TITLE: Negative Pressure Wound Therapy for …...Negative Pressure Wound Therapy for Infected Wounds 2 other treatments are required. NPWT or NPWTi are supported by some evidence in

Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by email or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.

TITLE: Negative Pressure Wound Therapy for Infected Wounds: A Review of Clinical Effectiveness, Cost-Effectiveness, and Recommendations for Use

DATE: 30 June 2015 CONTEXT AND POLICY ISSUES Negative pressure wound therapy (NPWT) involves the application of negative pressure to an acute or chronic wound in order to stimulate wound healing.1-3 NPWT is also known as topical negative pressure (TNP) therapy, while vacuum-assisted closure (VAC) therapy is based on the same premise, using negative pressure in the same manner to help close the wound. Pressure is administered using a vacuum pump attached to a tube which is placed within a porous wound filler that is sealed into the wound with an adhesive drape.1 This process allows for the creation of a moist wound healing milieu whereby excess fluid, exudate, and infectious material are either continuously or intermittently removed from the wound.1,2 Additional advantageous properties include reducing tissue edema by improving tissue perfusion, its ability to contract and alter the flow of blood to wound edges, to encourage the process of angiogenesis, to aid in the formation of granulation tissue, and to stimulate the wound mechanically.1,4 In addition, a newer form of NPWT called NPWT with instillation (NPWTi) has been increasing in popularity and involves the same principles as regular NPWT yet also combines two surgical procedures: namely irrigation and suction.4 Fluid instillation involves a cyclical delivery of an antiseptic solution to the wound bed.4 Many wounds can become hard to heal and are frequent clinical problems, a prime example being either the infected or the clean chronic diabetic foot wound.5 In addition to these, a subset of wounds that are infected such as deep sternal wound infections after cardiac or thoracic surgery,6 perivascular groin wound infections after vascular surgery,7 and open abdomens (both contaminated and clean)8 can also be difficult to heal and often either recur6 or have other complications (e.g. fistula formation in the open abdomen).8 Therefore, it is imperative that appropriate treatments are available in order to hasten the wound healing process. Conventional therapies to treat difficult to heal acute or chronic wounds are numerous; however, the most common and least expensive of which (in terms of the dressings themselves) involve different dressing types (e.g. alginate, sodium hypochlorite).9 However, many wounds remain difficult to heal, despite the use of the conventional therapies. It is in these circumstances that

Negative Pressure Wound Therapy for Infected Wounds 2

other treatments are required. NPWT or NPWTi are supported by some evidence in the realm of treating some difficult to heal wounds, with this therapy generally accepted as an adjunct therapy post-debridement.6,10,11 However, there remains some question as to its effectiveness in the treatment of the infected wound. A previous CADTH report on NPWT from 201012 found limited evidence for its use. In addition, there seemed to be some evidence indicating that NPWT may be associated with an increased risk of infection. It is for this reason that this review was undertaken in order to review and critically appraise the comparative clinical and cost-effectiveness of NPWT versus conventional therapy in infected wounds in the hospital, home care, and long-term care setting. In addition, evidence-based guidelines were sought to obtain recommendations of the indicated uses of NPWT for infected wounds. RESEARCH QUESTIONS 1. What is the comparative clinical effectiveness of topical negative pressure therapy versus

other wound packing and dressing change for patients with infected wounds in hospital, home care, and long-term care settings?

2. What is the comparative cost-effectiveness of topical negative pressure therapy versus

other wound packing and dressing change for patients with infected wounds in hospital, home care, and long-term care settings?

3. What are the recommended indications for negative pressure therapy for infected

wounds? KEY FINDINGS Regardless of infection status, treatment with negative pressure wound therapy has been recommended to be used as an adjunct therapy after debridement in acute and chronic wounds. Lower quality evidence suggests lower mortality rates and fewer recurrences using vacuum-assisted closure of deep sternal wound infections when compared to non-vacuum-assisted therapies, with contrasting evidence regarding length of hospital stay. Higher quality evidence suggests negative pressure wound therapy also results in faster wound healing in difficult to heal wounds (both infected and clean) and deep perivascular wound infections of the groin. Recommendations support the use of negative pressure wound therapy along with other sequential dynamic closure techniques to counteract retraction and facilitate healing when there is an option for delayed primary closure in patients with Grade 1 or 2 open abdomens that are both clean and contaminated, to manage abdominal fluid, and to be continuously used at settings up to -80 mmHg in clean and contaminated open abdomens. There are also recommendations surrounding certain variables of negative pressure wound therapy and that it may be used in patients with chronic diabetic foot wounds that are slow to heal; however, these recommendations are all based on lower quality evidence. No cost-effectiveness studies were identified that met the inclusion criteria.


METHODS Literature Search Methods A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) and ECRI databases, Canadian and major international health technology agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies, economic studies and guidelines. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2010 and May 27, 2015. Rapid Response reports are organized so that the evidence for each research question is presented separately. 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 Population Patients with infected wounds in hospital, home care, and long-term care

settings

Intervention Negative pressure therapy

Comparator Conventional wound packing, including, but not limited to:

Silver dressings

Moist wound healing dressings

Gauze

Outcomes Q1: Comparative clinical effectiveness Q2: Comparative cost-effectiveness

Q3: Evidence-based guidelines and recommendations Study Designs Health technology assessments, systematic reviews, meta-analyses,

randomized controlled trials, evidence-based guidelines

Exclusion Criteria Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, were published prior to 2010, or were guidelines that were either not evidence-based or had no specified methodology. Critical Appraisal of Individual Studies The AMSTAR tool13 was used to guide the critical appraisal of the design, comprehensiveness, and quality of the included meta-analyses (MA), while the Downs and Black Checklist14 was used to guide the critical appraisal of the reporting, internal and external validity, and power of the included RCTs. The scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability, and editorial independence of the included evidence-based


