a decrease in the popularity of antiseptics for wound cleansing and there was a decline in their use with more emphasis on antibiotics in the treatment of contaminated/infected wounds. However, with the emergence of bacterial resistance to antibiotics, there has been a reappraisal in the use of antiseptics, and especially iodine compounds.
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Iodine is one of the long established antiseptics. Early preparations caused local pain and tissue reaction. Povidine iodine was introduced 40 years ago. It contains polyvinylpyrrolidone iodine, which is a water soluble complex of elemental iodine with a synthetic polymer. 10% solution in water is the most commonly manufactured form. It has a bactericidal action and is effective against a wide range of bacteria, fungi and even spores24 . The killing action occurs in seconds and is thought to be from inactivation of vital cytoplasmic substrates, which are necessary for bacterial viability25. Plasm~ proteins can bind up to 80% of free iodine'6 The presence of organic matter has a marked depressant effect on the minimum lethal concentrations of iodine. In the absence of inhibitors the disinfection is rapid, probably less than 10 seconds 27 • Antiseptics were the main stay of wound management until the mid-1980s, when research by Brennan and Leaper showed the effects of antiseptic solutions on wound healing physiology. They evaluated the effects of various antiseptics on wound micro-circulation in the rabbit ear chamber model of healing. The action of antiseptics on micro-circulation within the granulation tissue was examined with a laser Doppler flow meter. In wounds exposed to Eusol and chloramines T, the tissue perfusion ceased immediately and even after several days of observation these vessels did not re-open. Sahne and hydrogen peroxide did not result in any change in the pattern of blood flow. Chlorhexidine caused a few capillaries to close down. The effect of povidine iodine was concentration dependent. At a concentration of 5%, blood flow ceased in small blood vessels but a 1% solution was innocuous. This study is quoted as the strongest evidence against the use of antiseptics. However, the sample size was small, with only two wounds for each cell type. In order to be statistically significant this study needs to be rephcated. There should also be some concern in transferring the data from an experimental model to a clinical situation. Furthermore there is no strong evidence on human models of wound healing. The authors have shown that the apphcation of antiseptics irreversibly destroys angiogenesis, however it should be remembered that angiogenesis is just one step in the complex healing cascade. The Doppler flow meter used by the authors to monitor the micro-circulation could not be calibrated in order to provide a reading of flow per unit time. This may have affected the rehabihty of measurements. They also used the term 'flooding the ear chambers with antiseptic', which needs clear definition. Further in vitro studies have shown that the weaker solutions of hypochlorites, compatible with the preservation of fibroblast function, can still inhibit the growth of bacteria including Staphylococcus aureus, Pseudomonas, Bacteriodes, and Eschericia colf 8
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WOUND CLEANSING
But it must be remembered that in vivo the presence of pus, blood and exudate can further dilute the concentrations of these antiseptics and decrease their efficacy. Hypochlorites also result in skin irritation and are harmful to granulation tissue 29 . Research by Tatnall et a13 0 has shown that at concentrations recommended for wound cleansing, hypochlorite, hydrogen peroxide and chlorhexidine, all result in 100% killing of cultured keratinocytes and fibroblasts, with the hypochlorites being the most toxic. Hence the routine use of hypochlorites in wound cleansing is not advisable.
Iodine There have been conflicting studies regarding the usefulness of iodine in managing traumatic wounds",n Clinical trials have shown mixed success33 ,34,35. Roberts et a136 published a series of 418 patients with hand lacerations who were randomly allocated to a group where the injury was treated with povidone iodine before suturing and to a control group. They found no adverse effects of iodine on healing and the overall infection rate was significantly lower in the group treated with povidone iodine. Similar results were seen by Gravett et al (1987) when they compared 1% povidone iodine to normal saline in the management of traumatic lacerations and found a statistically significant difference between the two groups with an infection rate of 5.4% and 15.4% respectively''. Gordon (1993) found iodine very effective against MRSA and its value in helping control MRSA outbreaks is well recognised 38 ,39. Similarly Goldenheim (1993) demonstrated that povidine iodine .preparations do not have a deleterious effect on healing, It is useful in the treatment of burns because of its broad-spectrum activity and high penetration power'o. However, he recommended that it should not be used in pregnant women, newborns and those with thyroid disorders. Research by Cooper and Lawrence" found that wound cleansing with povidone iodine or cetrimide did not significantly reduce the number of bacteria present in contaminated lacerations. The mere presence of bacteria in a wound does not necessarily mean infection as wounds are usually colonised by bacteria. However, if the bacterial count reaches a certain level where the host defences cannot maintain the balance of organisms in the wound, it is referred to as critical colonisation42 and it can be a predecessor of invasive infection, Timely and appropriate use of topical antiseptics may return a wound from critical colonisation back to the state conducive to wound healing. Bacteria in the wound not only delay healing but also produce malodour; their
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toxins can be destructive to the wound bed and they can result in an increase in the amount of exudate. Medicated wound dressings impregnated with iodine have also been evaluated in the management of acute wounds and have met with m.i..,'Xed success. Cadexomer iodine ointment has been found to be highly efficacious and has been reported to accelerate epithelisation as compared to air exposed wounds, with out any deleterious effects". It has also proven effective against proliferation of MRSA in wounds. Davison and Keenan" have reported a randomised trial of three different wound dressings after nail matrix ablation with phenol. Povidone-iodine dressing,' amorphous hydrogel dressing and a paraffin gauze dressing were compared, The main outcome measure was clinical infection rate and there was no statistically significant difference between the three groups. Iodine released from cadexomer iodine has been shown to have a pro-oxidant effect, which could stimulate fibroblast proliferation in vitro". It also induces tumour necrosis factor alpha and inhibits the production of Interleukin-6 (IL-6) from macrophages, growth factors that are important for inflammation induction'6. Development of resistance to antiseptics is thought to be rare. However, certain species such as bacterial spores, mycobacteria and