CADTH Health Technology Review

Antimicrobial or Antiseptic Cleansers for Wounds

Rapid Review

Authors: Khai Tran, Carolyn Spry

Key Messages

• For chronic wound care, the majority of evidence suggested that antiseptic agents do not add additional clinical benefits compared with saline. No differences were observed between antiseptics and saline in the incidence of adverse events.

• For surgical wound care, irrigation with antibiotic agents is likely associated with lower rates of surgical site infections compared with saline irrigation. Depending on the type of antiseptic agent, type of surgery, and depth of infection, antiseptic irrigation may have superior or similar efficacy compared with saline in surgical site infection and wound healing rates. Indirect evidence suggested antibiotics were not superior to antiseptics for prevention of surgical site infections. No differences were observed between antiseptic irrigation and saline irrigation in the incidence of adverse events and length of hospital stay.

• For acute traumatic wound care, a limited number of studies provided mixed results on the effectiveness of povidone-iodine compared with saline for preventing infection. The effect of antiseptic agents on bacterial load was unclear. No robust conclusions could be drawn due to very low certainty of the evidence.

• The economic evaluation study showed that irrigation with hypochlorous acid preserved wound cleanser was a cost-effective strategy in the short term compared with saline for the treatment of severely complex wounds during ultrasonic debridement. However, we have little confidence in the findings due to several limitations in the methods of the study.

• We did not identify any studies that compared the clinical effectiveness and cost-effectiveness of antimicrobial or antiseptic wound cleansers with antimicrobial dressings or of different types of antimicrobial or antiseptic wound cleansers for the management of wounds.

• We did not identify any evidence-based guidelines regarding the use of antimicrobial or antiseptic wound cleansers for the management of wounds.

Context and Policy Issues

A wound is an injury that can be opened from disruption of the skin and tissue architecture or closed when there is a damage of tissue under the intact skin.¹ There are various types of open wounds that can be grouped into 3 commonly occurring wounds: chronic and difficult-to-heal wounds (usually ulcers that fail to heal within 4 weeks to 3 months), surgical wounds (having high risk of infection depending how contaminated or clean the wound is), and acute trauma wounds (caused by puncture, burns, bites and stings, or gunshot).¹ Closed wounds are often caused by blunt force trauma which results in damage to the skin and/or the underlying tissues.¹

Wounds are a serious health issue that are a major burden to patients and health care systems. The Canadian Institute for Health Information used data from hospitals, home care, hospital-based continuing care, and long-term care facilities in Canada during the fiscal year 2011–2012 to estimate the prevalence of compromised wounds (defined as wounds that are persistent and healing poorly, wounds that result from an infection introduced through the skin, and wounds that result from surgical interventions that fail to heal through normal stages) by type and by health care setting.² The estimated prevalence of compromised wounds, including pressure ulcers or injuries; arterial venous wounds; skin barriers breaches, such as cellulitis; and surgical wounds, ranged between 3.7% in acute care settings to 28.2% in complex continuing care settings. The prevalence of all different types of wounds was highest in complex continuing care settings and lowest in acute care settings.²

Wound cleansing is an important process in wound management to prevent infection and promote wound healing.³ There are many types of solutions used for wound cleansing, including antiseptic and nonantimicrobial solutions; the criteria for choosing a cleanser include type of wound, type of infection, effect on bacterial biofilms, ease of use and availability, clinical effectiveness, and cost-effectiveness.³ The nonantimicrobial solutions include sterile normal saline (0.9% sodium chloride), sterile water, and potable tap water. These solutions are isotonic or hypotonic and have no cytotoxicity and no effect on biofilm.³ The antiseptic wound cleansers include polyhexamethylene biguanide; octenidine dihydrochloride; superoxidized solution (hypochlorous acid and sodium hypochlorite); hydrogen peroxide; povidone-iodine (PVI); and chlorhexidine.^3,4 Solutions of antibiotic agents are also widely used in wound irrigation for prevention of surgical site infection.⁴

Wound dressings are also used in wound management to provide an optimal environment for wound healing.⁵ An ideal dressing should have the following characteristics: able to keep the wound moist while removing excess exudate, nontoxic and nonallergic, able to protect the wound from further damage, can be removed without causing damage to the wound, impermeable to bacteria, thermally insulating, allows for gas exchange, comfortable, cost-effective, and has a long shelf life.⁵ There are different types of wound dressings, including low adherent dressings, semipermeable films, hydrocolloids, hydrogels, alginates, foam dressings, and antimicrobial dressings.⁵ The latter are dressings impregnated with silver or iodine for reducing bacterial load in many types of wounds.⁵

Because there is ongoing discussion, debate, and research about what type of wound management options (i.e., antiseptic, antibiotic, and nonantimicrobial solutions and/or wound dressings) are clinically effective, easy to use, accessible and cost-effective, this report aims to summarize the clinical effectiveness and cost-effectiveness of antimicrobial or antiseptic wound cleansers compared with saline, antimicrobial dressings, and to one another in the management of wounds. This report also aims to summarize the recommendations from evidence-based guidelines regarding the use of antimicrobial or antiseptic wound cleansers for the management of wounds.

Research Questions

1. What is the clinical effectiveness of antimicrobial or antiseptic wound cleansers versus saline for the management of wounds?

2. What is the clinical effectiveness of antimicrobial or antiseptic wound cleansers versus antimicrobial dressings for the management of wounds?

3. What is the clinical effectiveness of different types of antimicrobial or antiseptic wound cleansers for the management of wounds?

4. What is the cost-effectiveness of antimicrobial or antiseptic wound cleansers versus saline for the management of wounds?

5. What is the cost-effectiveness of antimicrobial or antiseptic wound cleansers versus antimicrobial dressings for the management of wounds?

6. What is the cost-effectiveness of different types of antimicrobial or antiseptic wound cleansers for the management of wounds?

7. What are the evidence-based guidelines regarding the use of antimicrobial or antiseptic wound cleansers for the management of wounds?

Methods

Literature Search Methods

An information specialist conducted a literature search on key resources, including MEDLINE, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were wounds and cleansers. CADTH-developed search filters were applied to limit retrieval to health technology assessments, systematic reviews (SRs), meta-analyses (MAs), or indirect treatment comparisons, any types of clinical trials or observational studies, economic studies, and guidelines. Comments, newspaper articles, editorials, and letters were excluded. Retrieval was limited to the human population. The search was completed on May 12, 2023, and limited to English-language documents published since January 1, 2018.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1 or were published before 2018. SRs in which all relevant studies were captured in other more recent or more comprehensive SRs were excluded. Primary studies retrieved by the search were excluded if they were captured in 1 or more included SRs. Guidelines were excluded if they did not provide recommendations on the use of antimicrobial or antiseptic wound cleansers for the management of wounds.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2)⁶ for SRs, the Questionnaire to assess the relevance and credibility of a network meta-analysis⁷ for network meta-analyses (NMAs), the Downs and Black checklist⁸ for randomized and nonrandomized studies, and the Drummond checklist⁹ for economic evaluations. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 372 citations were identified in the literature search. Following screening of titles and abstracts, 335 citations were excluded and 37 potentially relevant reports from the electronic search were retrieved for full-text review. One potentially relevant publication was retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 21 publications were excluded for various reasons, and 17 publications met the inclusion criteria and were included in this report. These comprised 6 SRs, 4 randomized controlled trials (RCTs), 6 nonrandomized studies, and 1 economic evaluation study. Appendix 1 presents the PRISMA¹⁰ flow chart of the study selection.