guidelines were assessed with the aid of the AGREE II instrument.15 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described narratively. SUMMARY OF EVIDENCE Quantity of Research Available A total of 546 citations were identified in the literature search. Following screening of titles and abstracts, 497 citations were excluded and 49 potentially relevant reports from the electronic search were retrieved for full-text review. Three potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles, 44 publications were excluded for various reasons, while eight publications met the inclusion criteria and were included in this report. Appendix 1 describes the PRISMA flowchart of the study selection. Additional references of potential interest, including any relevant non-randomized studies, are provided in Appendix 2. Summary of Study Characteristics Detailed study characteristics for the MAs6,11 and the RCTs7,9 are provided in Appendix 3, Tables 2 and 3, respectively. Systematic Reviews and Meta-Analyses The two included MAs both examined the effectiveness of vacuum-assisted closure (VAC) on infected sternal wounds, comparing VAC to non-VAC conventional therapies (including re-exploration and removal of sternal wiring and debridement, open dressings, closed irrigation, pectoral muscle flaps, omentum flaps, traditional closed drainage techniques, continuous irrigation, sternal resection and musculocutaneous flap, or closed drainage and irrigation).11 One MA originated in Italy6,11 while the authors of the second were from Greece and the United States.6 Falagas et al.6 included 22 retrospective cohort studies (publication dates ranging from 2000 to 2012) from various countries in Europe and Asia, while Damiani et al.11 included six observational studies (dates ranging from 2000 to 2005) from various countries in Europe. Patients were those with infected sternal wounds resulting from cardiac or thoracic surgery.6,11 Outcomes included length of hospital stay,6,11 recurrence,6 mortality (no definition on length after treatment provided),11 in-hospital mortality,6 or 30 to 90 day mortality.6 Randomized Controlled Trials Two RCTs were identified that met the inclusion criteria.7,9 The RCT by de Laat et al.9 from the Netherlands examined the comparative effectiveness of topical negative pressure (TPN) therapy (using the VAC system, KCI United states, San Antonio, Texas) with conventional dressing therapy (wet to moist dressing) using a sodium hypochlorite 0.25% solution in patients with difficult to heal wounds. These patients formed two groups: difficult to heal surgical wounds with various etiology (either infected or non-infected) and patients with spinal cord injury (SCI) with grade IV pressure ulcers.9 Patients were first subdivided into groups based on having either difficult-to-heal wounds surgical wounds or having SCI with grade IV difficult-to-heal pressure ulcers and then randomized to their respective treatments (TNP or conventional dressings).9 The primary outcome of interest in the de Laat et al. RCT9 was the time to 50% wound volume


reduction, with a maximum follow-up time of six weeks. Secondary outcomes included wound healing failure rates and any other adverse event.9 The Swedish RCT by Monsen et al.7 examined either VAC therapy or alginate dressings in patients who had developed deep perivascular infections (Szilagyi grade III) after vascular surgery. Outcomes of interest for this review included wound healing, amputation, and mortality.7 Evidence-Based Guidelines Four evidence-based guidelines (with dates ranging between 2011 and 2014)5,8,16,17 were included in this review; two international guidelines (consisting of experts from around the world),8,17 one from Germany,16 and one from the United States (with global experts aiding in the development of the recommendations).5 The International Expert Panel on Negative Pressure Wound Therapy (NPWT-EP)17 included a global panel of experts aiming to obtain consensus regarding the treatment variables surrounding NPWT therapy, while the Infectious Disease Society of America (IDSA) also included a global panel to develop recommendations on the use of NPWT for the treatment of diabetic foot infections.5 Recommendations surrounding the use of NPWT in “contaminated” open abdomen (OA) wounds were provided by Bruhin et al.8, while Back et al.16 provided recommendations regarding the appropriate use of antiseptic solutions when using NPWTi in infected wounds. Summary of Critical Appraisal Critical appraisal details for the MAs,6,11 RCTs,7,9 and evidence-based guidelines5,8,16,17 are provided in Appendix 4, Tables 4, 5, and 6, respectively. Systematic Reviews and Meta-Analyses A priori inclusion and exclusion criteria were provided in both meta-analyses.6,11 The Damiani et al. MA11 specified having a dual author system in place for methodology quality assessment and data extraction, but did not specify duplicate article selection. A systematic or comprehensive literature search (e.g. not defined as systematic) was performed in the Falagas et al.6 and Damiani et al.11 MAs, respectively, with the authors of the Falagas et al. MA6 also performing an extensive grey literature search. Search strategies were provided in both MAs;6,11 however, the Damiani et al.11 MA did not include the word “infected” anywhere in their search strategy or in their descriptions of included studies (unlike Falagas et al.6). Therefore, it was only the title and the abstract which indicated that this MA11 was specific for infected sternal wounds and it was assumed that references chosen for the MA were specific to deep sternal wounds infections (DSWI). Characteristics of the included studies were provided in both MAs6,11 while Damiani et al.11 also included a grading system for potential sources of bias (although this grading system was not referenced as being previously used). The only study designs included in both MAs were observational, with Falagas et al.6 specifying them as retrospective studies; however, the search strategies did not appear to limit study type. While Falagas et al.6 compared VAC to without-VAC therapies, there was no formal description of these without-VAC therapies; rather there was only a description of the type of VAC therapy used. Methods to meta-analyze the data and assess its heterogeneity (Chi-squared and I2) were appropriately performed in both MAs,6,11 while Damiani et al.11 also performed a funnel plot to assess publication bias (of which there was found to be none, though data was not show).


Neither MA provided a list of excluded studies; however, PRISMA diagrams were provided.6,11 In addition, both MAs had a declaration of conflicts of interest and funding sources (or lack thereof).6,11 Randomized Controlled Trials Both of the identified RCTs7,9 had clearly presented objectives, outcomes, interventions, patient characteristics, inclusion criteria, and main study findings, while only the de Laat et al. RCT9 reported clear exclusion criteria. Patients with grade III Szilagyi wounds (deep perivascular groin infections) were randomly assigned to receive either VAC therapy or alginate dressings after debridement;7 however, as with the de Laat et al. RCT,9 randomization was performed using sealed envelopes with no evidence that randomization codes were obtained using a computer generated system.7,9 Only the wound experts responsible for measuring the wounds were blinded to the treatments in the de Laat et al. RCT9, minimizing the chance of reporting bias; however, there was the possibility of observer bias as both the patients and investigators were non-blinded to the treatments.9 There was no apparent blinding in the Monsen et al. RCT;7 thereby increasing the potential for observer and reporting bias. Statistical rigour was obtained by a null hypothesis statement,9 an intention-to-treat (ITT) analysis,9 appropriate power calculations,7,9 and appropriate statistical tests to examine any statistical significance.7,9 It should be noted, however, that the numbers required to obtain appropriate power were not obtained in the Monsen et al.7 treatment arms. In terms of external validity, there remains the possibility that results obtained from the de Laat et al. RCT would only be generalizable to patients that have very difficult-to-heal wounds (i.e. surgical wounds or those with grade IV pressure ulcers) and not necessarily for those patients with hard-to-heal wounds in an out-patient scenario or in patients with lesser grade pressure ulcers.9 Results would only be generalizable to patients who developed deep perivascular infections after having undergone vascular surgery in the Monsen et al. RCT.7 Evidence-Based Guidelines Three of the identified guidelines had clearly defined and presented objectives and recommendations,5,8,17 while clearly stated questions were not evident in either the NPWT-PE17 or the Back et al.16 studies. Full systematic reviews accompanied three guidelines5,8,17 and three of the four guidelines also included a grey literature search.5,8,17 While the search in Back et al.16 included MedLine and the Cochrane Library database, there was no evidence of it being systematic, nor were keywords provided. Global experts were a part of the guideline panels that graded the identified evidence in three guidelines,5,8,17 while three authors from Germany were involved in producing their own recommendations.16 Most recommendations were developed through an evidence-based consensus approach.5,8,17 The Scottish Intercollegiate Guidelines Network (SIGN) method for evidence quality assessment was used in two of the guidelines,8,17 the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used by the IDSA,5 while the guideline by Back et al.16 did not specify any formal procedure for either the evidence quality assessment or for the development of their recommendations.16 In addition, they also used all levels of evidence (including in vitro studies) to formulate guidance. The rationale for using all evidence-types included that the process of NPWT with instillation remains relatively new and there remains a