gram-negative bacteria possess intrinsic resistance and several bacteria can acquire plasmid mediated resistance". Development of resistance to povidone iodine is very unlikely because it requires alteration in the bacterial cell proteins'8. Povidone iodine also has an effect on the bacterial exotoxins and enzymes, which can cause further tissue damage'9. Yasuda et al's study'° looked at the antiseptic resistance of 20 bacterial strains and found that povidone iodine killed all bacteria within 20 seconds, This study showed that iodine is effective against intrinsically resistant and non-resistant gram negative bacteria. Studies have shown that the acquisition of resistance to the long-term use of povidone iodine is not observed". Iodine solutions are deactivated in the presence of organic material, pus, slough and necrotic tissue in the wound52 ,53,5'. In vitro experiments by Lawrence 5s have shown that although the presence of exudate deactivates povidone iodine dressings, they can reduce the bacterial counts of the wounds to a very low level as compared to controls. Studies by others have shown different results. Kunisada et a1'6 tested povidine iodine, chlorhexidine and benzalkonium chloride solutions against different nosocomial bacteria. They used solutions of different concentrations and exposed them for varying lengths of time, The bacteria were suspended in different concentrations of neutralising plasma serum. The results showed that povidine iodine was highly effective against all the test organisms at a very low concentration and over a short period of time. However, the in vitro
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evaluation of the antibacterial activity of an antiseptic may not necessarily be a good guide to its activity in clinical use. Its effects on the immune system, toxic effects on wound healing and inactivation by the body fluids should also be taken into accounf 5 • Animal studies involving antiseptics have shown chlorhexidine, iodine and hydrogen peroxide to be toxic to fibrobiasts'l. Povidine iodine even at low concentrations has been shown to be toxic to granulocytes and monocytes" and results in decreased chemotaxis 5". It is also capable of suppressing lymphocyte functions 59 . Mulliken et al60 studied the tensile strength of heahng wounds in winstar rats and found no statistical difference in the rate of gain of tensile strength and histological appearance between the control and experimental groups. They concluded that apphcation of 1 % povidone iodine solution to clean incised wounds does not affect fibroplasia or collagen cross-linking. In vivo studies have shown that application of 5% povidone iodine solution inhibits polymorphonuclear leukocytes and fibroblast migration and activity61. In contrast, research in 2001 by Bennett et a1 62 on porcine models of wound healing has shown that apphcation of 10% povidone iodine solution is associated with increase in the number of proliferating fibroblasts at day four and enhanced angiogenesis at day seven as compared to the controls6'. However, different research methodologies make the comparison of these studies difficult. Work in 2002 by Balin and Pratt has shown that even dilute solutions of povidone iodine can be toxic to human fibroblasts as at concentrations of 0.1 % and 1%, human fibroblast growth is totally inhibited"3. Concentrations lower than 0.1 % progressively retard the growth. However, they have also noted that there was partial recovery of cell growth after limited exposure. The results of the above studies are conflicting, however it must be remembered that the relationship between povidone iodine and free iodine concentrations is not linear, as it forms a bell shaped curve, which peaks at 0.7% concentration. Higher concentration of povidone iodine can paradoxically bind more free iodine to the carrier molecule, thereby lowering the available free iodine6'. Iodine compounds are not hazard free. Toxic symptoms can result from systemic absorption. These include nervousness, depression, insomnia, myxoedema, hypersensitivity and skin reactions 6s . The absorption depends upon the concentration and the particular use of iodine. Absorption is increased in the presence of damaged tissue, hence its use is not recommended in burns involving more than 20% of the body surface area 66 . Metabolic acidosis and hypernatremia are the other possible toxicities 6'.
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Conclusion Wound cleansing remains a corner stone in the management of acute traumatic wounds". Due to the lack of powerful clinical studies, a standardised regimen has yet to be established54 • The existing evidence regarding the use of povidone iodine is complicated by the mixture of laboratory, human and animal studies. In vitro studies have shown toxic effects at cellular level but clinical studies have failed to show statistically Significant differences with control groups. With the emergence of antibiotic resistance, there has been a re-appraisal of the use of povidone iodine especially in the management of contaminated and infected wounds. Well designed in vivo studies are required to prove its efficacy, however the debate seems to be far from resolved.
Acknowledgements We are grateful to Dr. Sadaf Rafique for her generous help with the hterature search and proofreading.
References 1. Leaper DJ, Harding KG. (Eds). Wounds: Biology and Management. Oxford University Press: Oxford; 1998. 2. Singer AJ, Mach C, Thode HC, Hemachandra 5, Shofer FS, Hollander JE. Patient priorities with traumatic lacerations. American Joumal of Emergency Medicine. 2000; 18(6): 683-6. 3. Holmes JD. Classification of wounds and their management. Surgery 1999; 17(3): 63-7. 4. Moscati RM, Reardon RF, Lerner EB, Mayrose 1. Wound irrigation with tap water. Acad Emerg Med 1998; 5(11): 1076-80. 5. Towler 1. Cleansing traumatic wounds with swabs, water or saline. Joumal of Wound Care 2001; 10(6): 231-3. 6. Riyat MS, Quinton DN (1997). Tap water as a wound cleansing agent in accident and emergency. J Accid Emerg Med 1997; 14(3): 165-6. 7. Longmire AW, Broom LA, Burch 1. Wound infection following high-pressure syringe and needle irrigation. Am J Emerg Med 1987; 5(2): 179-81. 8. Dire DJ, Welsh AP. A comparison of wound irrigation solutions used in the emergency department. Ann El11erg Med. 1990; 19(6): 704-8. 9. Morrison M. Wound cleansing, which solution) Professional Nurse 1989; 4(5): 220-5. IO.Punder R. Wound cleansing. Joumal of Community Nursing 1997; 11(7): 30-6. 11. Bale 5, Jones V. Wound care nursing: A patient centred approach. Bailliere Tindall: London; 1997. 12.Koh S. Dressing practices. Nursing Times 1993; 89(42): 82-6. 13.Trevelyan 1. Wound cleaning: principles and practices. Nursing Times 1996; 92(16): 46-8. 14.Thomlinson D. To clean or not to clean? Nursing Times 1987; 83(9): 71-5. 15. Chrisholm CD. Wound evaluation and cleansing. Emerg Med ClinNorthAm 1992; 10(4): 665-72. 16. Gilchrist B. Treating bacterial wound infection. Nursing Times 1994; 90(50): 55-8. 17.Harding K. Managing wound infection. Joumal of Wound Care 1996; 15(8): 391-2. 18.Scanlon E, Stubbs N. To use or not to use? The debate on the use of antiseptics in wound care. Joumal of H/0und Care 2.002; 8-20. 19.Cape BR, Dobson P. Bailliere's Nurses Dictionary 18th ed.