Summary of Study Characteristics

Additional details regarding the characteristics of 6 included SRs^11-16 (Table 3), 10 primary clinical studies^17-26 (Table 4), and 1 economic evaluation study²⁷ (Table 5) are provided in Appendix 2.

Study Design

The SR by Barrigah-Benissan et al. (2022)¹¹ included 6 RCTs (published between 1989 and 2020) with a total of 725 patients with chronic wounds, ranging from 40 to 289 patients in each RCT. All included studies were relevant to our report. The authors of the SR searched multiple databases since inception to January 2022 without restrictions for language, study status, date of publication, or country. Due to substantial heterogeneity in the study designs, methodology, and outcomes, the authors of the SR narratively summarized the results of the included studies without pooling.

The SR and MA by Fu et al. (2022)¹² included 24 studies (published between 1979 and 2021) with a total of 4,967 patients who underwent surgery at the beginning of the study. The study size ranged from 40 to 822 patients. All included studies were relevant to our report. The authors of the SR conducted a systematic search on multiple databases since inception to January 2022. The included studies comprised RCTs, prospective studies, and retrospective studies. All studies were included in the MA. A fixed-effects model MA was applied for the comparison between antibiotic irrigation and saline irrigation, while a random-effects model MA was used for the comparison between PVI irrigation and saline irrigation.

The SR by Soeselo et al. (2022)¹³ included 4 RCTs (published between 1987 to 2016) with a total of 875 patients with acute traumatic wounds, ranging from 61 to 395 patients in each RCT. All included studies were relevant to our report. The authors of the SR conducted a literature search on multiple databases to identify all published and unpublished studies through November 2020 with restriction to English and Indonesian languages. The last search was run on November 9, 2020. The authors of the SR narratively summarized the results of the included studies without pooling.

The SR by McLain et al. (2021)¹⁴ included 4 RCTs (published between 2012 and 2018) with a total of 254 patients with venous leg ulcers (a type of chronic wound), ranging from 27 to 126 patients in each RCT. All included studies were relevant to our report. The authors of the SR searched multiple databases since inception to September 2019 to identify reports of relevant RCTs. There were no restrictions with respect to language, date of publication, or study setting. The authors of the SR narratively summarized the results of the included studies without pooling.

The SR and NMA by Thom et al. (2021)¹⁵ included 42 RCTs (published between 1968 to 2016) with a total of 11,726 patients who underwent a surgical procedure, ranging from 14 to 3,270 patients in each RCT. Fourteen studies comparing no irrigation with saline, antibiotics, or antiseptics were not relevant to the report, but they were included in the NMA. The search was conducted on multiple databases since inception to February 1, 2017, with no restrictions on language, date of publication, or study setting. The authors of the SR used a random-effects Bayesian NMA to create a connected network of comparisons. Vague priors were assumed for all parameters. This SR¹⁵ and that by Fu et al. (2022)¹² had 5 overlapping primary studies. The overlap of the relevant studies between SRs is shown in Appendix 5.

The SR and MA by Wood et al. (2020)¹⁶ included 10 studies (published between 1990 and 2019) with a total of 29,596 patients who underwent a total joint arthroplasty, ranging from 41 to 11,738 patients in each study. The authors of the SR performed a literature search on multiple databases since inception to January 16, 2019. The included studies comprised 1 RCT, 8 retrospective cohort studies, and a case series. Nine studies were included in the random-effects MA.

The 10 included primary clinical studies comprised 4 RCTs,^17,19,22,25 2 prospective cohort studies,^23,26 and 4 retrospective cohort studies.^18,20,21,24 The studies were published between 2023 and 2018.

The economic evaluation study by Mallow et al. (2021)²⁷ was a cost-effectiveness analysis using a patient-level Monte Carlo simulation model. The study used clinical and utilization data from a single-centre prospective study previously published. The cost data were obtained from the publicly available sources in 2021 US dollars. The analyses were conducted from the US health care system perspective and with time horizon of 14 days post-debridement procedure. Sensitivity analyses including one-way deterministic and probabilistic sensitivity analyses were performed to test the reliability and robustness of the results.

Country of Origin

The SRs were conducted by authors from France,¹¹ China,¹² Indonesia,¹³ Ireland,¹⁴ the UK,¹⁵ and Canada.¹⁶

The primary clinical studies were conducted by authors from China,^17,24 the US,^18,21,25 Turkey,^19,23,26 Japan,²⁰ and Nigeria.²² Eight studies^{17,19-22,24,26} were single-centre, and 2 studies^23,25 were multicentre (i.e., 2 sites in Turkey and 3 sites in the US, respectively).

The economic evaluation study was conducted by authors from US.²⁷

Patient Population

Patients in the studies included in the SR by Barrigah-Benissan et al. (2022)¹¹ were adults with chronic wounds, including the following 4 types: diabetic foot ulcers, vascular ulcers (containing venous and arterial ulcers), pressure ulcers, and “chronic wounds” without a definition of the type of wound. The age of patients ranged from 18 years to 93 years. Three of the included studies defined chronic wounds as wounds with a minimum duration ranging from 4 weeks to 3 months. Other included studies did not state the definition.

Patients in the studies included in the SR and MA by Fu et al. (2022)¹² were those undergoing a surgical procedure. Type of surgery, age, and sex or gender were not reported.

Patients in the studies included in the SR by Soeselo et al. (2022)¹³ were adults with simple, uncomplicated, acute traumatic wounds, which occurred less than 12 hours from the incident and required debridement and/or sutures. The mean age of patients was 38.2 years and ranged from 30.5 years to 47.7 years. Sex or gender was not reported.

Patients in the studies included in the SR by McLain et al. (2021)¹⁴ were adults with venous leg ulcers. The mean age of patients in the included studies was 65.3 years, ranging from 58.4 years to 73.5 years. The proportion of males ranged from 33% to 46%; and the proportion of female ranged from 34% to 67%.

Patients in the studies included in the SR and NMA by Thom et al. (2021)¹⁵ were those undergoing a surgical procedure. Types of surgery included appendectomy, colorectal surgery, caesarian section, mastectomy, spinal surgery, gastrectomy, intra-abdominal or open inguinal hernia surgery, orthopedic surgery, gastrointestinal surgery, cholecystectomy, cardiac surgery, enterotomy, general surgery, surgery for peritonitis, liver resection, and surgery for endometrial cyst. Age and sex or gender were not reported.

Patients in the studies included in the SR and MA by Wood et al. (2020)¹⁶ were adults who underwent total joint (hip and knee) arthroplasty. The mean age of the patients in the included studies ranged from 60 years to 80 years. Sex or gender were not reported.

Patients in the included primary studies were those with serious and infected wounds who underwent negative-pressure wound therapy with instillation^18,21 or those who had wounds related to a surgical procedure (i.e., gastrectomy,¹⁷ caesarean sections,¹⁹ hepatobiliary-pancreatic surgery,²⁰ neurosurgical procedures,²² multisegmental lumbar spine surgery,²⁴ pediatric posterior spine fusion,²⁵ surgery for pilonidal disease,²³ and temporary loop ileostomy closure²⁶). The surgical population had a mean age ranging from 15 years to 73 years, with 20% to 85% male, and 15% to 80% female. The severe and infected wound population had a mean age ranging from 36 years to 61 years, with predominantly male, ranging from 64% to 86%, and 14% to 36% female. All patients were treated in a hospital setting.