paucity of available evidence.16 Explicit links between recommendations and corresponding supporting evidence were provided in two guidelines,8,17 while two other groups did not clearly make a link to the supporting evidence.5,16 Three of the guidelines5,8,16 did not include patients or patient groups as a formal part of their recommendation development process; however the NPWT-PE group did discuss some options in their recommendations to alleviate pain, especially in the context of dressing removal from wounds.17 In the context of bias, there was a distinct possibility for publication bias in some of the guidelines as non-English studies (or non-German)16 were excluded from those identified in the primary electronic searches;16,17 however, the NPWT-PE17 explicitly mentioned their attempt to translate any of the non-English studies identified from the grey literature search only. In addition, most groups did not lay a framework for discussions pertaining to the updating of their recommendations.8,16,17 Funding sources and declarations of conflicts of interest were provided in most of the guidelines.5,8,17 Of note, in the guidelines for the use of NPWT on OAs, there was not a clear distinction as to the context of the word “contaminated” when describing the alternative to the clean OA.8 It was presumed that this included OAs that may have been infected and, hence, these guidelines were included in this review. This, however, remains a limitation. Summary of Findings Details of the study findings from the primary studies are provided in Appendix 5, Table 7, while the recommendations from the evidence based guidelines are provided in Appendix 5, Table 8. In addition, descriptions of evidence quality assessment and grading schemes from the evidence-based guidelines are provided in Appendix 6, Table 9. What is the comparative clinical effectiveness of topical negative pressure therapy versus other wound packing and dressing change for patients with infected wounds in hospital, home care, and long-term care settings? Mortality VAC was compared with non-VAC therapies in the two identified MAs6,11 in patients with DSWIs. Both MAs examined mortality as either the primary6 or secondary11 outcome. Falagas et al.6 observed a pooled risk ratio (RR) of 0.40 (95% confidence interval [CI] 0.28 to 0.57) indicating statistically significant lower mortality when using VAC therapy when compared with using non-VAC therapy. Statistical significance remained for VAC therapy when the authors performed adjusted analyses by excluding potential outlier studies that showed significantly lower mortality (RR 0.60, 95% CI 0.41 to 0.89), when looking at studies that used a historical non-VAC control group (RR 0.32, 95% CI 0.20 to 0.50), or in studies that did not provide criteria for their selection of therapy (RR 0.45, 95% CI 0.23 to 0.88).6 In addition, in-hospital mortality was also lower in patients receiving VAC therapy (RR 0.40, 95% CI 0.26 to 0.62); however, no statistical difference between therapies was observed for 30 or 90 day mortality (RR 2.28 95% CI 0.30 to 17.25; RR 0.21, 95% CI 0.03, 1.30, respectively); however, patients numbers were smaller in these comparisons.6 Patients with undetermined DSWIs or mediastinitis treated with VAC therapy also had lower mortality when compared to non-VAC therapies (RR 0.38, 95% CI 0.24 to 0.60).6 While Damiani et al.11 did observe a reduction in mortality in patients treated with VAC therapy compared with those treated with non-VAC therapies, these results were not statistically significant (odds ratio 0.61, 95% CI 0.29 to 1.27). A sensitivity analysis validated these results


when the most influential studies were removed.11 Deaths were reported in the Monsen et al. RCT in patients with deep perivascular wounds;7 two patients who received VAC therapy and five patients who received alginate dressing therapy died. Recurrence and Length of Stay (LOS) in Hospital Differences in DSWI recurrence6 and LOS6,11 in hospital when VAC therapies were compared with non-VAC therapies were also examined. A pooled analysis from the Falagas et al. MA showed that DSWI recurrence was not as common in patients treated with VAC therapies compared to those treated with non-VAC therapies (RR 0.34, 95% CI 0.19 to 0.59).6 Falagas et al.6 did not show any statistically significant difference in the LOS when comparing patients with DSWIs treated with VAC therapy to those treated with non-VAC therapies (-2.25, 95% CI -7.52 to 3.02). In contrast to this, Damiani et al.,11 reported that LOS was significantly reduced by 7.18 days (95% CI 10.82 to 3.54). Consequently, it remains difficult to ascertain the true effect of LOS in these MAs Wound Healing The RCT by de Laat et al.9 examined the effectiveness of TNP therapy compared to conventional dressings (using a sodium hypochlorite 0.25% solution) in patients with difficult to heal surgical wounds or grade IV pressure ulcers in SCI patients. A total of 24 of the 28 observed surgical wounds had achieved the primary outcome of a 50% reduction in wound volume by six weeks follow-up.9 The median treatment time until 50% wound volume reduction was two weeks (interquartile range [IQR] of 1) in the TNP therapy group, which was statistically significantly shorter than that of the conventional dressing therapy (3.5 weeks [IQR of 1.5]; P