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Bailhere Tindall: London; 1974. 20.Stringer MD, Lawrence JC, Lilly HA. Antiseptics and the casualty wound. J Hosp Infec ]983; 4: 410-3. 21. Brennan SS, Leaper OJ. The effect of antiseptics on the healing wound: a study using the rabbit ear chamber. Br J Surg ]985; 72(10): 780-2. 22.Fergusson A. Best performer. Nursing Times 1988; 84(14): 52-5. 23.Mertz P. A new in vivo model for the evaluation of topical antiseptics on superficial wounds. The effect of 70% alcohol and povidine iodine solution. Archives of Dennatology 1984; 120(1): 58-62. 24.La Rocca. Microbiology of povidone iodine; an overview. Proceedings of the International Symposium on povidone. Lexingtom Ky College of Pharmacy. University of Kentucky: Kentucky; ]983: 10]-9. 25.lvlisra A. Use of gauze soaked in povidone iodine for dressing acute open wounds. Journal of Plastic & Reconstructive Surge1y 2003; 111(6): 2015-6. 26.Abdullah ME, Said SA, Al-AShora H. Influence of biological fluids on the release of iodine from povidone iodine. ATZneimittelforschung ] 981; 31: 828. 27.Lacey RW, Catto A. Action of povidone iodine against methicillin sensitive and resistant cultures of Staphylococcus aureus. Post Graduate Medical Journal 1993; 69(Suppl 3): S78-83. 28.McKenna PJ, Lehr GS, Leist P, Welling RE. Antiseptic effectiveness with fibroblast preservation. Ann Plast Surg 1991. 27: 265-8. 29.Gorse GJ, Messner RL. Improved pressure sore healing with hydrocolloid dressing. AI'ch Dennatol1987; 123: 766-71. 30.Tatnall FM, Leigh 1M, Gibson JR. Comparative study of antiseptic toxicity on basal keratinocytes, transformed keratinocytes and fibroblasts. Skin Phannacol1990; 3: 157-63. 31.Naunton-Morgan TC et al. Prophylactic povidone iodine in minor wounds. Injury 1980; 12(2): 104-6. 32.Bickerstaff KL, Regnard C. Prophylactic povidine iodine sprays in accidental wounds. Journal of the Royal College of Surgeons of Edinburgh 1984; 29(4): 234-36. 33.Stokes E, Howard E, Peters J, Hackworthy C, Milne S, Witherow M. Comparison of antibiotic and antiseptic prophyla-xis of wound infection in acute abdominal surgery. World Joumal of Surgely 1977; I: 777-82. 34.Kothius B. The effect of povidone iodine on postoperative wound infection in abdominal surgery. Netherlands Journal of Surge1y 1981; 33: 186-9. 35.Platt J, Bucknall A. An experimental evaluation of antiseptic wound irrigation. Journal of Hospital Infection 1984; 5: 181-8. 36. Roberts AH, Roberts FE, Hall RI, Thomas IH. A prospective trial of prophylactic povidone iodine in lacerations of the hand. J Hand Surg [BrJ 1985; 10(3): 370-4. 37.Gravett A, Sterner S, Clinton JE, Ruiz E. A trial of povidone iodine in the prevention of infection in sutured lacerations. Ann Emerg Med 1987; 16(2): 167-71. 38.Gordon J. Clinical significance of the Methicillin sensitive and Methicillin resistant Staphylococcus aureus in the UK hospitals and the relevance of povidine iodine in their control. The Fellowship of Post Graduate Medicine 1993; 3(Suppl): S106-16. 39.Jones MR, Martin DR. Outbreak of MRSA infection in a New Zealand Hospital. In: Selwyn S. Proceedings of the First Asian/Pacific Conference on antisepsis. The Royal Society of Medicine International Congress Series No. 129. The Royal Society of Medicine: London; 1988. 40. Goldenheim PD. An appraisal of povidone iodine and wound healing. Post Graduate Medical Joumal 1993; 69(SuppI)3: S97-SI05. 41.Cooper R, Lawrence Jc. The role of antimicrobial agents in wound care. Journal ofHl ound Care 1996; 5: 374-7.
