J Bone Joint Infect 2017; 2(1):3-9. doi:10.7150/jbji.16690
Hydrogen Peroxide Wound Irrigation in Orthopaedic Surgery
Department of Orthopaedic Surgery University of California San Francisco, San Francisco, California, USA.
Lu M, Hansen EN. Hydrogen Peroxide Wound Irrigation in Orthopaedic Surgery. J Bone Joint Infect 2017; 2(1):3-9. doi:10.7150/jbji.16690. Available from http://www.jbji.net/v02p0003.htm
As the burden of deep hardware infections continues to rise in orthopaedics, there is increasing interest in strategies for more effective debridement of colonized tissues and biofilm. Hydrogen peroxide has been used medically for almost a century, but its applications in orthopaedic surgery have yet to be fully determined. The basic science and clinical research on the antiseptic efficacy of hydrogen peroxide have demonstrated its efficacy against bacteria, and it has demonstrated potential synergy with other irrigation solutions such as chlorhexidine and povidone-iodine. While hydrogen peroxide is effective in infection reduction, there are concerns with wound healing, cytotoxicity, and embolic phenomena, and we recommend against hydrogen peroxide usage in the treatment of partial knee replacements, hemiarthroplasties, or native joints. Additionally, due to the potential for oxygen gas formation, hydrogen peroxide should not be used in cases of dural compromise, when pressurizing medullary canals, or when irrigating smaller closed spaces to avoid the possibility of air embolism. Finally, we present our protocol for irrigation and debridement and exchange of modular components in total joint arthroplasty, incorporating hydrogen peroxide in combination with povidone-iodine and chlorhexidine.
Keywords: Infection, Antiseptics, Hydrogen peroxide, Irrigation, Complications.
Deep surgical site infection (SSI) remains a challenging and devastating problem in orthopaedic surgery. The implantation of hardware devices can result in difficult to treat infections, often necessitating reoperations and prolonged antibiotic therapy [1, 2]. An episode of infection places a significant strain on the patient, physician, and healthcare system. In complex spine surgery, the incidence is approaching 10% [3, 4], and in arthroplasty, the infection burden is continuing to rise  with increasing bacterial resistance, surgical complexity and patient comorbidities.
Although complete removal of foreign hardware and nonviable tissue is widely considered the gold standard for infection eradication, acute infections may be amenable to aggressive irrigation and debridement, modular component exchange, and hardware retention before bacterial glycocalyx becomes entrenched. Surgical reduction of bacterial bioburden can potentially control the infection by shifting balance in favor of the host immune system and antibiotic therapy, while minimizing morbidity related to hardware removal. The holy grail in the field of infection management is to optimize the feasibility of a single stage procedure, thereby minimizing morbidity to the patient, while maintaining infection cure rates. To this end, various strategies have been implemented to enhance the success of an irrigation and debridement procedure. These are: 1) maintaining separate clean and contaminated instrument sets, 2) enhanced thoroughness and adequacy of debridement, 3) culture directed antibiotics and local antibiotic delivery, and 4) adjunct antiseptics to cleanse the surgical wound and retained implants.
One method of surgically reducing the bacterial load is irrigation with antiseptic agents [6, 7]. One advantage of antiseptic agents over topical antibiotics is that they are less selective in their action, and are less likely to result in infection with resistant organisms . The associated downside is their cytotoxicity to normal host tissue [9, 10]. In this paper, we will review and discuss the use of hydrogen peroxide as one adjunct for reducing infectious burden in orthopaedic surgery. We will discuss the history of its use, basic science mechanism of action, as well as clinical results.
Hydrogen peroxide was first discovered in 1818 by Louis Jacques Thenard, a French chemist . He named it “eau oxygene” or oxygen water, aptly describing its composition, even though the molecular formula and structure would not be discovered until many years later. It was first produced in pure form in the 1890s and medical use started in the early 1900s. A 1920 Lancet article describes the intravenous infusion of hydrogen peroxide, used to treat broncho-pneumonia on 25 patients in Manchester, England . Their treatment hypothesis was to increase oxygen delivery to cells, while “rendering circulating toxins inert by oxidation”. Since that time, hydrogen peroxide has been widely used throughout medicine, surgery and dentistry. Although its ingested and intravenous applications have decreased, it remains a popular topical antiseptic. Compared to other antimicrobial agents, it presents numerous theoretical advantages including its natural occurrence in host tissue, and effervescence which can aid in mechanical wound debridement . It is also cheap and widely available compared to many selective antimicrobial agents, and decomposes into non-toxic by-products.