The population in the economic evaluation study²⁷ consisted of 17 adult patients with chronic open wounds of multiple etiology requiring irrigation in conjunction with ultrasonic debridement. The age range was from 21 years to 69 years, and 53% were female (9 of 17) and 47% male (8 of 17).

Interventions and Comparators

We stratified 3 different types of wounds — chronic wounds, surgical wounds, and acute traumatic wounds — for which we describe the types of interventions (i.e., antimicrobial or antiseptic cleansers) used in wound care. Solution details and the delivery method of different types of interventions in the included primary studies are presented in Table 4 of Appendix 2.

For treating of chronic or infected wounds, 2 SRs^11,14 and 2 retrospective cohort studies^18,21 evaluated the effects of wound cleansing with antiseptic agents compared with saline. Interventions evaluated in these studies included:

• cadexomer iodine or povidone-iodine (PVI), polyhexanide, and octenidine for the care chronic wounds of different etiologies in the SR by Barrigah-Benissan et al. (2022)¹¹

• polyhexamethylene biguanide, aqueous oxygen peroxide, a solution containing propyl betaine and polyhexanide, and topical antiseptic agent octenidine dihydrochloride/phenoxyethanol for venous leg ulcer care in the SR by McLain et al. (2021)¹⁴

• negative-pressure therapy with instillation with hypochlorous acid preserved wound cleanser (HAPWOC)¹⁸ or a solution containing polyhexanide and PVI²¹ to treat severe and infected wounds in 2 retrospective cohort studies.

For surgical wound care with either antimicrobial (antibiotic) or antiseptic cleansers in postsurgical wound irrigation for prevention of surgical site infections (SSI), we identified 3 SRs,^12,15,16 4 RCTs,^17,19,22,25 2 prospective cohort studies,^23,26 and 2 retrospective cohort studies.^20,24

• The SR and MA by Fu et al. (2022)¹² included studies comparing antibiotics with saline and studies comparing PVI with saline.

• The SR and NMA by Thom et al. (2021)¹⁵ included comparisons among different types of interventions (i.e., antibiotics, antiseptics, saline, and no irrigation). Because the “no irrigation” intervention was not relevant, only findings from relevant comparisons (i.e., antibiotics versus saline, antiseptics versus saline, and antibiotics versus antiseptics) are presented in this report. There were no studies that directly compared antibiotics with antiseptics in this NMA. Most antiseptic interventions involved PVI. The antibiotics used in cleansers can be grouped into 3 main classes of antibiotic agents: cephalosporin, penicillin, and mono or combination therapy of aminoglycosides. Other antibiotics agents were classified as “others.”

• The SR and MA by Wood et al. (2020)¹⁶ included studies comparing chlorhexidine gluconate (CHG) with saline, PVI with saline, and triple prophylaxis (PVI, local antibiotic powder, IV antibiotics) with saline as various irrigation solutions during total hip and knee arthroplasty.

• The included primary studies compared PVI versus saline after gastrectomy,¹⁷ PVI plus saline versus rifampicin solution plus saline versus saline alone following caesarean sections,¹⁹ ceftriaxone versus saline in neurosurgical procedures,²² PVI versus saline in pediatric spinal surgery,²⁵ CHG versus saline during surgery for pilonidal disease,²³ CHG versus saline in closure of temporary loop ileostomy,²⁶ hydrogen peroxide versus saline after multisegmental lumbar spine surgery,²⁴ and PVI versus saline after hepatobiliary and pancreatic surgery.²⁰

For acute traumatic wounds, the SR by Soeselo et al. (2022)¹³ included studies comparing PVI with saline and comparing polyhexanide with Ringer solution.

Outcomes

The reported outcomes for chronic wound care included:

• wound healing, assessed by:

  • planimetry measurement^11,14

  • visual assessment¹¹

  • 13-item Bates-Jensen Wound Assessment Tool (BWAT) scale (total score of the 13-item scores; the higher the total score, the more severe the wound status)¹¹

  • NERDS (nonhealing, exudate, red friable tissue, debris [discoloration], and smell) and STONEES (size increasing, temperature elevation, os [probes to bone], new breakdown, erythema/edema, exudate, and smell) checklist¹¹

• length of hospital stay¹⁸

• visits to operating room^18,21

• pain evaluation (assessed with a 5-point Likert Verbal Descriptor Scale measuring satisfaction [very satisfied, satisfied, neutral, dissatisfied, and very dissatisfied] or a Likert scale from 0 to 100 [0 = no pain, 100 = very painful])^11,14

• adverse events (AEs).^11,14,21

For surgical wound care, most studies reported SSI (definitions varied among studies).^{12,15-17,19,20,22-26} Other outcomes included length of hospital stay,¹⁷ wound healing (assessed by visual assessment),²³ and AEs.^23,24

The reported outcomes for the acute traumatic wound care studies were wound infection rates¹³ and bacterial load.¹³

The primary outcome in the economic evaluation study²⁷ was an incremental cost-effectiveness ratio (ICER), which was calculated as the incremental cost of HAPWOC relative to saline per wound-related complication avoided. Another outcome was number needed to treat, which was defined as number of patients that need to be treated to avoid 1 wound-related complication.

Summary of Critical Appraisal

The detailed quality assessments of the SRs^11-16 (Table 6), the primary clinical studies^17-26 (Table 7), and the economic evaluation study²⁷ (Table 8) are provided in Appendix 3.

Systematic Reviews

Of the 6 included SRs, 3 SRs^11,13,14 narratively summarized the findings from the included studies, 2 SRs^12,16 quantitatively synthesized the findings of the included studies through meta-analysis, and 1 SR¹⁵ used an NMA approach to compare the effectiveness of multiple interventions.

All 5 SRs^11-14,16 (with or without MA) were explicit in their objectives, inclusion criteria for the review, and selection of the study designs for inclusion. The literature search strategy in 2 SRs^11,14 was comprehensive and clearly described, while that in the other 3 SRs^12,13,16 was partially comprehensive because the authors did not report whether grey literature or the reference lists of reviewed studies were searched for relevant studies. Providing details of the literature search strategy increases the reproducibility of the review. Four SRs^11,13,14,16 performed study selection and data extraction in duplicate, whereas 1 SR¹² did not report whether study selection and data extraction were performed in duplicate. Therefore, it is unclear whether a fully systematic approach was taken in study selection and data extraction in that SR; specifically, it is unclear whether the included and excluded studies were appropriate or the data extraction was accurate.¹² Two SRs^12,13 did not report whether a protocol had been published before the review was conducted, which could introduce bias by modifying the methods after the review had been conducted. Four SRs^11-13,16 did not report the sources of funding for the included studies. This is potentially a concern because funding received from industry can introduce bias in favour of the intervention. Four SRs^11-13,16 did not provide a list of excluded studies and the reasons for exclusion were not provided. No justification for the excluded studies could bias the results of the review. The characteristics of the included studies were described in adequate detail in 3 SRs,^11-14 but not in the other 2.^12,16 All 5 SRs^11-14,16 used appropriate tools to assess methodological quality of the included studies (i.e., the Cochrane risk of bias tool for RCTs and the Methodological Index for Non-Randomized Studies (MINORS) criteria for nonrandomized studies). The review authors of 3 SRs^11,13,14 acknowledged that the substantial heterogeneity in study designs, methodology, and outcomes in the included studies prevented the quantitative synthesis, and a systematic review with a summary of effect estimates was performed instead. An MA was used to combine the results in 2 SRs.^12,16 Assessment of publication bias was not performed in these 2 SRs.^12,16 One SR¹² did not assess the potential impact of risk of bias in individual studies on the results of the MA, and the potential effect of the heterogeneity of patients or study characteristics on the pooled estimate of efficacy was not explored which limits the certainty of the findings. The other SR¹⁶ performed sensitivity analysis by excluding studies with potential confounding effects. All 5 SRs^11-14,16 provided a discussion of the heterogeneity observed in the results, which was 1 of the limitations of the reviews. The authors of 3 SRs^11,14,16 reported the source of funding for their research and declared their potential conflicts of interest. The authors of 1 SR¹² declared no potential conflicts of interest but did not report the source of funding. The authors of 1 SR¹³ did not report the source of funding for the research or declare if there was any potential conflicts of interest. It is possible that the source of funding may bias the reporting of the results of an SR. Overall, some included SRs had several methodological limitations regarding literature search strategy, reporting, data collection process, and analysis that may increase the uncertainty of the findings.