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42.Kingsley A. A proactive approach to wound infection. Nursing Standard 2001; 15(30): 50-8. 43.Mertz P. The evaluation of cadexomer iodine ointment. Wounds 1994; 6(6): 184-93. 44.Davison R, Keenan A. Wound healing and infection in the nail matrix phenolization wounds. Does topical medication make a difference? JAm Podiatr MedAssoc 2001; 91(5): 230-3. 45.Schmidt R, Kirby A, Chung L. Cadexomer iodine formulations may modulate the redox environment of wounds. In: Iodine and Wound Physiology. Hunt T, Middelkoop E. (Eds.). Perstop Pharma: Cambridge; 1995: 6.1-6.26 46.Moore K, Thomas A, Harding K. Iodine released from the wound dressing lodosorb modulates the secretion of cytokines by the human macrophages responding to bacterial lipopolysaccharides. Inc J Biochem Cell Bioi 1997; 29: 163-71: 47.McDonnell G, Russell AD. Antiseptics and disinfectants: activity, action and resistance. Clin Microbiol Rev 1999; 12(1): 147-79. 48. Lanker Klosssner B, Widmer HR, Frey F. Non development of resistance to bacteria during hospital use of povidone iodine. Dennatology 1997; ]95(Suppl): 10-3. 49.Koing B, Reimer K, Fleicher W, Koing W. Effects of beta isodona on the parameters of host defence. Dennatology 1997; 195(Suppl 2): 42-8. 50.Yasuda T, Yoshimura Y, Takada H et al. Comparison of bactericidal effects of commonly used antiseptics against pathogens causing nosocomial infections. Dennatology 1997; 195(Suppl 2): 19-28. 51.Klossner B, Widmer H, Frey F. on development of resistance by bacteria during hospital use of povidone iodine. Dennatology 1997; 195(SuppI2): 10-3. 52. Rodeheaver G. (1988). Topical wound management. Ostomy/WoundiManagement 4: 59-68 53.Morgan D.ls there still a role for antiseptics) JoumalofTissue Viability 1993; 3(3): 80-4. 54. Heyworth J. Wound care. In: Skinner 0, Swain A, Payton R, Robertson C. (Eds.). Cambridge Text Book of A&E Medicine. Cambridge University Press: Cambridge; 1997. 55. Lawrence J. A povidone iodine medicated dressing. Joumal of Wound Care 1988; 7(7): 332-6. 56.Kunisada T, Yamada K, Oda S, Hara O. Investigation of the efficacy of povidone iodine against antiseptic resistant species. Dennatology 1997; 95(Suppl 2): 14-8. 57.Yan Den Broek. Interaction of povidone iodine compounds, phagocytic cells and micro-organisms. Antimicrobial Agents and Che1notherapy 1982; 22(4): 593-7. 58. Connolly JC, Gilmore OJ. A study of povidone iodine on polymorphonuclear leucocyte chemotaxis. Br J Exp Pathol 1979; 60(6): 662-6. 59.Ninnemann J, Stein MD. Suppressor cell induction by povidone iodine: in vitro demonstration of a consequence of clinical burn treatment with betadine. Journal of Immunology 1981; 126(5): 1905-8. 60.Mulliken JB, Healey NA, Glowacki J. Povidone-iodine and tensile strength of wounds in rats. J Trauma 1980; 20(4): 323-4. 61.Viljanto J. Disinfection of surgical wound without inhibition of normal wound healing. Arch Surg 1980; us: 253. 62. Bennett L, Richard S, Davidson C, Jeffrey M, Barton R, Nanney L. An in vivo comparison of topical agents on wound repair. Joumal of Plastic & Reco11Stnlctive SUTge1Y 2001; 108(3): 675. 63.Balin AK, Pratt L. Dilute povidone iodine solutions inhibit human skin fibroblast growth. Demtatologic Surge1Y 2002; 28(3): 210-4. 64. Zamora JL. Chemical and microbiological characteristics and toxicity of povidone iodine solutions. Am J Surg 1986; lSI: 400. 65. Reynolds 1. (Ed.). Martindale. The extra phannacopoeia (29th Ed.) The Pharmaceutical Press: London; 1989. 66.Pietsch J, Meakins JL. Complications of povidone iodine absorption in topically treated burn patients. Lancet 1976; 1: 280-2. 67.British National Formulary. 2004, available at www.bnforg.
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Antiseptics, iodine, povidone iodine and traumatic wound cleansing Muhammad N Khan General Surgery, North Hampshire Hospital NHS Trust, Basingstoke. Abul H Naqvi General Surgery, St Luke's Hospital Kilkenny, County Kilkenny, Ireland Key words: antiseptic, iodine, povidone, traumatic wound cleansing
Received 19 July 2005, accepted for publication 1 November 2005
Abstract Wound cleansing is an integral part of the management of acute traumatic wounds. There is consensus that it reduces infection rates. However, the choice of cleansing agent remains controversial, especially the use of antiseptics has been questioned. This article reviews the current literature on the use of antiseptics particularly povidine iodine in traumatic wound cleansing and discusses the beneficial and harmful effects of such practice.
account for about 20-25% of the accident and emergency department workload 2. Depending upon the mechanism of injury they can vary from abrasions and contusions to lacerations and avulsions or degloving injuries] Traumatic lacerations occur when the body is subjected to a force that exceeds the strength of skin or the underlying tissues" Due to the presence of devitalised tissue, foreign bodies and bacteria, traumatic wounds often predispose to the development of invasive infection, which may range from cellulites to deep myositis.
Introduction
Wound cleansing
Numerous studies have shown the conflicting results of bactericidal properties, cytotoxicity and suppression of wound healing with the use of antiseptics. Due to the lack of powerful clinical studies, a standardised regimen has yet to be established. The existing evidence regarding the use of povidone iodine is complicated by the mixture of laboratory, human and animal studies. In vitro studies have shown the toxic effects at a cellular level but clinical studies have failed to show statistically significant difference compared with control interventions. With the emergence of antibiotic resistance, there has been a reappraisal of the use of povidone iodine especially in the management of contaminated and infected wounds. Acute wounds are defined as wounds that heal within an expected time frame without complications'. Traumatic wounds are one category of acute wounds that
Wound cleansing forms a critical part of the management of these wounds. It applies to the application of fluid to aid removal of exudate, debris, slough and contaminants'. Any traumatic wound should be considered contaminated at presentation 6 . Thorough cleansing of these wounds has shown to reduce the infection rate 7•8 • The objective of wound cleansing is to remove the organic and inorganic debris and to create optimum local conditions for wound healing". However, unnecessary removal of the exudate may deprive the wound of the necessary repair agents and enzymes responsible for the coordinated sequence of wound healing and will result in drying of the wound, which goes against the principles of moist wound healing'o,,,. Different terms including wound cleansing, wound cleaning and wound irrigation have been used in the literature. Unfortunately these terms have not been standardised in studies and are used interchangeably. Swabbing and irrigation are the usual cleansing techniques but bathing or showering are other options
© 2006 Tissue Viability Society 6
VOL 16 NO.4 NOVEMBER 2006
described in the hterature. Apart from different techniques used for cleaning and irrigating wounds, there is disparity among the solutions used for cleansing. Different solutions ranging from tap water to normal sahne to antiseptics have been used, all having their own disadvantages and advantages. The assessment and protocol of management, however, seems rituahstic rather than evidence based 12•13 Although there is evidence to suggest that wound cleansing is not always necessari 4, there is no diagnostic test that would allow healthcare professionals to identify the bacterial load in the wound capable of causing wound infection". The situation is further complicated by studies showing that bacterial colonisation of the wound does not necessarily indicate infection and there is no need to remove the bacteria in the absence of clinical signs of infection'6.".