Mechanism of Action Against Bacteria and Biofilm
Hydrogen peroxide occurs naturally within animal and human tissues and serves various roles in cell signaling, tissue inflammation and aging . Additionally, it is a key component of the innate immune response to infection. Niethammer et al  in 2009 showed that reactive oxygen species including hydrogen peroxide serve a role in chemical signaling to leukocytes at the site of a wound. Furthermore, hydrogen peroxide combines with chloride to form hypochlorous acid as part of macrophages' and neutrophils' respiratory burst for killing bacteria.  It has been shown that enzyme deficient neutrophils incapable of generating these reactive oxygen species are much less efficient at killing many species of microorganisms. A well-known clinical manifestation of this is chronic granulomatous disease, where patients deficient in myeloperoxidase and hydrogen peroxide production are much more susceptible to infection .
A 3% solution of hydrogen peroxide demonstrates broad antimicrobial efficacy in vitro. Its greatest activity is against Gram-positive organisms, but the catalase enzyme present in these bacteria make dilutions under 3% less effective.  In vivo, the antimicrobial action can be affected by blood, pus and exudate, which dilute the effective concentration of hydrogen peroxide present. Similarly, catalase is present in normal human tissue and can compromise the efficacy of hydrogen peroxide in vivo . Hydrogen peroxide mediated bacterial killing is thought to occur through multiple pathways, including DNA damage , as well as oxidation of proteins and membrane lipids .
In addition to direct bactericidal activity, multiple in vitro studies have shown that hydrogen peroxide can reduce biofilm formation by bacteria . Glynn found that hydrogen peroxide induced stress downregulated biofilm development by Staphylococcus epidermidis . Meanwhile, another in vitro study found that hydrogen peroxide in combination with sodium hypochlorite actually completely removed or significantly reduced Pseudomonas aeruginosa biofilm from stainless steel and aluminum surfaces .
Effect on Wound Healing and Host Tissues
One of the main concerns regarding the use of antiseptics is whether they adversely affect host tissues as much as they do foreign bacteria.  Tatnall et al showed that at antibacterial concentrations, hydrogen peroxide also results in toxicity to keratinocytes and fibroblasts.  This has been supported by other in vitro studies  and one in particular  has shown toxicity to chick tibiae and osteoblasts.
Despite these in vitro studies, animal and human experiments have shown no in vivo deleterious effect on wound healing. In 1975, Gruber et al reported accelerated healing of experimental animal wounds as well as skin graft donor sites treated with topical hydrogen peroxide compared to saline or povidone-iodine . Lineweaver found that even though 3% hydrogen peroxide was found to be cytotoxic, it did not adversely affect wound reepithelialization . Tur et al found that topical hydrogen peroxide actually promoted increased vascular perfusion of ischemic ulcers in a guinea pig model .
Apart from its effects on wound healing and antiseptic properties, multiple studies have also investigated the effect of hydrogen peroxide on hemostasis in joint replacement surgery with mixed results. Hankin et al in 1984  showed that hydrogen peroxide led to less blood loss per unit area when applied to a metaphyseal bone bed in a dog model. A study out of Australia in 1992 showed that hydrogen peroxide irrigation could effectively achieve hemostasis at bone interfaces and improve cement interdigitation . More recently, Chen et al investigated the effect of topical hydrogen peroxide and tranexamic acid on blood loss after TKA. They applied 50 mL of 3% hydrogen peroxide after femoral and tibial bone cuts were completed, washed the surface with 0.9% normal saline and dried the bony surfaces in an attempt to reduce bleeding from bone cuts. They found no reduction in blood loss following hydrogen peroxide application compared to controls . Another study on hydrogen peroxide hemostatic effects in an animal model also demonstrated no benefit versus conventional hemostatic techniques .
Effect on Implants
One experiment has investigated the effect of hydrogen peroxide on materials commonly used in hip arthroplasty. Shigematsu et al  soaked samples of ultra-high molecular weight polyethylene (UHMWPE), titanium alloy and hydroxyapatite in 3% hydrogen peroxide and examined the samples under a scanning electron microscope. They found that it had no significant effect on the UHMWPE, and caused a slight darkening of the titanium surface representing an oxidated layer. Meanwhile, they did report etching and concern for erosion of hydroxyapatite. They conclude that the degradative effect on arthroplasty implants is minimal, but caution should be used in cases involving hydroxyapatite coating.