The SR and NMA by Thom et al. (2021)¹⁵ included relevant populations, interventions, and outcomes. This NMA also had several strengths contributing to its credibility related to the quality and comprehensiveness of the evidence base, appropriate analysis methods, and reporting and interpretation of results. Specifically, the rationale for the study and the study objectives were clearly stated. The authors clearly presented the literature search methods, search terms, search dates, search strategy, and criteria for the SR, with an attempt to identify and include all relevant RCTs. All included RCTs were assessed for the risk of bias using the Cochrane risk of bias tool, the results of which were presented and discussed about risk of bias and heterogeneity. However, the authors of the SR conducted sensitivity analysis to exclude to exclude studies at high risk of bias and found that the results of the primary analyses were not altered. Study selection, appraisal, and data extraction were performed in duplicate. The primary outcome (i.e., SSI) was clearly defined. The authors provided a description of analysis methods and models, description of statistics used, and justification. The analysis in the primary model was well-conducted using appropriate methodology. For instance, a random-effects Bayesian NMA was used to combine evidence from RCTs that form a connected network of intervention comparisons. This methodology combines both direct and indirect evidence and allows for comparisons of interventions not directly compared in head-to-head RCTs as long as the interventions form part of a connected network. Vague priors were assumed for all parameters. The model was implemented in the Bayesian OpenBUGS software. Studies were assessed for heterogeneity using the I² measure before inclusion in the analysis. Evidence of inconsistency was assessed globally using an unrelated mean effects and locally by comparing the direct and indirect evidence via node-splitting tests. There was no evidence of inconsistency because the unrelated mean effects model gave a similar model fit to the NMA model, and the between-studies heterogeneity standard deviation was unchanged. The local node-splitting tests also did not indicate inconsistency between direct and indirect evidence. The primary outcome assessed in the NMA was SSI, which is clinically relevant. Sensitivity analyses were conducted and discussed to explore the effect of differences between participants, surgical techniques, definitions of SSI, and the use of antibiotic agents over time on the findings. A network diagram of connected interventions was presented. Study characteristics and patient characteristics of the included RCTs were presented in an appendix. Forest plots were provided summarizing the results for each intervention. Heterogeneity observed in the results was discussed. The authors noted that the robustness of the analysis may be limited due to high risk of bias from the individual studies and heterogeneity (e.g., surgical procedures, publication dates, and treatment protocols). Thus, the effect estimates may not be driven solely by the assessed interventions. Other limitations in this review were that the results for the pairwise comparisons were not reported and the forest plots for individual studies and pairwise comparisons were not presented.

Primary Studies

For reporting, all primary clinical studies, including 4 RCTs^17,19,22,25 and 6 nonrandomized controlled studies^{18,20,21,23,24,26} (4 retrospectives^18,20,21,24 and 2 prospectives^23,26), clearly described the objective of the study, the intervention of interest, the main outcomes, and the main findings of the study. Eight studies (3 RCTs,^17,19,25 2 prospective cohort studies,^23,26 and 3 retrospective cohort studies^20,21,24) clearly described the patient characteristics at baseline, while 2 studies (1 RCT²² and 1 retrospective cohort study¹⁸) did not. Without a clear description of patient baseline characteristics, it is unknown if potential confounders may exist that could potentially affect the interpretation of the results. Six studies^17-20,22,25 did not report AEs related to the interventions. Actual probability values (i.e., P values) were reported in all studies, except 1.¹⁸

For external validity, the patients in 3 studies^18,20,21 may not represent the entire eligible population. One retrospective review¹⁸ included only 24 patients, 1 retrospective cohort study²⁰ included only the subset of patients who received preoperative biliary drainage before hepatobiliary-pancreatic surgery, and 1 retrospective cohort study²¹ reviewed data of patients remaining from an RCT after a 5-year follow-up period for long-term outcomes. The treatment settings (i.e., hospitals) in all studies^17-26 appeared to be representative of the treatment received by most of the patients.

For internal validity related to bias, most randomized and nonrandomized studies could be subject to risk of selection, performance, and detection biases due to the lack of appropriate blinding (patients, surgeons, or data analysts) and due to the nature of the study design of the retrospective studies. Sometimes blinding of surgeons was not possible because the solutions were in different colours. In 9^17,19-26 out of 10 studies, all patients were followed up for the same period of time, which was usually 30 days, statistical tests were used appropriately, and the main outcome measures were accurate and reliable. One retrospective chart review study¹⁸ did not report follow-up time, therefore it was unclear if all patients were followed up for the same period of time.

For internal validity related to confounding, all nonrandomized studies did not identify and adjust for potential confounding factors in the analyses. Method of concealment allocation was not reported in 2 RCTs.^19,22 This might be associated with risk of selection bias. Five studies^18,20-22,24 did not report whether sample size calculations were performed, and it is unclear whether the nonsignificant differences in certain outcomes were because the studies were underpowered for those outcomes. Overall, several limitations related to the external and internal validity in some studies may reduce the certainty of the findings.

Economic Evaluation Study

The included economic evaluation study²⁷ clearly stated the objective, the economic importance of the research question, and the type of economic evaluation (i.e., cost-effectiveness analysis) that was conducted. The analysis was performed from the US health care system perspective. The study used a cost-effectiveness approach to compare the incremental costs per incremental complication avoided between HAPWOC and saline treatments. For data collection, the study clearly stated the source of clinical and utilization data with details of the design and findings (i.e., an RCT recently published with a population of 17 patients; 9 patients receiving HAPWOC and 8 patients receiving saline), the primary outcome measures for the economic evaluation (i.e., ICER expressed as the incremental cost per wound-related complication avoided), and the currency and price data. A patient-level Monte Carlo simulation model was developed to assess the cost-effectiveness of HAPWOC versus saline. For the analysis and interpretation of results, the study clearly stated the time horizon of costs and benefits, statistical tests and confidence intervals (CIs), justification for the choice of variables for sensitivity analyses, and the ranges over which the variables were varied. Discount rate was not applicable as the time horizon was only 14 days. The study reported incremental analysis and presented major outcomes in a disaggregated as well as aggregated form. The conclusion in the study was based on the data reported and were accompanied by the appropriate caveats. The limitations of this study were that the analyses were based on a small sample size (N = 17) and a short time horizon (14 days after debridement procedures). Because “wound-related complication” was defined as a postoperative closure failure, the difference in complications between HAPWOC and saline treatments may be smaller with a longer follow-up because wounds treated with saline may take more time to heal.

Summary of Findings

Appendix 4 presents the main study findings, which were summarized by outcome from each type of wound care (i.e., clinical effectiveness results for wound cleansers in chronic wound care are presented in Table 8, Table 9, Table 10, Table 11, and Table 12; results for surgical wound care are in Tables 13, Table 14, Table 15, and Table 16, and results for acute traumatic wounds are in Table 17 and Table 18).