Antiseptics The use of antiseptics, particularly povidone iodine, in the management of acute traumatic wounds has remained a controversial issue over the last two decades. It is also important to realise that the term iodine has sometimes been used to describe all formulations including povidone iodine, cadexomer iodine and others. These preparations have different iodine concentrations and different characteristics of their component parts. This raises the question of whether they should be grouped and studied separately. The term antiseptic was first used by Pringle in 1750'"' An antiseptic is a substance that inhibits the growth and development of micro-organisms causing sepsis in wounds'9. They may be either bactericidal or bacteriostatic. Commonly used antiseptics for wound cleansing include chlorhexidine, iodine compounds, alcohol, benzalkonium chloride and hydrogen peroxide. The use of antiseptics in wound care is controversial. The debate started after Fleming's lecture in 1919 about his work on antiseptics in septic wounds. The use of antiseptics began to decrease in 1929 after the discovery of penicillin. Stringer et al showed that antiseptics confer no benefit as compared to sahne in cleansing wounds'o In vitro experiments by Brennan and Leaper 2' demonstrated antiseptics were detrimental to the production of collagen, impairing epithehal migration and inhibiting microcirculation. Furthermore antiseptics are inactivated by contact with body fluids, blood, and proteins»' However, they need to be in contact long enough to reduce bacterial numbers 23 This evidence led to a decrease in the popularity of antiseptics for wound cleansing and there was a decline in their use with more emphasis on antibiotics in the treatment of contaminated/infected wounds. However, with the emergence of bacterial resistance to antibiotics, there has been a reappraisal in the use of antiseptics, and especially iodine compounds.
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Iodine is one of the long established antiseptics. Early preparations caused local pain and tissue reaction. Povidine iodine was introduced 40 years ago. It contains polyvinylpyrrolidone iodine, which is a water soluble complex of elemental iodine with a synthetic polymer. 10% solution in water is the most commonly manufactured form. It has a bactericidal action and is effective against a wide range of bacteria, fungi and even spores24 . The killing action occurs in seconds and is thought to be from inactivation of vital cytoplasmic substrates, which are necessary for bacterial viability25. Plasm~ proteins can bind up to 80% of free iodine'6 The presence of organic matter has a marked depressant effect on the minimum lethal concentrations of iodine. In the absence of inhibitors the disinfection is rapid, probably less than 10 seconds 27 • Antiseptics were the main stay of wound management until the mid-1980s, when research by Brennan and Leaper showed the effects of antiseptic solutions on wound healing physiology. They evaluated the effects of various antiseptics on wound micro-circulation in the rabbit ear chamber model of healing. The action of antiseptics on micro-circulation within the granulation tissue was examined with a laser Doppler flow meter. In wounds exposed to Eusol and chloramines T, the tissue perfusion ceased immediately and even after several days of observation these vessels did not re-open. Sahne and hydrogen peroxide did not result in any change in the pattern of blood flow. Chlorhexidine caused a few capillaries to close down. The effect of povidine iodine was concentration dependent. At a concentration of 5%, blood flow ceased in small blood vessels but a 1% solution was innocuous. This study is quoted as the strongest evidence against the use of antiseptics. However, the sample size was small, with only two wounds for each cell type. In order to be statistically significant this study needs to be rephcated. There should also be some concern in transferring the data from an experimental model to a clinical situation. Furthermore there is no strong evidence on human models of wound healing. The authors have shown that the apphcation of antiseptics irreversibly destroys angiogenesis, however it should be remembered that angiogenesis is just one step in the complex healing cascade. The Doppler flow meter used by the authors to monitor the micro-circulation could not be calibrated in order to provide a reading of flow per unit time. This may have affected the rehabihty of measurements. They also used the term 'flooding the ear chambers with antiseptic', which needs clear definition. Further in vitro studies have shown that the weaker solutions of hypochlorites, compatible with the preservation of fibroblast function, can still inhibit the growth of bacteria including Staphylococcus aureus, Pseudomonas, Bacteriodes, and Eschericia colf 8
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But it must be remembered that in vivo the presence of pus, blood and exudate can further dilute the concentrations of these antiseptics and decrease their efficacy. Hypochlorites also result in skin irritation and are harmful to granulation tissue 29 . Research by Tatnall et a13 0 has shown that at concentrations recommended for wound cleansing, hypochlorite, hydrogen peroxide and chlorhexidine, all result in 100% killing of cultured keratinocytes and fibroblasts, with the hypochlorites being the most toxic. Hence the routine use of hypochlorites in wound cleansing is not advisable.