Synergy with other Antiseptics
In addition to its own antimicrobial action, hydrogen peroxide has further been shown to be both synergistic with chlorhexidine and dilute povidone-iodine. Steinberg  found chlorhexidine and hydrogen peroxide to be synergistic against species of Streptococcus and Staphylococcus. They postulate that chlorhexidine may alter the bacterial cell surface allowing increased hydrogen peroxide penetration. Similarly, hydrogen peroxide has been found to act synergistically with povidone-iodine. Zubko observed that at test concentrations, hydrogen peroxide and povidone-iodine proved to be bacteriostatic when used separately, whereas in combination, they were bacteriocidal . They postulate that this is due to metabolic stresses induced by povidone-iodine, which then allows hydrogen peroxide to act unfettered against weakened cells. The significance of antiseptic synergy is that by combining multiple agents, 1) a wider range of organisms can be covered effectively and 2) lower cytotoxic concentrations of the individual compounds can be used.
The effect of hydrogen peroxide on wound healing and infection control has been studied in both general and plastic surgery with mixed results. A randomized trial by Lau et al evaluated the effectiveness of hydrogen peroxide on reducing infection rate in appendectomy wounds . It found hydrogen peroxide to be safe to use, but also did not demonstrate any statistically significant change in infection rates. Likewise, another clinical study  on human blister wounds contaminated with Staphylococcus Aureus found hydrogen peroxide to neither retard wound healing nor effectively decrease bacterial load. Conversely, in plastic surgery multiple studies have shown benefit of hydrogen peroxide on chronic wounds. Mohammadi et al in a randomized clinical trial of chronic colonized burn wounds showed that 2% hydrogen peroxide wound cleansing significantly improved skin graft take rates . Another trial by Irkoren demonstrated that hydrosurgery with hydrogen peroxide was superior to controls without hydrogen peroxide for infected wounds, resulting in shorter hospital stay and enhanced graft viability .
In orthopaedics, the effectiveness of wound irrigation with hydrogen peroxide has been demonstrated in the spine literature. Dauch et al filled the surgical wound prior to closure with a solution of 10cc of 10% povidone-iodine + 5cc of water + 1cc of hydrogen peroxide, and then after one minute of action, rinsed it out with copious irrigation with sterile saline to minimize the risk of toxicity . Ulivieri adapted this protocol and performed this systematically over one year. They noted no cases of deep infection out of 490 cases, whereas they had a baseline infection rate of 1.5% (7 of 460) the year prior to institution of this protocol. They noted that hydrogen peroxide was only applied in cases when the dura was intact to mitigate the risk of air embolism .
In the arthroplasty literature, Kosashvili et al reported their usage of wound irrigation with a combination of povidone-iodine, hydrogen peroxide and bacitracin . Their overall infection rate was 2.14% in revision cases and 1.35% in first time revisions using this protocol. George et al described their protocol for single stage exchange arthroplasty for hip and knee periprosthetic joint infections . They use a combination of 1% povidone iodine and a 50:50 dilution of 3% hydrogen peroxide. Using their protocol, they were able to achieve no recurrences of infection in 11 hips at a mean of 5 years and 28 knees at a mean of 6.5 years.
Hydrogen peroxide has also been applied in orthopaedic oncology and trauma surgery. Wooldrige et al used nondiluted hydrogen peroxide as an adjuvant in soft tissue sarcoma resection . They noted statistically insignificant improvement in local recurrence (hazard ratio 0.81, 95% CI 0.27-2.48) and SSIs (0.52, 95% CI 0.15-1.81). Hydrogen peroxide has been shown to be an effective adjuvant on giant cell tumors in vitro [48, 49] as well as in vivo . There is mixed literature on the efficacy of hydrogen peroxide in preventing external fixator pin tract infection with one trial supporting its use  and another showing no difference compared with other cleaning regimens .
The main concerns related to hydrogen peroxide usage pertain to its cytotoxicity and potential for air embolism. Multiple basic science studies have shown that hydrogen peroxide adversely affects articular cartilage by inhibiting normal chondrocyte metabolic function [53-55]. It has been shown to deplete adenosine triphosphate (ATP) in cells, and reduce proteoglycan and hyaluronic acid synthesis in cartilage. While there have been no human clinical studies to our knowledge, these findings are sufficiently consistent that we recommend against hydrogen peroxide usage in the treatment of partial knee replacements, hemiarthroplasties, or native joints. Despite this cytotoxicity towards host tissue, hydrogen peroxide has not been shown to adversely affect the osteoconductivity or structural integrity of allografts when used in the sterilization process . Therefore, it is potentially safe to use hydrogen peroxide with allograft tissue, although we would caution against allograft use if there is any concern for infection.