Clinical Effectiveness of Antimicrobial or Antiseptic Wound Cleansers Versus Saline for the Management of Wounds

We identified 2 SRs^11,14 and 2 retrospective cohort studies^18,21 for chronic wounds, 3 SRs,^12,15,16 4 RCTs,^17,19,22,25 2 prospective cohort studies,^23,26 and 2 retrospective cohort studies^20,24 for surgical wounds and 1 SR¹³ for acute traumatic wounds.

Table 2 presents the reported outcomes for the different types of antimicrobial or antiseptic wound cleansers compared with saline for different types of wounds in the included studies that addressed this research question.

Table 2: Overview of Clinical Effectiveness Evidence on Antimicrobial or Antiseptic Wound Cleansers Versus Saline for the Management of Wounds

CHG = chlorhexidine gluconate; HAPWOC = hypochlorous acid preserved wound cleanser; MA = meta-analysis; NMA = network meta-analysis; PVI = povidone-iodine; RCT = randomized controlled trial; SR = systematic review.

^aRefer to Table 9.

^bRefer to Table 12.

^cRefer to Table 13.

^dRefer to Table 11.

^eRefer to Table 10.

^fRefer to Table 14.

^gRefer to Table 15.

^hRefer to Table 16.

ⁱRefer to Table 17.

^jRefer to Table 18.

^kRefer to Table 19.

Wound Healing in Chronic Wound Care

A summary of results regarding wound healing in chronic wound care is presented in Table 9.

Antiseptics Compared With Saline or Ringer Solution

Iodine (Cadexomer Iodine or Povidone-Iodine)

Three RCTs identified in the SR by Barrigah-Benissan et al. (2022)¹¹ provided mixed results comparing iodine with saline for complete wound healing in chronic care:

• No statistically significant difference was found between the 2 groups in the proportion of patients with complete wound healing at 8 weeks (P = 0.978; 1 RCT) and a statistically significant higher percentage of patients achieving complete wound healing at 12 weeks for patients treated with cadexomer iodine (P < 0.001; 1 RCT).

• However, the pooled data of these 2 RCTs showed that treatment with iodine compared with saline was associated with a statistically significant higher percentage of patients achieving complete wound healing (relative risk [RR] = 1.85; 95% CI, 1.27 to 2.69).

• The third RCT reported the time to complete healing; no statistically significant difference was found between the iodine and saline groups (P = 0.54).

Polyhexanide

One RCT identified in the SR by Barrigah-Benissan et al. (2022)¹¹ found a statistically significant improvement in healing rate in the group of patients treated with polyhexanide compared with those treated with saline(P = 0.025), and the other RCT found no statistically significant difference between groups in the median reduction of the wound surface (P = 0.85).

Octenidine

One RCT identified in the SR by Barrigah-Benissan et al. (2022)¹¹ found no statistically significant difference between groups of patients treated with octenidine or saline in the proportion of patients with complete wound healing (P = 0.882), the time to complete healing (P = 0.952), and the rate of wound healing (P = 0.769).

One RCT identified in the SR by McLain et al. (2021)¹⁴ also found no statistically significant difference in the number of wounds completely healed (RR = 0.96; 95% CI, 0.53 to 1.72) between octenidine dihydrochloride/phenoxyethanol and Ringer lactate solution, a balanced or buffered solution used for fluid replacement.

Aqueous Oxygen Peroxide

One RCT identified in the SR by McLain et al. (2021)¹⁴ found a statistically significantly higher number of wounds healed completely with aqueous oxygen peroxide treatment compared with saline (RR = 1.88; 95% CI 1.10 to 3.20); however, there was no significant difference between the groups in wound size reduction (mean difference = −1.32 cm²; 95% CI −4.35 cm² to 1.59 cm²).

Overall, the results for wound healing in chronic wounds were mixed for iodine or aqueous oxygen peroxide compared with saline, and no statistically significant difference between groups for polyhexanide or octenidine compared with saline was observed.

Length of Hospital Stay in Chronic Wound Care

A summary of results regarding length of hospital stay in chronic wound care is presented in Table 10.

Antiseptics Compared With Saline

HAPWOC

One retrospective chart review study by Gallagher et al. (2022)¹⁸ with 27 patients (19 patients in the HAPWOC group; 8 patients in the saline group) found the HAPWOC group had a shorter average of length of hospital stay (−3.1 days) compared with the saline group, but the difference did not reach statistical significance.

Visits to Operating Room in Chronic Wound Care

A summary of results regarding visits to operating room in chronic wound care is presented in Table 11.

Antiseptics Compared With Saline

HAPWOC

One retrospective chart review study by Gallagher et al. (2022)¹⁸ found no statistically significant difference in the mean number of subsequent visits to the operating room between groups of patients treated with HAPWOK or saline.

Polyhexanide Plus PVI

A retrospective cohort study by Meshkin et al. (2021)²¹ found no statistically significant difference between groups in the proportion of patients visiting the operating room for additional operations, including debridement or incision and drainage (P = 0.98), primary closure (P = 0.98), and secondary closure (P = 0.62).

Overall, no statistically significant difference between HAPWOC or polyhexanide plus PVI versus saline in operating room visits was observed.

Pain Evaluation in Chronic Wound Care

A summary of results regarding pain evaluation in chronic wound care is presented in Table 12.

Antiseptics Compared With Saline

Iodine (Cadexomer Iodine or PVI)

One RCT identified in the SR by Barrigah-Benissan et al. (2022)¹¹ found no statistically significant difference between groups of patients treated with iodine or saline in pain reduction (P = 0.96).

Polyhexanide

Two RCTs identified in the SR by Barrigah-Benissan et al. (2022)¹¹ provided mixed results for pain evaluation. One RCT found similar pain scores with no statistically significant difference between groups (P = 0.85), whereas the other RCT reported statistically significant pain reduction in the polyhexanide group compared with the saline groups (P = 0.02).

Aqueous Oxygen Peroxide

One RCT identified in the SR by McLain et al. (2021)¹⁴ compared treatment with aqueous oxygen peroxide with saline and found no statistically significant difference between groups in overall pain scores (mean difference = 3.80; 95% CI, −10.83 to 18.43).

Overall, there were no statistically significant differences in pain outcomes between antiseptics (i.e., iodine, polyhexanide, aqueous oxygen peroxide) and saline.

Adverse Events in Chronic Wound Care

A summary of results regarding adverse events in chronic wound care is presented in Table 13.

Antiseptics Compared With Saline or Ringer Solution

Iodine (Cadexomer Iodine or Povidone-Iodine)

Pooled data from 3 RCTs identified in the SR by Barrigah-Benissan et al. (2022)¹¹ showed no statistically significant difference in AE incidence between groups treated with iodine or saline (RR = 1.44; 95% CI, 0.77 to 2.68). Types of AEs were not reported.

Polyhexanide

Pooled data from 2 RCTs identified in the SR by Barrigah-Benissan et al. (2022)¹¹ showed no statistically significant difference in AE incidence between groups treated with polyhexanide or saline (RR = 0.2; 95% CI, 0.01 to 4.18). Types of AEs were not reported.

One RCT identified in the SR by McLain et al. (2021)¹⁴ found no AEs occurred in the polyhexanide plus propyl betaine group or the saline group.