and one metatarsal amputation due to critical limb ischemia worsening) were reported in patients receiving alginate dressing therapy.7 While adverse events or complications were planned to be examined in the Falagas et al MA6 only narrative descriptions of the actual adverse events were provided due to the fact that only one of their included studies presented complication numbers from each treatment arm. These reported adverse events are listed in Appendix 5, Table 7. What is the comparative cost-effectiveness of topical negative pressure therapy versus other wound packing and dressing change for patients with infected wounds in hospital, home care, and long-term care settings? No relevant literature was identified regarding the comparative cost-effectiveness of topical negative pressure therapy versus other wound packing and dressing change for patients with infected wounds in hospital, home care, and long-term care settings; therefore, no summary can be provided. What are the recommended indications for negative pressure therapy for infected wounds? Acute and Chronically Infected Wounds Most of the guidelines, at least in part, focused on the use of NPWT and what aspects of its use were most beneficial.5,8,17 A general consensus inherent to NPWT6,7,9-11 and explicitly stated in two of the guidelines remains the fact that NPWT should not be used in isolation to treat infected wounds; instead it is recommended to be used as an adjunct to other methods of controlling already present wound infection (e.g. after debridement).5,17 With regard to the wound fillers, lower level evidence indicates that anti-microbial gauze may be a contributing factor for infection control (Grade C), while even lower level evidence indicated the possibility that silver foam could provide some infection control (Grade D).17 An anti-microbial wound contact layer placed underneath the wound filler may also contribute towards infection control; however, even though this was supported by very low level evidence (Grade D), it remains a good practice point as an essential part of the NPWT procedure.17 The area of fluid instillation in conjunction with NPWTi has become more popular in recent years.16,17 Very low level evidence (Grade D) supports the practice of fluid instillation with NPWT in contributing to infection control.17 Back et al.16 examined the appropriate use of antiseptic solutions used in NPWTi in deep and infected wounds and provided recommendations surrounding the concentrations, fluid delivery, soak times, and cycle frequency for polyhexanide, acetic acid, and povidone-iodine solutions (see Appendix 5, Table 8 for specifics).16 Diabetic Foot Infections While the IDSA examined most aspects in the treatment of diabetic foot infections, there was little in the way of recommendations made with regard to NPWT in treating infections.5 No evidence was available to support the use of NPWT as an adjunct to other therapies for treating diabetic foot osteomyelitis; however, in the case of hard to heal diabetic foot wounds (excluding osteomyelitis) they state that clinicians may consider the use of NPWT as adjunctive therapy, even though it has not been proven to help resolve infections.5


Open Abdomen (OA) Bruhin et al.8 systematically examined the evidence for the use of NPWT in the realm of the OA. The general recommendations provided were not specific to either clean or “contaminated” wounds per se; rather, they were grouped together.8 This may have to do with the fact that there is either no recommended difference in how OAs are treated with NPWT regardless of any “contamination” present or there is no identified evidence to support separating the types of wounds.8 In general, there was some evidence (Grade B) for the use of a foam-based dressing kit specialized for NPWT on the OA.8 Lower level evidence (Grade C) supports the use of NPWT to manage OA wound fluid and low level evidence (Grade D) supports the use of continuous NPWT settings of up to -80 mmHg. No evidence was specifically identified for the recommended use of an interface layer between the bowel and abdominal wall for protection; however this was considered good clinical practice.8 Grade 1 and 2 OAs were defined as those OAs without or with adherence of the bowel to the abdominal wall, respectively, with “contaminated” OAs as subgroups to both Grades 1 and 2 (See Appendix 5, Table 8 footnotes for descriptions of Grades).8 Recommendations based on Grades 1 and 2 OAs (regardless of whether OAs were “contaminated” or clean) were provided and supported by medium level evidence (Grade B). They include the use of NPWT in the hands of an experienced physician as first line therapy in a situation whereby there is an option for delayed primary closure, using NPWT to “counteract retraction and facilitate delayed primary closure” in the application of a “sequential dynamic closure technique,” and the consideration of using NPWT on a closed incision in order to facilitate healing.8 As previously stated, the use of a non-adherent interface layer was recommended to protect organs and to prevent progression to higher grades of OAs; however, this is again was only good clinical practice and was not supported by evidence.8 Limitations The results of the MAs6,11 were based upon retrospective observational studies which are, in comparison to RCTs, considered lower quality evidence. Like the guidelines included in this review, they highlighted the need for higher quality RCTs to be performed in order to ascertain the true effects of NPWT. The MA by Damiani et al.,11 according to the title and abstract, observed the effectiveness of vacuum assisted closure (VAC) in patients with infected sternal wounds; however, their search strategy along with any subsequent description of their included studies did not specify infected sternal wounds. The inclusion criteria stated that they included “studies that focused on sternal wounds.”11 Unless these wounds are generally known to be infected (mainly sternal osteomyelitis or mediastinitis), it remains unclear whether all wounds considered in the MA were infected wounds. The Falagas et al. MA6 did not provide any description of the non- or without-VAC therapies; therefore, it was impossible to draw conclusions regarding the superiority of VAC compared with specific conventional treatments. It can only be concluded that VAC therapy in patients with DSWI lowers mortality when compared with non-VAC therapies, but not any particular non-VAC therapy. While the Monsen et al. RCT7 reported significantly shorter wound healing times for patients with deep perivascular infections (Szilagyi grade III) treated with VAC therapy when compared