The other potential serious complication related to hydrogen peroxide relates to its breakdown to form oxygen gas, and the possibility of air embolism. While the effervescence of hydrogen peroxide is considered a unique benefit in terms of providing some aid in mechanical debridement, this can also be a problem in certain circumstances. Since one milliliter of hydrogen peroxide produces about 10 mL of oxygen, this can be deleterious when used in closed cavities . In the spine literature, there have been reports of fatal pneumocephalus [58, 59] when hydrogen peroxide was used for wound irrigation in the lumbar spine. Authors have advocated for hydrogen peroxide use only when the dura is intact, as a dural flap may act as a one-way valve, trapping any oxygen that is produced.
The sequelae of air emboli are also reported in other areas of orthopedic surgery. Timperley and Bracey reported the case of a cardiac arrest following hydrogen peroxide application in an unvented femoral canal prior to cementing . The authors postulate that oxygen bubbles under pressure were rapidly absorbed into the vascular cancellous bone causing air embolism and circulatory collapse. Henley et al reported two cases of air embolism leading to circulatory collapse in patients where hydrogen peroxide was used for irrigation of medullary bone after removal of external fixator pins .
As a result of these cases, the authors speculate that the irrigation of a closed cavity with hydrogen peroxide is associated with a higher risk than irrigation of an open surgical field. Large volumes of oxygen gas formed in a closed space are pressurized into small vascular channels. An extreme example of this is when hydrogen peroxide is used in neurosurgery after cranial procedures, which represents a closed nonexpendable space in the human body. One report cited a cardiovascular complication rate of 3% in this context . Given these rare but potentially serious risks, hydrogen peroxide should not be used for medullary canal irrigation unless ventilation of the canal is performed. It should not be instilled immediately preceding wound closure, and any application of hydrogen peroxide should be followed by copious wound irrigation to dilute and remove it after a period of activity. A surgical drain is advisable to further decrease the risk of any trapped oxygen gas and lastly, the anesthesiology team should be notified when hydrogen peroxide is utilized intraoperatively to closely monitor for changes in patient oxygen saturation and hemodynamic status.
In terms of our own protocol, we currently use hydrogen peroxide as an antiseptic, in cases of irrigation and debridement with modular component exchange (i.e. prosthesis retention) . In these cases, we find it imperative to reduce bioburden and use hydrogen peroxide as a means to cleanse retained hardware implants. We do not use antiseptics routinely for two-stage procedures or infection prophylaxis in primary or revision cases. In cases where hardware is completely removed and newly replaced, we feel that tissues can be adequately cleansed surgically and mechanically without the added cytotoxicity of antiseptics.
Our antiseptic irrigation protocol consists of five steps. First, the wound is soaked in a 50:50 dilution of 3% hydrogen peroxide and normal saline for three minutes. This is followed by pulsatile lavage irrigation with 3L normal saline. The wound then is soaked in 0.3% dilute povidone-iodine, while continuing to mechanically debride wound with scrub brushes and sponges. After another three-minute period, the wound is again irrigated with 3L normal saline. The final step is soaking the wound with 4% chlorhexidene gluconate. This is followed with repeat irrigation with 3L saline with 500,000 units polymyxin B and 50,000 units bacitracin.
The multistep approach carries several advantages. It is a commonly held surgical tenet that the “solution to pollution is dilution” and by employing multiple steps, we instill a large volume (>9L) of saline through the wound while simultaneously performing mechanical debridement with brushes and a pulse irrigator. Secondly, our multifaceted regimen takes advantage of the synergistic effects of povidone-iodine, chlorhexidine, and hydrogen peroxide. It theoretically decreases risk of bacterial resistance by employing various antiseptic and antimicrobial agents. Lastly, by washing with numerous agents and liters of saline after hydrogen peroxide, we minimize risk of retained hydrogen peroxide at wound closure and consequent risk of air emboli.
Currently, we perform irrigation and debridement along with modular component exchange in a limited subset of patients. These include healthy patients with well-fixed arthroplasty components and a relative acute course of symptoms in the setting of acute postoperative or acute hematogenous infection, or patients who are too medically infirm to undertake a full two-stage exchange. Previous studies have spoken to the importance of microorganism [65-69], timing of infection onset [70-73], and host immune status [67, 74, 75] on the successfulness of irrigation and debridement. At this point, we do not perform any true one-stage exchange arthroplasties, although there is emerging literature support for this practice. [46, 76-79] We believe that hydrogen peroxide and other antiseptic irrigations would be a useful adjunct in this setting based on limited literature.