A retrospective cohort study by Meshkin et al. (2021)²¹ found no statistically significant difference between groups (polyhexanide plus PVI versus saline) in the rates of dehiscence (P = 0.90), wound recurrence (P = 0.55), amputation during 5-year period (minor: P = 0.97; major: P = 0.16), and 5-year mortality (P = 0.45).

Octenidine

One RCT identified in the SR by Barrigah-Benissan et al. (2022)¹¹ found no statistically significant difference in AE incidence between groups treated with octenidine or saline (RR = 0.56; 95% CI, 0.28 to 1.11). Types of AEs were not reported.

One RCT identified in the SR by McLain et al. (2021)¹⁴ also found no statistically significant difference in AE incidence between the octenidine dihydrochloride/phenoxyethanol group and the Ringer lactate solution group (RR = 0.58; 95% CI, 0.29 to 1.14).

Overall, there were no statistically significant differences in the incidence of AEs between antiseptics (i.e., iodine, polyhexanide, octenidine) and saline.

Surgical Site Infections in Surgical Wound Care

A summary of results regarding SSIs in surgical wound care is presented in Table 14.

Antibiotics Compared With Saline

Any Antibiotics

Pooled data of the studies identified in the SR by Fu et al. (2022)¹² showed that antibiotic irrigation had a statistically significantly lower rates of SSI compared with saline irrigation for patients undergoing surgery (odds ratio [OR] = 0.48; 95% CI, 0.36 to 0.62).

The NMA results from the SR by Thom et al. (2021)¹⁵ also showed that antibiotic irrigation was associated with better prevention of SSI compared with saline (OR = 0.44, 95% credible interval [CrI], 0.28 to 0.67). When stratifying by types of antibiotics, the NMA results showed that all types of antibiotic agents, including aminoglycoside, penicillin, cephalosporin, and other antibiotics, were favoured over saline for the prevention of SSI.

Ceftriaxone

The RCT by Okunlola et a. (2021)²² found no statistically significant difference in overall SSI rates (P = 1.00) between ceftriaxone and saline used for intraoperative wound irrigation during neurosurgical procedures.

Antiseptics Compared With Saline

Antiseptics (Combined)

The NMA results from the SR by Thom et al. (2021)¹⁵ showed that antiseptic irrigation was associated with better prevention of SSI compared with saline (OR = 0.57; 95% CrI, 0.32 to 0.95). However, pooled data from the SR by Wood et al. (2020)¹⁶ showed no statistically significant difference in deep infection rates (RR = 0.69; 95% CI, 0.41 to 1.15) in the antiseptic group (PVI and CHG) compared with the saline group in total joint arthroplasty.

Chlorhexidine

Pooled data of 2 studies identified in the SR by Wood et al. (2020)¹⁶ showed no statistically significant difference in deep infection rates (RR = 0.74; 95% CI, 0.33 to 1.65) between CHG and saline groups.

The prospective cohort study by Arslan et al. (2020)²³ found that the CHG group was associated with a statistically significantly lower rate of total SSI (P = 0.001) compared with the saline group in pilonidal disease surgery. The difference was mainly attributed by the superficial SSI (5% [7 of 138] versus 18% [23 of 129]), but not deep SSI (1.4% [2 of 138] versus 2.3% [3 of 129]).

The prospective cohort study by Goztok et al. (2018)²⁶ found a statistically significantly lower rate of SSI in the CHG group compared with the saline group (P < 0.001) in closure of temporary loop ileostomy. The difference between treatment with CHG versus saline was mainly attributed by the superficial SSIs (3.2% [2 of 62] versus 21.6% [13 of 60]), and less by deep SSIs (1.6% [1 of 62] versus 10% [6 of 60]).

Povidone-Iodine

Pooled data of 6 studies identified in the SR by Wood et al. (2020)¹⁶ showed no statistically significant difference in deep infection rates (RR = 0.62; 95% CI 0.33 to 1.19) between groups treated with PVI and saline.

The rates of SSI were not statistically significant different in 4 studies, between groups (PVI and saline) of patients undergoing gastric surgery,¹⁷ caesarian sections,¹⁹ spinal surgery,²⁵ or hepatobiliary-pancreatic surgery.

Hydrogen Peroxide

The retrospective cohort study by Chen et al. (2020)²⁴ found no statistically significant difference in total SSI rate (P = 0.068) and in superficial SSI rate (P = 0.809), but a statistically significant difference in deep SSI rate (P = 0.006) favouring the hydrogen peroxide group over the saline group after multisegmental lumbar spine surgery.

Overall antibiotic irrigation was associated with lower SSI rates compared with saline. The efficacy of antiseptic agents compared with saline was either superior or comparable, depending on the type of antiseptics, type of surgery, and depth of infection.

Length of Hospital Stay in Surgical Wound Care

A summary of results regarding length of hospital stay in surgical wound care is presented in Table 15.

Antiseptics Compared With Saline

Povidone-Iodine

The RCT by Zhao et al. (2023)¹⁷ found no statistically significant difference in the length of hospital stay between the PVI and saline groups in both the intention-to-treat set (P = 0.301) and the as-treated set (P = 0.248) of patients who underwent gastric surgery.

Wound Healing in Surgical Wound Care

A summary of results regarding wound healing in surgical wound care is presented in Table 16.

Antiseptics Compared With Saline

Chlorhexidine

The prospective cohort study by Arslan et al. (2020)²³ found that the primary healing rate was statistically significantly higher in the CHG group compared with the saline group (P = 0.001) in patients who underwent pilonidal disease surgery. However, the secondary healing rate was lower in the CHG group compared with the saline group (5.8% versus 19.4%); statistical comparison was not reported. Primary wound healing refers to a wound that is closed for healing by primary intention, while secondary wound healing refers to a wound that is left open and allowed to heal by secondary intention. The mean time to healing expressed as days was statistically significantly shorter in the CHG group compared with the saline group (P < 0.001).

Adverse Events in Surgical Wound Care

A summary of results regarding adverse events in surgical wound care is presented in Table 17.

Antiseptics Compared With Saline

Chlorhexidine

The prospective cohort study by Arslan et al. (2020)²³ found no statistically significant differences between groups in seroma formation (P = 0.515) and wound dehiscence (P = 0.537) in patients who underwent pilonidal disease surgery.

Hydrogen Peroxide

The retrospective cohort study by Chen et al. (2020)²⁴ found no statistically significant difference between groups of patients who received wound care with hydrogen peroxide or saline for complications after multisegmental lumbar spine surgery, such as hematencephalon (P = 0.754), deep vein thrombosis (P = 0.73), pulmonary embolism (P = 0.97), and myocardial infarction (P = 0.75).

Wound Infection Rates in Acute Traumatic Wound Care

A summary of results regarding wound infection rates in acute traumatic wound care is presented in Table 18.

Antiseptics Compared With Saline

Povidone-Iodine

The SR by Soeselo et al. (2022)¹³ identified 3 RCTs that provided mixed results on the effectiveness of PVI compared with saline in reducing wound infection rate:

• There was no statistically significant difference in infection rates between groups (1 RCT, 390 patients).

• There were statistically significantly fewer wound infection events in the PVI group compared with the saline group (2 RCTs with 395 patients and 23 patients).

Overall, 2 of 3 studies reported that PVI was associated with a lower wound infection rate compared with saline in acute traumatic wounds.

Bacterial Load in Acute Traumatic Wound Care

A summary of results regarding bacterial load in acute traumatic wound care is presented in Table 19.