Iodine There have been conflicting studies regarding the usefulness of iodine in managing traumatic wounds",n Clinical trials have shown mixed success33 ,34,35. Roberts et a136 published a series of 418 patients with hand lacerations who were randomly allocated to a group where the injury was treated with povidone iodine before suturing and to a control group. They found no adverse effects of iodine on healing and the overall infection rate was significantly lower in the group treated with povidone iodine. Similar results were seen by Gravett et al (1987) when they compared 1% povidone iodine to normal saline in the management of traumatic lacerations and found a statistically significant difference between the two groups with an infection rate of 5.4% and 15.4% respectively''. Gordon (1993) found iodine very effective against MRSA and its value in helping control MRSA outbreaks is well recognised 38 ,39. Similarly Goldenheim (1993) demonstrated that povidine iodine .preparations do not have a deleterious effect on healing, It is useful in the treatment of burns because of its broad-spectrum activity and high penetration power'o. However, he recommended that it should not be used in pregnant women, newborns and those with thyroid disorders. Research by Cooper and Lawrence" found that wound cleansing with povidone iodine or cetrimide did not significantly reduce the number of bacteria present in contaminated lacerations. The mere presence of bacteria in a wound does not necessarily mean infection as wounds are usually colonised by bacteria. However, if the bacterial count reaches a certain level where the host defences cannot maintain the balance of organisms in the wound, it is referred to as critical colonisation42 and it can be a predecessor of invasive infection, Timely and appropriate use of topical antiseptics may return a wound from critical colonisation back to the state conducive to wound healing. Bacteria in the wound not only delay healing but also produce malodour; their
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toxins can be destructive to the wound bed and they can result in an increase in the amount of exudate. Medicated wound dressings impregnated with iodine have also been evaluated in the management of acute wounds and have met with m.i..,'Xed success. Cadexomer iodine ointment has been found to be highly efficacious and has been reported to accelerate epithelisation as compared to air exposed wounds, with out any deleterious effects". It has also proven effective against proliferation of MRSA in wounds. Davison and Keenan" have reported a randomised trial of three different wound dressings after nail matrix ablation with phenol. Povidone-iodine dressing,' amorphous hydrogel dressing and a paraffin gauze dressing were compared, The main outcome measure was clinical infection rate and there was no statistically significant difference between the three groups. Iodine released from cadexomer iodine has been shown to have a pro-oxidant effect, which could stimulate fibroblast proliferation in vitro". It also induces tumour necrosis factor alpha and inhibits the production of Interleukin-6 (IL-6) from macrophages, growth factors that are important for inflammation induction'6. Development of resistance to antiseptics is thought to be rare. However, certain species such as bacterial spores, mycobacteria and gram-negative bacteria possess intrinsic resistance and several bacteria can acquire plasmid mediated resistance". Development of resistance to povidone iodine is very unlikely because it requires alteration in the bacterial cell proteins'8. Povidone iodine also has an effect on the bacterial exotoxins and enzymes, which can cause further tissue damage'9. Yasuda et al's study'° looked at the antiseptic resistance of 20 bacterial strains and found that povidone iodine killed all bacteria within 20 seconds, This study showed that iodine is effective against intrinsically resistant and non-resistant gram negative bacteria. Studies have shown that the acquisition of resistance to the long-term use of povidone iodine is not observed". Iodine solutions are deactivated in the presence of organic material, pus, slough and necrotic tissue in the wound52 ,53,5'. In vitro experiments by Lawrence 5s have shown that although the presence of exudate deactivates povidone iodine dressings, they can reduce the bacterial counts of the wounds to a very low level as compared to controls. Studies by others have shown different results. Kunisada et a1'6 tested povidine iodine, chlorhexidine and benzalkonium chloride solutions against different nosocomial bacteria. They used solutions of different concentrations and exposed them for varying lengths of time, The bacteria were suspended in different concentrations of neutralising plasma serum. The results showed that povidine iodine was highly effective against all the test organisms at a very low concentration and over a short period of time. However, the in vitro
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evaluation of the antibacterial activity of an antiseptic may not necessarily be a good guide to its activity in clinical use. Its effects on the immune system, toxic effects on wound healing and inactivation by the body fluids should also be taken into accounf 5 • Animal studies involving antiseptics have shown chlorhexidine, iodine and hydrogen peroxide to be toxic to fibrobiasts'l. Povidine iodine even at low concentrations has been shown to be toxic to granulocytes and monocytes" and results in decreased chemotaxis 5". It is also capable of suppressing lymphocyte functions 59 . Mulliken et al60 studied the tensile strength of heahng wounds in winstar rats and found no statistical difference in the rate of gain of tensile strength and histological appearance between the control and experimental groups. They concluded that apphcation of 1 % povidone iodine solution to clean incised wounds does not affect fibroplasia or collagen cross-linking. In vivo studies have shown that application of 5% povidone iodine solution inhibits polymorphonuclear leukocytes and fibroblast migration and activity61. In contrast, research in 2001 by Bennett et a1 62 on porcine models of wound healing has shown that apphcation of 10% povidone iodine solution is associated with increase in the number of proliferating fibroblasts at day four and enhanced angiogenesis at day seven as compared to the controls6'. However, different research methodologies make the comparison of these studies difficult. Work in 2002 by Balin and Pratt has shown that even dilute solutions of povidone iodine can be toxic to human fibroblasts as at concentrations of 0.1 % and 1%, human fibroblast growth is totally inhibited"3. Concentrations lower than 0.1 % progressively retard the growth. However, they have also noted that there was partial recovery of cell growth after limited exposure. The results of the above studies are conflicting, however it must be remembered that the relationship between povidone iodine and free iodine concentrations is not linear, as it forms a bell shaped curve, which peaks at 0.7% concentration. Higher concentration of povidone iodine can paradoxically bind more free iodine to the carrier molecule, thereby lowering the available free iodine6'. Iodine compounds are not hazard free. Toxic symptoms can result from systemic absorption. These include nervousness, depression, insomnia, myxoedema, hypersensitivity and skin reactions 6s . The absorption depends upon the concentration and the particular use of iodine. Absorption is increased in the presence of damaged tissue, hence its use is not recommended in burns involving more than 20% of the body surface area 66 . Metabolic acidosis and hypernatremia are the other possible toxicities 6'.