Irrigation with antimicrobial agents, although widely performed, is selective in its efficacy and can foster development of resistant organisms. Antiseptics, on the other hand, are not as selective but frequently pose cytotoxicity to host tissue that is already compromised in the setting of infection. Hydrogen peroxide carries many theoretic advantages in this regard. It is cheap and widely available, it is naturally occurring in host tissue and decomposes into nontoxic byproducts, its mechanism of action is highly effective and can potentially remove biofilm from implant surfaces, and it has shown to have synergy with other antiseptic compounds. Overall, there is ample general literature to show that hydrogen peroxide does not impair wound healing, and that it may be beneficial for chronically infected wounds. This may suggest that in tissue that is already damaged by infection, the relative antiseptic benefit of hydrogen peroxide outweighs any secondary harm it may produce.
Although hydrogen peroxide has been used medically for over a century, its applications in orthopaedic surgery require further study. While we believe it to be useful in settings of retained hardware, more large-scale clinical studies are needed to determine its effectiveness and safety as an adjunct antiseptic. Much of the existing literature consists of case series, and few reports specifically isolate hydrogen peroxide as the lone study variable. In arthroplasty clinical series for example, it has frequently been used in conjunction with other antiseptics, making it difficult to evaluate the effect of hydrogen peroxide alone. Finally, due to the potential for oxygen gas formation, hydrogen peroxide should not be used in cases of dural compromise, when pressurizing medullary canals, or when irrigating smaller closed spaces to avoid the possibility of air embolism.
The authors have declared that no competing interest exists.
1. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med. 2004;351:1645-54
2. Moyad TF, Thornhill T, Estok D. Evaluation and management of the infected total hip and knee. Orthopedics. 2008;31:581-8 quiz 9-90
3. Banco SP, Vaccaro AR, Blam O, Eck JC, Cotler JM, Hilibrand AS. et al. Spine infections: variations in incidence during the academic year. Spine (Phila Pa 1976). 2002;27:962-5
4. Pull ter Gunne AF, Cohen DB. Incidence, prevalence, and analysis of risk factors for surgical site infection following adult spinal surgery. Spine (Phila Pa 1976). 2009;34:1422-8
5. Kurtz SM, Lau E, Watson H, Schmier JK, Parvizi J. Economic burden of periprosthetic joint infection in the United States. J Arthroplasty. 2012;27:61-5 e1
6. Cheng MT, Chang MC, Wang ST, Yu WK, Liu CL, Chen TH. Efficacy of dilute betadine solution irrigation in the prevention of postoperative infection of spinal surgery. Spine (Phila Pa 1976). 2005;30:1689-93
7. Brown NM, Cipriano CA, Moric M, Sporer SM, Della Valle CJ. Dilute betadine lavage before closure for the prevention of acute postoperative deep periprosthetic joint infection. J Arthroplasty. 2012;27:27-30
8. Russell AD. Antibiotic and biocide resistance in bacteria: introduction. J Appl Microbiol. 2002;92(Suppl):1S-3S
9. Muller G, Kramer A. Biocompatibility index of antiseptic agents by parallel assessment of antimicrobial activity and cellular cytotoxicity. J Antimicrob Chemother. 2008;61:1281-7
10. Thomas GW, Rael LT, Bar-Or R, Shimonkevitz R, Mains CW, Slone DS. et al. Mechanisms of delayed wound healing by commonly used antiseptics. J Trauma. 2009;66:82-90 discussion -1
11. Janoff LE. Origin and development of hydrogen peroxide disinfection systems. CLAO J. 1990;16:S36-42
12. Oliver T, Murphy D. INFLUENZAL PNEUMONIA: THE INTRAVENOUS INJECTION OF HYDROGEN PEROXIDE. The Lancet. 1920;195:432-3
13. Rodeheaver G, Ratliff C. Wound cleansing, wound irrigation, wound disinfection. Chronic wound care: A clinical source book for healthcare professionals. Wayne, Pa: Health Management Publications. 1997:97-108
14. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417:1-13
15. Niethammer P, Grabher C, Look AT, Mitchison TJ. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature. 2009;459:996-9
16. Wittmann C, Chockley P, Singh SK, Pase L, Lieschke GJ, Grabher C. Hydrogen peroxide in inflammation: messenger, guide, and assassin. Adv Hematol. 2012;2012:541471
17. Clifford DP, Repine JE. Hydrogen peroxide mediated killing of bacteria. Mol Cell Biochem. 1982;49:143-9
18. McDonnell G, Russell AD. Antiseptics and disinfectants: activity, action, and resistance. Clin Microbiol Rev. 1999;12:147-79
19. Brown CD, Zitelli JA. A review of topical agents for wounds and methods of wounding. Guidelines for wound management. J Dermatol Surg Oncol. 1993;19:732-7
20. Imlay JA, Chin SM, Linn S. Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro. Science. 1988;240:640-2
21. Linley E, Denyer SP, McDonnell G, Simons C, Maillard JY. Use of hydrogen peroxide as a biocide: new consideration of its mechanisms of biocidal action. J Antimicrob Chemother. 2012;67:1589-96
22. Presterl E, Suchomel M, Eder M, Reichmann S, Lassnigg A, Graninger W. et al. Effects of alcohols, povidone-iodine and hydrogen peroxide on biofilms of Staphylococcus epidermidis. J Antimicrob Chemother. 2007;60:417-20
23. Glynn AA, O'Donnell ST, Molony DC, Sheehan E, McCormack DJ, O'Gara JP. Hydrogen peroxide induced repression of icaADBC transcription and biofilm development in Staphylococcus epidermidis. J Orthop Res. 2009;27:627-30
24. DeQueiroz GA, Day DF. Antimicrobial activity and effectiveness of a combination of sodium hypochlorite and hydrogen peroxide in killing and removing Pseudomonas aeruginosa biofilms from surfaces. J Appl Microbiol. 2007;103:794-802
25. Khan MN, Naqvi AH. Antiseptics, iodine, povidone iodine and traumatic wound cleansing. J Tissue Viability. 2006;16:6-10
26. Tatnall FM, Leigh IM, Gibson JR. Comparative study of antiseptic toxicity on basal keratinocytes, transformed human keratinocytes and fibroblasts. Skin Pharmacol. 1990;3:157-63
27. Brennan SS, Leaper DJ. The effect of antiseptics on the healing wound: a study using the rabbit ear chamber. Br J Surg. 1985;72:780-2
28. Kaysinger KK, Nicholson NC, Ramp WK, Kellam JF. Toxic effects of wound irrigation solutions on cultured tibiae and osteoblasts. J Orthop Trauma. 1995;9:303-11
29. Gruber RP, Vistnes L, Pardoe R. The effect of commonly used antiseptics on wound healing. Plast Reconstr Surg. 1975;55:472-6
30. Lineaweaver W, Howard R, Soucy D, McMorris S, Freeman J, Crain C. et al. Topical antimicrobial toxicity. Arch Surg. 1985;120:267-70
31. Tur E, Bolton L, Constantine BE. Topical hydrogen peroxide treatment of ischemic ulcers in the guinea pig: blood recruitment in multiple skin sites. J Am Acad Dermatol. 1995;33:217-21
32. Hankin FM, Campbell SE, Goldstein SA, Matthews LS. Hydrogen peroxide as a topical hemostatic agent. Clin Orthop Relat Res. 1984:244-8
33. Howells RJ, Salmon JM, McCullough KG. The effect of irrigating solutions on the strength of the cement-bone interface. Aust N Z J Surg. 1992;62:215-8
34. Chen JY, Rikhraj IS, Zhou Z, Tay DK, Chin PL, Chia SL. et al. Can tranexamic acid and hydrogen peroxide reduce blood loss in cemented total knee arthroplasty?. Arch Orthop Trauma Surg. 2014;134:997-1002
35. Ackland DC, Yap V, Ackland ML, Williams JF, Hardidge A, de Steiger R. Pulse-lavage brushing followed by hydrogen peroxide-gauze packing for bone-bed preparation in cemented total hip arthroplasty: a bovine model. J Orthop Surg (Hong Kong). 2009;17:296-300
36. Shigematsu M, Kitajima M, Ogawa K, Higo T, Hotokebuchi T. Effects of hydrogen peroxide solutions on artificial hip joint implants. J Arthroplasty. 2005;20:639-46
37. Steinberg D, Heling I, Daniel I, Ginsburg I. Antibacterial synergistic effect of chlorhexidine and hydrogen peroxide against Streptococcus sobrinus, Streptococcus faecalis and Staphylococcus aureus. J Oral Rehabil. 1999;26:151-6