Antiseptics Compared With Saline or Ringer Solution

Povidone-Iodine

One RCT identified in the SR by Soeselo et al. (2022)¹³ found a statistically significant increase in bacterial count compared with baseline after treatment with saline (P = 0.0001). In the PVI group, there was a nonsignificant decrease in bacterial count compared with baseline. A comparison between PVI and saline was not reported.

Polyhexanide

One RCT identified in the SR by Soeselo et al. (2022)¹³ found a significant decrease in bacterial count at 60 minutes after treatment with polyhexanide compared with baseline (P < 0.001). However, there was no statistically significant difference in bacterial count between polyhexanide and Ringer solution groups at baseline (P = 0.06) or at 60 minutes (P = 0.28) following wound care.

Overall, it was unclear whether PVI or polyhexanide was associated with lower bacterial load compared with saline or Ringer solution, respectively.

Clinical Effectiveness of Antimicrobial or Antiseptic Wound Cleansers Versus Antimicrobial Dressings for the Management of Wounds

We did not identify any studies that assessed the clinical effectiveness of antimicrobial or antiseptic wound cleansers compared with antimicrobial dressings for the management of wounds; therefore, no summary can be provided.

Clinical Effectiveness of Different Types of Antimicrobial or Antiseptic Wound Cleansers for the Management of Wounds

We did not identify any studies that assessed the clinical effectiveness of different types of antibiotics compared with one another or different types of antiseptics compared to one another as wound cleansers for the management of wounds; therefore, no summary can be provided.

However, we identified studies (SR and NMA¹⁵ and 1 RCT¹⁹) that compared antibiotics with antiseptics for preventing SSI in surgical wound care (Table 14).

The NMA results from the SR by Thom et al. (2021)¹⁵ provided no evidence that the antibiotic agents were better than the antiseptics agents for prevention of SSIs based on indirect comparisons using saline as a common comparator (OR = 0.77; 95% CrI, 0.4 to 1.54).

The RCT by Karuserci and Sucu (2022)¹⁹ found the incidence of incisional SSI after caesarean sections was not statistically significantly different between the rifampicin group and the PVI group (P = 0.202).

Cost-Effectiveness of Antimicrobial or Antiseptic Wound Cleansers Versus Saline for the Management of Wounds

The economic evaluation study by Mallow et al. (2021)²⁷ assessed the cost-effectiveness of HAPWOC irrigation compared with saline irrigation in conjunction with low-frequency ultrasonic debridement for treatment of severe complex wounds of multiple etiologies. The analyses were conducted from the US health care system perspective and with a time horizon of 14 days post-debridement procedure. The authors assumed that the cost of HAPWOC was the total cost of materials, and there was no cost for saline. Thus, the incremental cost was the cost of HAPWOC, which was US$49.97. The clinical data were obtained from an RCT with a population of 17 adult patients with complex wounds (9 patients in the HAPWOC group and 8 patients in the saline group). Postoperative closure failure was considered a complication; the rate for the HAPWOC group was 25% compared with 80% in the saline group. Therefore, the rates of complication avoided in the HAPWOC and saline groups were 75% and 20%, respectively. The incremental effect was 0.55.

In the base case model, the ICER for HAPWOC was US$90.85 per wound-related complication avoided. Thus, compared with saline, it would cost US$90.85 to avoid 1 additional wound-related complication with HAPWOC. The number of patients needed to treat to avoid a wound-related complication was 2, and the cost per number needed to treat was US$99.94.

One-way sensitivity analysis revealed that the ICER was most sensitive to number of units of HAPWOC used during debridement and the cost of HAPWOC. Probabilistic sensitivity analysis showed that the probability that HAPWOC would become cost-effective at a willingness-to-pay threshold of US$100 or more was 100% (Table 20).

Cost-Effectiveness of Antimicrobial or Antiseptic Wound Cleansers Versus Antimicrobial Dressings for the Management of Wounds

We did not identify any study assessing the cost-effectiveness of antimicrobial or antiseptic wound cleansers compared with antimicrobial dressings for the management of wounds; therefore, no summary can be provided.

Cost-Effectiveness of Different Types of Antimicrobial or Antiseptic Wound Cleansers for the Management of Wounds

We did not identify any study assessing the cost-effectiveness of different types of antimicrobial or antiseptic wound cleansers for the management of wounds; therefore, no summary can be provided.

Guidelines Regarding the Use of Antimicrobial or Antiseptic Wound Cleansers for the Management of Wounds

We did not identify any evidence-based guideline regarding the use of antimicrobial or antiseptic wound cleansers for the management of wounds; therefore, no summary can be provided.

Limitations

One of the major limitations of the included studies (including SRs and primary studies) was that there was substantial heterogeneity among the studies in study design, methodology, patient population, type of wounds, and outcomes. We therefore summarized the results by type of wounds followed by interventions and comparisons. The type of antimicrobial and antiseptic agents, concentrations, surgical and treatment protocols, infection prevention and control measures, publication date of the included studies, volumes and methods of application of the irrigation interventions, time of follow-up, and wound infection criteria also contributed to the heterogeneity among the studies, which limits the interpretation of the results and the ability to draw a strong conclusion. Many of the studies were at high risk of bias due to lack of blinding to participants and personnel. However, blinding strategies were sometimes not possible due to the colour difference of the solutions used for the interventions. Confounding factors, such as nursing staff or surgeon’s ability and experience, patient characteristics, or infections occurring during wound care procedures, may limit the interpretation of the results and the ability to draw a strong conclusion. Some included studies had small sample sizes which could lead to inconsistency and imprecision among studies and result in a very low level of evidence. There is insufficient evidence to determine the superiority of 1 antiseptic agent or 1 antibiotic agent over the others. Despite these limitations, collective evidence regarding the clinical effectiveness of antibiotic and antiseptic agents as wound cleansers compared with saline may by applicable to the Canadian context.

The economic evaluation study also had several limitations. First, the results were based on data from a single-centre study of a small population (17 patients with complex wounds; 9 patients in HAPWOC group and 8 patients in saline group). The results may not be generalizable to other patient populations or other settings with different treatment protocols. Second, the clinical study used in the analysis only followed patients for 14 days for any wound-related complication, which may have been an insufficient length of time to observe these outcomes in the saline group. As wound-related complication was defined as postoperative closure failure, wound closure in the saline group may be delayed, and thus fewer complications in this group may occur with a longer time of follow-up. There were no AEs, which may have been due to the small sample size and short-term follow-up, therefore no additional costs were incurred beyond the use of HAPWOC. Third, the effect measure was broadly defined as “wound-related complication,” ranging from minor to major. Finally, the study did not include cost of therapy, additional cost of wound-related services, and cost due to loss of productivity. Overall, had the authors accounted for a longer time of follow-up, detection of AEs with a larger population, a well-defined wound-related complication (i.e., wound closure), cost of saline and other costs, the results of the analysis may be different than the current ones and HAPWOC may not be cost-effective compared with saline. The analysis was also performed from the US health care system perspective, which may not be applicable to the Canadian health care system.

Conclusions and Implications for Decision- or Policy-Making

We reviewed the evidence from 6 SRs,^11-16 10 primary clinical studies,^17-26 and 1 economic evaluation study²⁷ for the use of antimicrobial or antiseptic wound cleansers compared with saline in wound management. We did not identify any study that compared antimicrobial or antiseptic wound cleansers with antimicrobial dressings or compared antibiotics with one another or antiseptics with one another as wound cleansers. We also did not identify any evidence-based guideline regarding the use of antimicrobial or antiseptic wound cleansers for the management of wounds.