to alginate dressings, the study itself lacked the power to detect such effects. The authors performed the necessary power calculation in order to obtain 90% power and 5% level of significance (requiring 42 patients in total, 21 randomized to each treatment arm); however, 10 patients were actually randomized to each treatment, with one additional patient crossing over from the alginate arm to the VAC arm. The authors did note this discrepancy but proceeded to conclude that the results were “very good” in VAC-treated patients and it was difficult to obtain appropriate numbers in this type of population. Due to this lack of study power, these observations in this particular population must be observed with caution. As stated in the critical appraisal regarding the Bruhin et al. guidelines,8 the terminology used for an unclean OA was termed “contaminated.” It was unclear whether any of these wounds were infected or only contaminated. This may not be the case as “contaminated” could refer to the wound being dirty (i.e. compromised by foreign objects), necrotic tissue, or any other items rendering it unclean. Therefore, caution is required when following these recommendations as these may not be specific to infected or partially infected OAs. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING The previous CADTH review (2010) of NPWT12 indicated a paucity of evidence for the use of NPWT, suggesting the potential for increased infection rates with its use; however, the latter finding may have been made due to the poor quality evidence identified. In the current review, NPWT appears to be a plausible therapy to use in a variety of different circumstances pertaining to acute and chronic wound infections. While there is evidence for its use, consensus surrounding this treatment indicate that NPWT should be used as an adjunct therapy after debridement in the treatment of wounds, wound infections, and wound closures (including closure of infected wounds).6,10,11 Meta-analysis evidence on retrospective studies suggest lower mortality rates,6,11 and fewer recurrences6 with vacuum-assisted closure of deep sternal wound infections when compared with non-vacuum-assisted therapies, with contrasting evidence regarding length of hospital stays. Randomized controlled trial evidence suggests that NPWT (or topical negative therapy) results in faster wound healing in difficult to heal wounds9 and deep perivascular wound infections of the groin.7 Four evidence-based guidelines were identified that produced recommendations for the different types of infected wounds and different forms of NPWT. In general, there seems to be lower quality evidence supporting the use of different NPWT treatment variables that may provide some infection control in chronically infected wounds; specifically, the use of anti-microbial gauze and silver foam as wound fillers,17 the use of an anti-microbial wound contact layer,17 and the use of NPWTi.16 In addition, specific antiseptic solutions, their concentrations, the amounts required, and soak times were provided when applying them with NPWTi.16 Patients with chronic diabetic foot wounds that are slow to heal may also benefit from NPWT (if no other therapies are working); however, NWPT is contraindicated in patients with osteomyelitis.5 There is some evidence to suggest that NPWT may be considered along with other sequential dynamic closure techniques to counteract retraction and facilitate healing when there is an option for delayed primary closure in patients with Grade 1 or 2 open abdomens that are both clean and “contaminated.”8 In addition, lower level evidence supports the use of NPWT to manage abdominal wound fluid and to be continuously used at settings up to -80 mmHg in clean and “contaminated” open abdomens.8 There remains a paucity of high-level evidence on VAC, NPWT, and NPWTi in acute and chronically infected wounds of different origins. Most evidence is produced in lower level studies


(i.e. observational studies) or in few randomized controlled trials of acute and chronic wounds that are not infected, yet still difficult to treat. Therefore, it is up to the practitioner to manage their patient’s wound infection according to the best available evidence, which appears to be mostly of lower quality. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

http://www.cadth.ca/


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3. Negative pressure wound therapy for the open abdomen [Internet]. London (GB): National Institute for Health and Care Excellence; 2013 Nov. [cited 2015 Jun 9]. (NICE interventional procedure guidance 467). Available from: http://www.nice.org.uk/guidance/ipg467

4. Dale AP, Saeed K. Novel negative pressure wound therapy with instillation and the management of diabetic foot infections. Curr Opin Infect Dis. 2015 Apr;28(2):151-7.

5. Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis [Internet]. 2012 Jun [cited 2015 Jun 30];54(12):e132-e173. Available from: http://cid.oxfordjournals.org/content/54/12/e132.long

6. Falagas ME, Tansarli GS, Kapaskelis A, Vardakas KZ. Impact of vacuum-assisted closure (VAC) therapy on clinical outcomes of patients with sternal wound infections: a meta-analysis of non-randomized studies. PLoS ONE [Internet]. 2013 May 31 [cited 2015 Jun 9];8(5):e64741. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669405

7. Monsen C, Wann-Hansson C, Wictorsson C, Acosta S. Vacuum-assisted wound closure versus alginate for the treatment of deep perivascular wound infections in the groin after vascular surgery. J Vasc Surg. 2014 Jan;59(1):145-51.

8. Bruhin A, Ferreira F, Chariker M, Smith J, Runkel N. Systematic review and evidence based recommendations for the use of negative pressure wound therapy in the open abdomen. Int J Surg [Internet]. 2014 Oct [cited 2015 Jun 9];12(10):1105-14. Available from: http://www.sciencedirect.com/science/article/pii/S1743919114008814

9. de Laat EH, van den Boogaard MH, Spauwen PH, van Kuppevelt DH, van Goor H, Schoonhoven L. Faster wound healing with topical negative pressure therapy in difficult-to-heal wounds: a prospective randomized controlled trial. Ann Plast Surg. 2011 Dec;67(6):626-31.

10. Arzt H, Fromantin I, Ribinik P, Barrois B, Colin D, Michel JM, et al. Which medical device and/or which local treatment are to be used, as of 2012, in patients with infected pressure sore? Developing French guidelines for clinical practice. Ann Phys Rehabil Med [Internet]. 2012 Oct [cited 2015 Jun 9];55(7):498-507. Available from: http://www.sciencedirect.com/science/article/pii/S1877065712012249

http://www.ncbi.nlm.nih.gov/books/NBK49010/http://www.nice.org.uk/guidance/ipg467http://cid.oxfordjournals.org/content/54/12/e132.longhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669405http://www.sciencedirect.com/science/article/pii/S1743919114008814http://www.sciencedirect.com/science/article/pii/S1877065712012249


11. Damiani G, Pinnarelli L, Sommella L, Tocco MP, Marvulli M, Magrini P, et al. Vacuum-assisted closure therapy for patients with infected sternal wounds: a meta-analysis of current evidence. J Plast Reconstr Aesthet Surg. 2011 Sep;64(9):1119-23.

12. Negative pressure therapy for patients infected wounds: a review of the clinical and cost-effectiveness evidence and recommendations for use [Internet]. Ottawa: CADTH; 2010 Jul 14. [cited 2015 Jun 29]. (Health Technology Inquiry Service). Available from: https://www.cadth.ca/sites/default/files/pdf/l0194_negative_pressure_therapy_htis-2.pdf

13. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet]. 2007 [cited 2015 Jun 30];7:10. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf

14. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet]. 1998 Jun [cited 2015 Jun 30];52(6):377-84. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdf

15. Brouwers M, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing guideline development, reporting and evaluation in healthcare. CMAJ [Internet]. 2010 Dec [cited 2015 Jun 30];182(18):E839-E842. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001530/pdf/182e839.pdf

16. Back DA, Scheuermann-Poley C, Willy C. Recommendations on negative pressure wound therapy with instillation and antimicrobial solutions - when, where and how to use: what does the evidence show? Int Wound J. 2013 Dec;10(Suppl 1):32-42.