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Conclusion Wound cleansing remains a corner stone in the management of acute traumatic wounds". Due to the lack of powerful clinical studies, a standardised regimen has yet to be established54 • The existing evidence regarding the use of povidone iodine is complicated by the mixture of laboratory, human and animal studies. In vitro studies have shown toxic effects at cellular level but clinical studies have failed to show statistically Significant differences with control groups. With the emergence of antibiotic resistance, there has been a re-appraisal of the use of povidone iodine especially in the management of contaminated and infected wounds. Well designed in vivo studies are required to prove its efficacy, however the debate seems to be far from resolved.
Acknowledgements We are grateful to Dr. Sadaf Rafique for her generous help with the hterature search and proofreading.
References 1. Leaper DJ, Harding KG. (Eds). Wounds: Biology and Management. Oxford University Press: Oxford; 1998. 2. Singer AJ, Mach C, Thode HC, Hemachandra 5, Shofer FS, Hollander JE. Patient priorities with traumatic lacerations. American Joumal of Emergency Medicine. 2000; 18(6): 683-6. 3. Holmes JD. Classification of wounds and their management. Surgery 1999; 17(3): 63-7. 4. Moscati RM, Reardon RF, Lerner EB, Mayrose 1. Wound irrigation with tap water. Acad Emerg Med 1998; 5(11): 1076-80. 5. Towler 1. Cleansing traumatic wounds with swabs, water or saline. Joumal of Wound Care 2001; 10(6): 231-3. 6. Riyat MS, Quinton DN (1997). Tap water as a wound cleansing agent in accident and emergency. J Accid Emerg Med 1997; 14(3): 165-6. 7. Longmire AW, Broom LA, Burch 1. Wound infection following high-pressure syringe and needle irrigation. Am J Emerg Med 1987; 5(2): 179-81. 8. Dire DJ, Welsh AP. A comparison of wound irrigation solutions used in the emergency department. Ann El11erg Med. 1990; 19(6): 704-8. 9. Morrison M. Wound cleansing, which solution) Professional Nurse 1989; 4(5): 220-5. IO.Punder R. Wound cleansing. Joumal of Community Nursing 1997; 11(7): 30-6. 11. Bale 5, Jones V. Wound care nursing: A patient centred approach. Bailliere Tindall: London; 1997. 12.Koh S. Dressing practices. Nursing Times 1993; 89(42): 82-6. 13.Trevelyan 1. Wound cleaning: principles and practices. Nursing Times 1996; 92(16): 46-8. 14.Thomlinson D. To clean or not to clean? Nursing Times 1987; 83(9): 71-5. 15. Chrisholm CD. Wound evaluation and cleansing. Emerg Med ClinNorthAm 1992; 10(4): 665-72. 16. Gilchrist B. Treating bacterial wound infection. Nursing Times 1994; 90(50): 55-8. 17.Harding K. Managing wound infection. Joumal of Wound Care 1996; 15(8): 391-2. 18.Scanlon E, Stubbs N. To use or not to use? The debate on the use of antiseptics in wound care. Joumal of H/0und Care 2.002; 8-20. 19.Cape BR, Dobson P. Bailliere's Nurses Dictionary 18th ed.
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Bailhere Tindall: London; 1974. 20.Stringer MD, Lawrence JC, Lilly HA. Antiseptics and the casualty wound. J Hosp Infec ]983; 4: 410-3. 21. Brennan SS, Leaper OJ. The effect of antiseptics on the healing wound: a study using the rabbit ear chamber. Br J Surg ]985; 72(10): 780-2. 22.Fergusson A. Best performer. Nursing Times 1988; 84(14): 52-5. 23.Mertz P. A new in vivo model for the evaluation of topical antiseptics on superficial wounds. The effect of 70% alcohol and povidine iodine solution. Archives of Dennatology 1984; 120(1): 58-62. 24.La Rocca. Microbiology of povidone iodine; an overview. Proceedings of the International Symposium on povidone. Lexingtom Ky College of Pharmacy. University of Kentucky: Kentucky; ]983: 10]-9. 25.lvlisra A. Use of gauze soaked in povidone iodine for dressing acute open wounds. Journal of Plastic & Reconstructive Surge1y 2003; 111(6): 2015-6. 26.Abdullah ME, Said SA, Al-AShora H. Influence of biological fluids on the release of iodine from povidone iodine. ATZneimittelforschung ] 981; 31: 828. 27.Lacey RW, Catto A. Action of povidone iodine against methicillin sensitive and resistant cultures of Staphylococcus aureus. Post Graduate Medical Journal 1993; 69(Suppl 3): S78-83. 28.McKenna PJ, Lehr GS, Leist P, Welling RE. Antiseptic effectiveness with fibroblast preservation. Ann Plast Surg 1991. 27: 265-8. 29.Gorse GJ, Messner RL. Improved pressure sore healing with hydrocolloid dressing. AI'ch Dennatol1987; 123: 766-71. 30.Tatnall FM, Leigh 1M, Gibson JR. Comparative study of antiseptic toxicity on basal keratinocytes, transformed keratinocytes and fibroblasts. Skin Phannacol1990; 3: 157-63. 31.Naunton-Morgan TC et al. Prophylactic povidone iodine in minor wounds. Injury 1980; 12(2): 104-6. 32.Bickerstaff KL, Regnard C. Prophylactic povidine iodine sprays in accidental wounds. Journal of the Royal College of Surgeons of Edinburgh 1984; 29(4): 234-36. 33.Stokes E, Howard E, Peters J, Hackworthy C, Milne S, Witherow M. Comparison of antibiotic and antiseptic prophyla-xis of wound infection in acute abdominal surgery. World Joumal of Surgely 1977; I: 777-82. 34.Kothius B. The effect of povidone iodine on postoperative wound infection in abdominal surgery. Netherlands Journal of Surge1y 1981; 33: 186-9. 35.Platt J, Bucknall A. An experimental evaluation of antiseptic wound irrigation. Journal of Hospital Infection 1984; 5: 181-8. 36. Roberts AH, Roberts FE, Hall RI, Thomas IH. A prospective trial of prophylactic povidone iodine in lacerations of the hand. J Hand Surg [BrJ 1985; 10(3): 370-4. 37.Gravett A, Sterner S, Clinton JE, Ruiz E. A trial of povidone iodine in the prevention of infection in sutured lacerations. Ann Emerg Med 1987; 16(2): 167-71. 38.Gordon J. Clinical significance of the Methicillin sensitive and Methicillin resistant Staphylococcus aureus in the UK hospitals and the relevance of povidine iodine in their control. The Fellowship of Post Graduate Medicine 1993; 3(Suppl): S106-16. 39.Jones MR, Martin DR. Outbreak of MRSA infection in a New Zealand Hospital. In: Selwyn S. Proceedings of the First Asian/Pacific Conference on antisepsis. The Royal Society of Medicine International Congress Series No. 129. The Royal Society of Medicine: London; 1988. 40. Goldenheim PD. An appraisal of povidone iodine and wound healing. Post Graduate Medical Joumal 1993; 69(SuppI)3: S97-SI05. 41.Cooper R, Lawrence Jc. The role of antimicrobial agents in wound care. Journal ofHl ound Care 1996; 5: 374-7.