38. Zubko EI, Zubko MK. Co-operative inhibitory effects of hydrogen peroxide and iodine against bacterial and yeast species. BMC Res Notes. 2013;6:272
39. Lau WY, Wong SH. Randomized, prospective trial of topical hydrogen peroxide in appendectomy wound infection. High risk factors. Am J Surg. 1981;142:393-7
40. Leyden JJ, Bartelt NM. Comparison of topical antibiotic ointments, a wound protectant, and antiseptics for the treatment of human blister wounds contaminated with Staphylococcus aureus. J Fam Pract. 1987;24:601-4
41. Mohammadi AA, Seyed Jafari SM, Kiasat M, Pakyari MR, Ahrari I. Efficacy of debridement and wound cleansing with 2% hydrogen peroxide on graft take in the chronic-colonized burn wounds; a randomized controlled clinical trial. Burns. 2013;39:1131-6
42. Irkoren S, Sivrioglu N. A hydrosurgery system (Versajet) with and without hydrogen peroxide solutions for the debridement of subacute and chronic wounds: a comparative study with hydrodebridement. Adv Skin Wound Care. 2014;27:127-31
43. Dauch WA. Infection of the intervertebral space following conventional and microsurgical operation on the herniated lumbar intervertebral disc. A controlled clinical trial. Acta Neurochir (Wien). 1986;82:43-9
44. Ulivieri S, Toninelli S, Petrini C, Giorgio A, Oliveri G. Prevention of post-operative infections in spine surgery by wound irrigation with a solution of povidone-iodine and hydrogen peroxide. Arch Orthop Trauma Surg. 2011;131:1203-6
45. Kosashvili Y, Backstein D, Safir O, Lakstein D, Gross AE. Dislocation and infection after revision total hip arthroplasty: comparison between the first and multiply revised total hip arthroplasty. J Arthroplasty. 2011;26:1170-5
46. George DA, Konan S, Haddad FS. Single-Stage Hip and Knee Exchange for Periprosthetic Joint Infection. J Arthroplasty. 2015;30:2264-70
47. Wooldridge AN, Kolovich GP, Crist MK, Mayerson JL, Scharschmidt TJ. Predictors of local recurrence in high-grade soft tissue sarcomas: hydrogen peroxide as a local adjuvant. Orthopedics. 2013;36:e207-15
48. Gortzak Y, Kandel R, Deheshi B, Werier J, Turcotte RE, Ferguson PC. et al. The efficacy of chemical adjuvants on giant-cell tumour of bone. An in vitro study. J Bone Joint Surg Br. 2010;92:1475-9
49. Nicholson NC, Ramp WK, Kneisl JS, Kaysinger KK. Hydrogen peroxide inhibits giant cell tumor and osteoblast metabolism in vitro. Clin Orthop Relat Res. 1998:250-60
50. Balke M, Schremper L, Gebert C, Ahrens H, Streitbuerger A, Koehler G. et al. Giant cell tumor of bone: treatment and outcome of 214 cases. J Cancer Res Clin Oncol. 2008;134:969-78
51. Patterson MM. Multicenter pin care study. Orthop Nurs. 2005;24:349-60
52. Egol KA, Paksima N, Puopolo S, Klugman J, Hiebert R, Koval KJ. Treatment of external fixation pins about the wrist: a prospective, randomized trial. J Bone Joint Surg Am. 2006;88:349-54
53. Asada S, Fukuda K, Nishisaka F, Matsukawa M, Hamanisi C. Hydrogen peroxide induces apoptosis of chondrocytes; involvement of calcium ion and extracellular signal-regulated protein kinase. Inflamm Res. 2001;50:19-23
54. Asada S, Fukuda K, Oh M, Hamanishi C, Tanaka S. Effect of hydrogen peroxide on the metabolism of articular chondrocytes. Inflamm Res. 1999;48:399-403
55. Bates EJ, Johnson CC, Lowther DA. Inhibition of proteoglycan synthesis by hydrogen peroxide in cultured bovine articular cartilage. Biochim Biophys Acta. 1985;838:221-8
56. DePaula CA, Truncale KG, Gertzman AA, Sunwoo MH, Dunn MG. Effects of hydrogen peroxide cleaning procedures on bone graft osteoinductivity and mechanical properties. Cell Tissue Bank. 2005;6:287-98
57. Mut M, Yemisci M, Gursoy-Ozdemir Y, Ture U. Hydrogen peroxide-induced stroke: elucidation of the mechanism in vivo. J Neurosurg. 2009;110:94-100
58. Chhabra R, Pathak A, Ray P. Fatal posterior fossa pneumocephalus due to hydrogen peroxide irrigation of lumbar wound. Br J Neurosurg. 2000;14:549-51