17. Birke-Sorensen H, Malmsjo M, Rome P, Hudson D, Krug E, Berg L, et al. Evidence-based recommendations for negative pressure wound therapy: treatment variables (pressure levels, wound filler and contact layer)--steps towards an international consensus. J Plast Reconstr Aesthet Surg. 2011 Sep;64 Suppl:S1-S16.

https://www.cadth.ca/sites/default/files/pdf/l0194_negative_pressure_therapy_htis-2.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001530/pdf/182e839.pdf


APPENDIX 1: Selection of Included Studies

497 citations excluded

49 potentially relevant articles retrieved for scrutiny (full text, if

available)

3 potentially relevant reports retrieved from other sources (grey

literature)

52 potentially relevant reports

44 reports excluded: - irrelevant population (23) - irrelevant intervention (1) - irrelevant comparator (3) - irrelevant outcomes (2) - irrelevant study design (9) - review articles (6)

8 reports included in review

546 citations identified from electronic literature search screened


APPENDIX 2: Additional References of Potential Interest CADTH Reports Negative pressure wound therapy for managing diabetic foot ulcers: a review of the clinical effectiveness, cost-effectiveness, and guidelines [Internet]. Ottawa: CADTH; 2014 Aug 28 [cited 2015 Jun 30]. (Rapid response report: summary with critical appraisal). Available from: https://www.cadth.ca/sites/default/files/pdf/htis/dec-2014/RC0579-001%20Diabetic%20Foot%20Ulcers%20Final.pdf Systematic Review and Meta-analyses – Infected Wounds Not Specified Game FL, Hinchliffe RJ, Apelqvist J, Armstrong DG, Bakker K, Hartemann A, et al. A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes Metab Res Rev. 2012 Feb;28 Suppl 1:119-41. Suissa D, Danino A, Nikolis A. Negative-pressure therapy versus standard wound care: a meta-analysis of randomized trials. Plast Reconstr Surg. 2011 Nov;128(5):498e-503e. Different Forms of NPWT as Comparator Gabriel A, Kahn K, Karmy-Jones R. Use of negative pressure wound therapy with automated, volumetric instillation for the treatment of extremity and trunk wounds: clinical outcomes and potential cost-effectiveness. Eplasty [Internet]. 2014 Nov 3 [cited 2015 Jun 30];14:e41. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226049 Economic Evaluations – Infected Wounds Not Specified Dowsett C, Davis L, Henderson V, Searle R. The economic benefits of negative pressure wound therapy in community-based wound care in the NHS. Int Wound J. 2012 Oct;9(5):544-52. Gnanaraj J, Gnanaraj D, Prasad A. Salvaging a diabetic foot: a new cost-effective method. Trop Doct. 2012 Apr;42(2):88-9.

https://www.cadth.ca/sites/default/files/pdf/htis/dec-2014/RC0579-001%20Diabetic%20Foot%20Ulcers%20Final.pdfhttps://www.cadth.ca/sites/default/files/pdf/htis/dec-2014/RC0579-001%20Diabetic%20Foot%20Ulcers%20Final.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226049


APPENDIX 3: Characteristics of Included Publications

Table 2: Characteristics of Included Systematic Reviews and Meta-Analyses Author,

Publication Year,

Country

Included Study Characteristics

Population Characteristics

Intervention Comparator(s) Clinical Outcomes

Falagas et al.,

6

2013 Greece, US

a

22 retrospective cohorts incl

Up to 2012

Greece, US

Pts with DSWI VAC Without-VACb Mortality:

o n=2233 (mortality) o n=1186 (in-hospital mortality) o n=1534 (mortality on pts with

mediastinitis/undetermined DSWI

LOS: o n=983

Recurrence of DSWI: o n=1197

Complications: o Narratively described; no analysis

performed

Damiani et al.,

11

2011 Italy

6 obs studies incl

2000 – 2005

Germany, Sweden, NL, CH, UK

N=321

Pts with sternal wounds

c

VAC (n=169) CTd (n=152) LOS

Mortality in 5/6 studies (n=160 VAC; n= 142 CT)

CH = Switzerland, CT = conventional therapy; DSWI = deep sternal wound infection; incl = included; LOS = length of stay; NL = Netherlands; obs = observational; pts = patients; UK = United Kingdom; US = United States; VAC = vacuum-assisted closure. a Most authors Greek, while one was Greek but had affiliation with United States medical school.

b No description of other non-VAC treatments.

c Presumed infected sternal wounds; only specified in title and abstract but nowhere is article.

c Conventional therapies differed between included studies and included the following techniques: removal of sternal wiring and debridement, closed irrigation, open dressings,

pectoral muscle or omentum flaps, traditional closed drainage techniques, continuous irrigation, sternal resection and musculocutaneous flap, closed drainage and irrigation.


Table 3: Characteristics of Included Randomized Controlled Trials Author,

Publication Year,

Country

Study and Patient Characteristics Intervention(s) Comparator(s) Clinical Outcomes

Randomized Controlled Trials De Laat et al.

9

2011 Netherlands

Study:

Prospective RCT

N=24 patients (n=28 wounds)

ITT analysis Patients:

≥18 years of age

2 groups: o Admitted to hospital with difficult-

to-heal wounds Infected diabetic foot (TNP=2;

NaCIO=1) Infected hematoma (TNP=1;

NaCIO=3) o SCI grade IV pressure ulcers

a

During therapy debridement took place before start of therapy and as required during therapy

Topical negative pressure therapy; n=15 (VAC system, pads changed 3x/week)

Conventional dressing therapy; n=13 (NaCIO 0.25% solution moist dressing changed 2-3 times/day))

Primary Outcome:

Time to 50% wound volume reduction with maximum follow-up of 6 weeks

Secondary Outcomes:

Safety (wound healing failure rates and any AE)

Monsen et al.7

2014 Sweden

Study:

Prospective RCT

N=20 Patients:

≥60 years of age

Patients with deep perivascular groin wound infections (Szilagyi grade III), after vascular surgery

Co-morbidities:

o Ischemic heart disease o Diabetes mellitus o Cerebrovascular diseases o Any previous vascular surgery o BMI

VAC therapy Alginate dressings Outcomes:

Microbiology

Wound healing: o Time to full skin

epithelialization o Wound surface area

Amputation

Mortality

AE = adverse event; BMI = body mass index; ITT = intention to treat; NaCIO = sodium hypochlorite; RCT = randomized controlled trial; SCI = spinal cord injury; TNP = topical negative pressure. a According to the European Pressure ulcer Advisory Panel grading system.