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42.Kingsley A. A proactive approach to wound infection. Nursing Standard 2001; 15(30): 50-8. 43.Mertz P. The evaluation of cadexomer iodine ointment. Wounds 1994; 6(6): 184-93. 44.Davison R, Keenan A. Wound healing and infection in the nail matrix phenolization wounds. Does topical medication make a difference? JAm Podiatr MedAssoc 2001; 91(5): 230-3. 45.Schmidt R, Kirby A, Chung L. Cadexomer iodine formulations may modulate the redox environment of wounds. In: Iodine and Wound Physiology. Hunt T, Middelkoop E. (Eds.). Perstop Pharma: Cambridge; 1995: 6.1-6.26 46.Moore K, Thomas A, Harding K. Iodine released from the wound dressing lodosorb modulates the secretion of cytokines by the human macrophages responding to bacterial lipopolysaccharides. Inc J Biochem Cell Bioi 1997; 29: 163-71: 47.McDonnell G, Russell AD. Antiseptics and disinfectants: activity, action and resistance. Clin Microbiol Rev 1999; 12(1): 147-79. 48. Lanker Klosssner B, Widmer HR, Frey F. Non development of resistance to bacteria during hospital use of povidone iodine. Dennatology 1997; ]95(Suppl): 10-3. 49.Koing B, Reimer K, Fleicher W, Koing W. Effects of beta isodona on the parameters of host defence. Dennatology 1997; 195(Suppl 2): 42-8. 50.Yasuda T, Yoshimura Y, Takada H et al. Comparison of bactericidal effects of commonly used antiseptics against pathogens causing nosocomial infections. Dennatology 1997; 195(Suppl 2): 19-28. 51.Klossner B, Widmer H, Frey F. on development of resistance by bacteria during hospital use of povidone iodine. Dennatology 1997; 195(SuppI2): 10-3. 52. Rodeheaver G. (1988). Topical wound management. Ostomy/WoundiManagement 4: 59-68 53.Morgan D.ls there still a role for antiseptics) JoumalofTissue Viability 1993; 3(3): 80-4. 54. Heyworth J. Wound care. In: Skinner 0, Swain A, Payton R, Robertson C. (Eds.). Cambridge Text Book of A&E Medicine. Cambridge University Press: Cambridge; 1997. 55. Lawrence J. A povidone iodine medicated dressing. Joumal of Wound Care 1988; 7(7): 332-6. 56.Kunisada T, Yamada K, Oda S, Hara O. Investigation of the efficacy of povidone iodine against antiseptic resistant species. Dennatology 1997; 95(Suppl 2): 14-8. 57.Yan Den Broek. Interaction of povidone iodine compounds, phagocytic cells and micro-organisms. Antimicrobial Agents and Che1notherapy 1982; 22(4): 593-7. 58. Connolly JC, Gilmore OJ. A study of povidone iodine on polymorphonuclear leucocyte chemotaxis. Br J Exp Pathol 1979; 60(6): 662-6. 59.Ninnemann J, Stein MD. Suppressor cell induction by povidone iodine: in vitro demonstration of a consequence of clinical burn treatment with betadine. Journal of Immunology 1981; 126(5): 1905-8. 60.Mulliken JB, Healey NA, Glowacki J. Povidone-iodine and tensile strength of wounds in rats. J Trauma 1980; 20(4): 323-4. 61.Viljanto J. Disinfection of surgical wound without inhibition of normal wound healing. Arch Surg 1980; us: 253. 62. Bennett L, Richard S, Davidson C, Jeffrey M, Barton R, Nanney L. An in vivo comparison of topical agents on wound repair. Joumal of Plastic & Reco11Stnlctive SUTge1Y 2001; 108(3): 675. 63.Balin AK, Pratt L. Dilute povidone iodine solutions inhibit human skin fibroblast growth. Demtatologic Surge1Y 2002; 28(3): 210-4. 64. Zamora JL. Chemical and microbiological characteristics and toxicity of povidone iodine solutions. Am J Surg 1986; lSI: 400. 65. Reynolds 1. (Ed.). Martindale. The extra phannacopoeia (29th Ed.) The Pharmaceutical Press: London; 1989. 66.Pietsch J, Meakins JL. Complications of povidone iodine absorption in topically treated burn patients. Lancet 1976; 1: 280-2. 67.British National Formulary. 2004, available at www.bnforg.
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