59. Kleffmann J, Ferbert A, Deinsberger W, Roth C. Extensive ischemic brainstem lesions and pneumocephalus after application of hydrogen peroxide (H2O2) during lumbar spinal surgery. Spine J. 2015;15:e5-7
60. Timperley AJ, Bracey DJ. Cardiac arrest following the use of hydrogen peroxide during arthroplasty. J Arthroplasty. 1989;4:369-70
61. Henley N, Carlson DA, Kaehr DM, Clements B. Air embolism associated with irrigation of external fixator pin sites with hydrogen peroxide. A report of two cases. J Bone Joint Surg Am. 2004;86A:821-2
62. Spiriev T, Prabhakar H, Sandu N, Tzekov C, Kondoff S, Laleva L. et al. Use of hydrogen peroxide in neurosurgery: case series of cardiovascular complications. JRSM Short Rep. 2012;3:6
63. Zmistowski B, Karam JA, Durinka JB, Casper DS, Parvizi J. Periprosthetic joint infection increases the risk of one-year mortality. J Bone Joint Surg Am. 2013;95:2177-84
64. Hansen E, Parvizi J. Eradicate periprosthetic infection with irrigation and debridement. Orthopedics Today. 2012;32:24
65. Koyonos L, Zmistowski B, Della Valle CJ, Parvizi J. Infection control rate of irrigation and debridement for periprosthetic joint infection. Clin Orthop Relat Res. 2011;469:3043-8
66. Deirmengian C, Greenbaum J, Lotke PA, Booth RE Jr, Lonner JH. Limited success with open debridement and retention of components in the treatment of acute Staphylococcus aureus infections after total knee arthroplasty. J Arthroplasty. 2003;18:22-6
67. Azzam KA, Seeley M, Ghanem E, Austin MS, Purtill JJ, Parvizi J. Irrigation and debridement in the management of prosthetic joint infection: traditional indications revisited. J Arthroplasty. 2010;25:1022-7
68. Bradbury T, Fehring TK, Taunton M, Hanssen A, Azzam K, Parvizi J. et al. The fate of acute methicillin-resistant Staphylococcus aureus periprosthetic knee infections treated by open debridement and retention of components. J Arthroplasty. 2009;24:101-4
69. Odum SM, Fehring TK, Lombardi AV, Zmistowski BM, Brown NM, Luna JT. et al. Irrigation and debridement for periprosthetic infections: does the organism matter?. J Arthroplasty. 2011;26:114-8
70. Crockarell JR, Hanssen AD, Osmon DR, Morrey BF. Treatment of infection with debridement and retention of the components following hip arthroplasty. J Bone Joint Surg Am. 1998;80:1306-13
71. Marculescu CE, Berbari EF, Hanssen AD, Steckelberg JM, Harmsen SW, Mandrekar JN. et al. Outcome of prosthetic joint infections treated with debridement and retention of components. Clin Infect Dis. 2006;42:471-8
72. Burger RR, Basch T, Hopson CN. Implant salvage in infected total knee arthroplasty. Clin Orthop Relat Res. 1991:105-12
73. Hartman MB, Fehring TK, Jordan L, Norton HJ. Periprosthetic knee sepsis. The role of irrigation and debridement. Clin Orthop Relat Res. 1991:113-8
74. Segawa H, Tsukayama DT, Kyle RF, Becker DA, Gustilo RB. Infection after total knee arthroplasty. A retrospective study of the treatment of eighty-one infections. J Bone Joint Surg Am. 1999;81:1434-45
75. Silva M, Tharani R, Schmalzried TP. Results of direct exchange or debridement of the infected total knee arthroplasty. Clin Orthop Relat Res. 2002:125-31
76. Ilchmann T, Zimmerli W, Ochsner PE, Kessler B, Zwicky L, Graber P. et al. One-stage revision of infected hip arthroplasty: outcome of 39 consecutive hips. Int Orthop. 2016;40:913-8
77. Kendoff D, Gehrke T. Surgical management of periprosthetic joint infection: one-stage exchange. J Knee Surg. 2014;27:273-8
78. Zeller V, Lhotellier L, Marmor S, Leclerc P, Krain A, Graff W. et al. One-stage exchange arthroplasty for chronic periprosthetic hip infection: results of a large prospective cohort study. J Bone Joint Surg Am. 2014;96:e1
79. Gehrke T, Zahar A, Kendoff D. One-stage exchange: it all began here. Bone Joint J. 2013;95B:77-83
Corresponding author: Min Lu, Department of Orthopaedic Surgery, University of California San Francisco, 500 Parnassus Ave, (MU-320W), San Francisco, California 94143-0728. Phone 415/ 476-6548 Fax 415/ 476-1304.