APPENDIX 4: Critical Appraisal of Included Publications

Table 4: Strengths and Limitations of Systematic Reviews and Meta-Analysesa Strengths Limitations

Damiani et al., 201111

A prior inclusion and exclusion criteria defined

Comprehensive literature search performed

Article selection and quality assessment of studies was systematically performed (dual author system); PRISMA diagram provided

Characteristics of included studies were provided

Grading of evidence quality provided along with cut-off value for quality assessment (6 out of 10); however, unsure of where authors obtained grading system for assessing bias

Methods used to combine and analyze studies were appropriate (MA forest plot, Chi squared test for significance, I

2 for heterogeneity);

appropriate methods for publication bias assessment (funnel plots; data not shown)

No outside funding apparent

Conflict of interest statement provided (with none reported)

Sternal wound infections were not part of their search strategy and nowhere in the article (save the title and the abstract) sternal wounds explicitly defined as infected; therefore, the assumption made was that their included analysis was based on studies of sternal wound infections

Only observational studies included

Search was not specified as systematic in nature

List of excluded studies not provided

Falagas et al., 20136

A prior inclusion and exclusion criteria defined

Systematic and grey literature search performed; PRISMA diagram provided

Definitions of sternal wound infections provided

Characteristics of included studies were provided

Methods used to combine and analyze studies were appropriate (MA forest plot, Chi squared test for significance, I

2 for heterogeneity)

No outside funding apparent

Conflict of interest statement provided (with none reported)

Dual author system for article selections, methodologic quality assessment, or data extraction not apparent

Potential for publication bias as articles other than English, German, French, Spanish, Italian, or Greek not evaluated; no funnel plot provided to assess publication bias

Only retrospective cohorts included

Only 3 of the studies included in the Damiani et al.

11 MA were included in this MA; no reason

provided for not including the others

List of excluded studies not provided GRADE = Grading of Recommendations Assessment, Development and Evaluation; MA = meta-analysis; SIGN = Scottish Intercollegiate Guidelines Network. a AMSTAR was used to guide the critical appraisal of the systematic reviews.


Table 5: Strengths and Limitations of Randomized Controlled Trialsa

Strengths Limitations

Randomized Controlled Trials

Monsen et al. 20147

Prospective RCT

Objective, outcomes, patient characteristics, interventions, and main findings of study clearly presented

Inclusion criteria were provided

Patients randomized to treatment arms

Patients were representative of those with grade III Szilagyi wounds (after undergoing vascular surgery)

Outcome measures were valid

Exclusion criteria were not specifically provided

No discussion pertaining to blinding

Randomly assigned using sealed envelope that patient selected at random after surgery; no discussion as to computer generated randomization codes

No specificity surrounding which outcomes were of primary or secondary interest

Number of patients did not meet the power calculation requirements; hence insufficient power to make solid conclusions

De Laat et al., 20119

Prospective RCT

Objective, outcomes, patient characteristics, interventions, and main findings of study clearly presented

Inclusion and exclusion criteria provided

Patients in both of the two groups were randomized to 2 treatments

Wound experts were blinded to treatment patient received

Null hypothesis stated

ITT analysis performed on primary outcome

Power analysis provided (sample size of 12 wounds would suffice and was achieved)

Appropriate statistical tests to analyze the date used

Blinding not possible for investigators or patients

Not generalizable to entire population as some patients were admitted to hospital or were in-patients; follow-up for surgical patients took place in hospital and at home (these may have been more representative)

Randomly assigned using sealed envelope; no discussion as to computer generated randomization codes

Some room for error in wound area calculation; however, used validated Kundin formula and two wound experts to independently calculate wound area

ITT = intention -to-treat. a Downs and Black

14 was used to guide the critical appraisal of the clinical studies.

Table 6: Strengths and Limitations of Guidelinesa Strengths Limitations

Bruhin at al., 20148

Clearly defined objectives and recommendations

Full SR and grey literature search of the literature performed and criteria for selecting evidence provided

Defined levels of evidence and grading of recommendations

Links between recommendations and evidence provided

Global experts were included in the formulation of these recommendations

Role of funding provided; with disclosure regarding the lack of influence of funder

Conflicts of interest disclosed

No definitive definition of “contaminated” which was used to decipher from “clean” OAs

While these recommendations included those for “contaminated” OAs; there was nothing specified per se regarding the infections

No cost implications provided


No apparent discussion on the procedure to update the recommendations


Table 6: Strengths and Limitations of Guidelinesa Strengths Limitations

Back et al., 201316

Clearly stated objective

The review was evidence-based

Lack of full SR was used to identify and ascertain information

Lack of formal grading system of the evidence quality

Lack of information on how the recommendations were developed

Lack of link between the recommendations and corresponding supporting evidence

All evidence was used to assess efficacy of NPWTi (including in vitro studies)

Potential for publication bias as articles were limited to English and German only

No conflicts of interest disclosed

The manufacturer assisted with the editorial review of the manuscript

IDSA, 20125

Updated guideline

Clearly defined objectives, questions, and recommendations

Full systematic search and extensive grey literature search apparent

GRADE used to assess the quality of evidence and strength of recommendations

Consensus development was based on the evidence

Panel of experts included specialists in infectious diseases, wound care, podiatry, internal medicine, orthopedic surgery , and others

Future annual intervals were determined to examine whether updates in the guidelines will be necessary

Role of funding provided


List of excluded studies not provided; therefore, uncertainty around whether publication bias would be an issue

Lack of link between the recommendations and corresponding supporting evidence

NPWT-EP, 201117

Clearly defined objectives and recommendations

Full SR and grey literature search of the literature performed and criteria for selecting evidence provided

Every effort was made to translate identified grey literature evidence into English

Defined levels of evidence and grading of recommendations

Links between recommendations and evidence provided

Brief discussion on the cost benefits associated with NPWT

Global experts part of NPWT-EP

Role of funding provided; with disclosure regarding the lack of influence of funder


Questions were not presented per se; rather topics were grouped together

No formal patient groups were apparent in the development process; however, there were discussions on how to minimize wound pain from the patient perspective (potential strength)


Potential for publication bias as only articles in English were included from the SR

No apparent discussion on the procedure to update the recommendations

GRADE = Grading of Recommendations Assessment, Development and Evaluation; NPWT = negative pressure wound therapy; NPWT-EP = International Expert Panel on Negative Pressure Wound Therapy; OA = open abdomen; SR = systematic review. a AGREE II

15 was used to guide the critical appraisal of the guidelines.