For clinical evidence, we grouped the studies into 3 types of wounds: chronic wounds (2 SRs^11,14 and 2 retrospective cohort studies^18,21), surgical wounds (3 SRs,^12,15,16 4 RCTs,^17,19,22,25 2 prospective cohort studies,^23,26 and 2 retrospective cohort studies^20,24), and acute traumatic wounds (1 SR¹³). Overall, antimicrobial and antiseptic wound cleansers were not often associated with improved clinical outcomes compared with treatment with saline:

• For chronic wound care, the majority of evidence suggested that antiseptic agents did not add additional clinical benefits compared with saline. No differences were observed between antiseptic and saline groups for length of hospital stay, operating room visits, pain reduction, and incidence of AEs.

• For surgical wound care, irrigation with antibiotic agents was likely associated with lower rates of SSI compared with saline. Depending on the type of antiseptic agents, type of surgery, and depth of infection, antiseptic irrigation may have a superior or similar efficacy compared with saline in the prevention of SSI and in the facilitation of wound healing. No differences were observed between antiseptic irrigation and saline irrigation for the length of hospital stay and the incidence of AEs. Indirect comparisons provided no evidence that the antibiotic agents were better than the antiseptics agents for prevention of SSI.

• For acute traumatic wound care, a limited number of studies provided mixed results on the effectiveness of PVI compared with saline for preventing infection. The effect of PVI and polyhexanide on bacterial load was unclear. Thus, no robust conclusions could be drawn due to the very low certainty of evidence from an SR with only 4 included studies that had substantial heterogeneity.

For the economic evaluation, the identified study²⁷ showed that HAPWOC was a cost-effective strategy in the short term compared with saline for the treatment of severely complex wounds during ultrasonic debridement. However, several limitations of this study preclude a strong conclusion about the cost-effectiveness of HAPWOC compared with saline.

There is a lack of evidence about both clinical effectiveness and cost-effectiveness regarding the value of cleansing compared with antimicrobial dressings or different types of wound cleansers compared with one another. Treatment protocols in wound management and nursing staff or surgeon’s experience may play important roles in the control of wound infection and healing that should be investigated. Therefore, these questions should be answered by high-quality and well-controlled studies. There are various wound irrigation solutions available in clinical practice; therefore, it is important to assess the clinical effectiveness and cost-effectiveness of these agents for each type of wound. Currently, there are not any recommendations regarding wound cleansing for specific type of wounds. Therefore, wound management should be informed and guided by high-quality national or international guidelines based on high-quality evidence, costs, and patient preference. Until then, the findings in this review should be interpreted carefully, and decision-makers may wish to consider factors specific to their context (e.g., cost of cleansers) because the collective evidence does not clearly support the benefit of antimicrobial or antiseptic wound cleansers over saline in terms of clinical effectiveness and cost-effectiveness.

References

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Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix has not been copy-edited.

Table 6: Strengths and Limitations of Systematic Reviews and Network Meta-Analyses Using AMSTAR 2⁶ and the ISPOR Questionnaire⁷

AMSTAR 2 = A Measurement Tool to Assess systematic Reviews 2; CI = confidence interval; ISPOR = International Society for Pharmacoeconomics and Outcomes Research; NA = not applicable; NR = not reported; OR = odds ratio; PICO = population, intervention, comparator, outcome; RCT = randomized controlled trial; RR = risk ratio; SSI = surgical site infection.

Table 7: Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist⁸

PICO = population, intervention, comparator, outcome; RCT = randomized controlled trial; SSI = surgical site infection.

Table 8: Strengths and Limitations of Economic Evaluation Using the Drummond Checklist⁹

HAPWOC = hypochlorous acid preserved wound cleanser; ICER = incremental cost-effectiveness ratio; RCT = randomized controlled trial; WTP = willingness to pay.

Appendix 4: Main Study Findings

Note that this appendix has not been copy-edited.

Table 9: Summary of Findings by Outcome — Wound Healing in Chronic Wound Care

BWAT = Bates-Jensen Wound Assessment Tool; CI = confidence interval; MD = mean difference; NERDS = Nonhealing, Exudate, Red friable tissue, Debris (discoloration) and Smell, RCT = randomized controlled trial; RR = relative risk; SR = systematic review; STONES = Size increasing, Temperature elevation, Os (probes to bone), New breakdown, Erythema/Edema, Exudate and Smell; vs. = versus.

Table 10: Summary of Findings by Outcome — Length of Stay in Chronic Wound Care

HAPWOC = hypochlorous acid preserved wound cleanser; NR = not reported; NS = not statistical significance; SD = standard deviation.

Table 11: Summary of Findings by Outcome — Visits to Operating Room in Chronic Wound Care

HAPWOC = hypochlorous acid preserved wound cleanser; NS = not statistical significance; SD = standard deviation

Table 12: Summary of Findings by Outcome — Pain Evaluation in Chronic Wound Care

MD = mean difference; RCT = randomized controlled trial; SR = systematic review; vs. = versus.

Table 13: Summary of Findings by Outcome — Adverse Events in Chronic Wound Care

AE = adverse event; CI = confidence interval; NR = not reported; RCT = randomized controlled trial; RR = relative risk; SR = systematic review; vs. = versus.

Note: General note to table (e.g., how to interpret the data).

^aCorresponds to subgroup of patients with close/covered wounds at 30 days postdischarge.

^bCorresponds to patients with maintained wounds at 30 days postdischarge.

Table 14: Summary of Findings by Outcome — Surgical Site Infections in Surgical Wound Care

AE = adverse event; CHG = chlorhexidine gluconate; CI = confidence interval; CrI = credible interval; ITT = intention-to-treat; MA = meta-analysis; NMA = network meta-analysis; OR = odds ratio; PP = per protocol; PVI = povidone-iodine; RCT = randomized controlled trial; RR = relative risk; SR = systematic review; SSI = surgical site infection; TJA = total joint arthroplasty; vs. = versus.

Table 15: Summary of Findings by Outcome — Length of Hospital Stay in Surgical Wound Care

ITT = intention-to-treat; PP = per protocol; PVI = povidone-iodine; RCT = randomized controlled trial.

Table 16: Summary of Findings by Outcome — Wound Healing in Surgical Wound Care

CHG = chlorhexidine gluconate; NR = not reported; SD = standard deviation.

Table 17: Summary of Findings by Outcome — Adverse Events in Surgical Wound Care

CHG = chlorhexidine gluconate; H₂O₂ = hydrogen peroxide.

Table 18: Summary of Findings by Outcome — Wound Infection Rates in Acute Traumatic Wound Care

AE = adverse event; CI = confidence interval; MA = meta-analysis; OR = odds ratio; PVI = povidone-iodine; RCT = randomized controlled trial; SR = systematic review; vs. = versus.

Table 19: Summary of Findings by Outcome — Bacterial Load in Acute Traumatic Wound Care

AE = adverse event; CFU = colony forming unit; CI = confidence interval; MA = meta-analysis; NS = not statistically significant; OR = odds ratio; PVI = povidone-iodine; RCT = randomized controlled trial; SD = standard deviation; SR = systematic review; vs. = versus.

Table 20: Summary of Findings of Included Economic Evaluation

HAPWOC = hypochlorous acid preserved wound cleanser; ICER = incremental cost-effectiveness ratio; NA = not applicable; NNT = number needed to treat; NR = not reported; PSA = probabilistic sensitive analysis; WTP = willingness to pay.

Appendix 5: Overlap Between Included Systematic Reviews

Note that this appendix has not been copy-edited.

Table 21: Overlap in Relevant Primary Studies Between Included Systematic Reviews