APPENDIX 5: Main Study Findings, Author’s Conclusions, and Guideline Recommendations

Table 7: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions

Meta-Analsyes

Falagas et al., 20136

Comparing VAC to Without-VAC:

Mortality (pooled data, n=2233): o RR=0.40 (95% CI 0.28, 0.57) o I

2=16%

In-Hospital Mortality (n=1186): o RR=0.40 (95% CI 0.26, 0.62) o I

2=13%

o 30-day (n=193): RR= 2.28 (95% CI 0.30, 17.250)

o 90-day (n=194): RR=0.21 (95% CI 0.03,1.30)

Mediastinitis/Undetermined DSWI Mortality: o VAC (n=1534):

RR=0.38 (95% CI 0.24, 0.60) o Non-VAC (n=117):

RR=0.21 (95% CI 0.06, 0.73)

Recurrence of DSWI (pooled data): o RR=0.34 (95% CI 0.19, 0.59) o I

2=48%

LOS (n=983): o RR=-2.25 (95% CI -7.52, 3.02)

AEs reported in individual studies: o New AF, remote infections, partial flap

loss, sepsis, discharging sinus, cardiovascular/neurological/GI complications, seroma, renal failure, skin necrosis, bleeding, skin graft requirement, multiple organ failure, dehiscence, fistula, and empyema

“…the currently available data suggest a lower mortality and support the use of VAC therapy for the treatment of patients with DSWIs following cardiothoracic surgery.” page 9

“VAC therapy was associated with fewer recurrences than conventional treatment in the meta-analysis.” page 8

“…it is difficult to draw conclusions regarding LOS.” page 9

Damiani et al., 201111

LOS: o Compared to CT, VAC reduced LOS

by 7.18 days (95% CI: 10.82, 3.54)

Mortality: o Reduction in mortality favouring VAC

(but non-significant): OR=0.61 (95% CI: 0.29, 1.27)

“The findings of our quantitative synthesis of scientific literature highlight that VAC therapy is a valid alternative to conventional therapy because it reduces not only wound size but also the duration of wound treatment and hospital stay without any significant impact on mortality rates.” page 1122

Randomized Controlled Trials

Monsen et al. 20147

Wound Healing – Full Skin Epithelialization: o VAC:

Median 57 days o Alginate:

Median 104 days o P=0.026

Wound Treatment Time Outside Hospital: o Shorter with VAC compared to alginate

“VAC therapy induced faster wound healing than alginate therapy in patients with deep perivascular wound infections in the groin after vascular surgery.” page 150


Table 7: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions

(P=0.034)

Wound Surface Area (cm2) After 21 Days:

o VAC (n=10): 3.5 (0-92.5)

o Alginate (n=9): 6.5 (2.7-26.3)

o P=0.24

Amputation (During Median Follow-Up of 14 Months):

o 3 patients receiving VAC o 2 patients in alginate

Mortality: o 2 patients receiving VAC o 5 patients in alginate

De Laat et al., 20119

50% Wound Volume Reduction: o Achieved in 24 of 28 wounds o TNP:

2.0 weeks (IQR=1) o CT:

3.,5 weeks (IQR=1.5) o P


Table 8: Summary of Recommendations from the Included Guidelinesa Recommendations

Back et al., 201316

Recommendations regarding the use of solutions with NPWTi in acute and chronically infected wounds

d:

“Polyhexanide: o Concentration of 0.1% polyhexanide or 0.04% polyhexanide. On cartilage at the wound

ground, the effective concentration of polyhexanide should be reduced to 0.005% to avoid adverse effects.

o Amount of instilled fluid depends on wound volume. User-selected instillation volume is controlled by the device.

o 20 minutes soak time, 4–8 times per day.” page 36

“Acetic acid:

o Concentrations between 0.25% and 1% are recommended. o Amount of instilled fluid depends on wound volume. User-selected instillation volume is

controlled by the device. o 20 minutes soak time, 4–8 times per day.” page 36

“Povidone-iodine: o A combination of ethanol/propan-2-ol and povidone-iodine [e.g. available as 100 ml solution,

3.24 povidone-iodine (this means 0.324%), 38.9g isopropanol and 38.9 g ethanol] is the first-choice antiseptic in the treatment of stabbing wounds at risk of infection with HBV, HCV or HIV and should be applied after bleeding has been encouraged. The same applies to the initial treatment of bite wounds.

o Amount of instilled fluid depends on wound volume. User-selected instillation volume is controlled by the device.

o 20 minutes soak time, 4–8 times per day.” page 36

IDSA, 20125

Recommendations for the Treatment Diabetic Foot Wounds:

For the treatment of osteomyelitis of the foot: o “For specifically treating DFO, we do not currently support using adjunctive treatments such

as topical negative pressure therapy (eg, vacuum-assisted closure) (weak, low).” page e154

For the treatment of infected diabetic foot wounds: o “No adjunctive therapy has been proven to improve resolution of infection, but for selected

diabetic foot wounds that are slow to heal, clinicians might consider using negative pressure wound therapy (weak, low).” page e160

NPWT-EP, 201117

Recommendations regarding the role of NPWT as an adjunct to infection management:

“ NPWT „should‟ be used only as an adjunctive therapy to combat wound infection (Grade B),” pages S10 – S11

“Anti-microbial gauze „may‟ contribute towards infection control; Grade C,” pages S11 – S12

“It is „possible‟ that silver foam may contribute to infection control; Grade D,” pages S11 – S12

“When applied underneath the NPWT wound filler, it is possible that anti-microbial WCL may contribute towards infection control. Grade D,” pages S11 – S12

“It is possible that fluid instillation may contribute to infection control; Grade D,” pages S11, S13 DFO = diabetic foot osteomyelitis; GPP = good practice point; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = immunodeficiency virus; IDSA = Infectious Disease Society of America; NPWT = negative pressure wound therapy; NPWT-EP = International Expert Panel on Negative Pressure Wound Therapy; NPWTi = negative pressure wound therapy with instillation; WCL = wound contact layer. a Verbatim from the guidelines.

b Contaminated assumed to be “infected.”

c Grade 1 and 2 open abdomens (OA) were classified as: “1a) Without adherence between bowel wall and abdominal wall or fixity;

1b) Contaminated OA without adherence/fixity; 2a) Clean OA developing adherence/fixity; 2b) Contaminated OA developing adherence/fixity.” d NPWTi to be used as adjunct therapy after surgical debridement.


APPENDIX 6: Levels of Evidence and Grading Schemes

Table 9: Levels of Evidence and Grading of Recommendationsa

Quality of Level of Evidence Grading/Strength of Recommendation

Bruhin at al., 2014,8 NPWT-EP, 2011

17

Adapted from SIGN method of classification: 1++ High quality meta-analyses, systematic

reviews of RCTs, or RCTs with a very low risk of bias.

1+ Well-conducted meta-analyses, systematic

reviews, or RCTs with a low risk of bias. 1. Meta-analyses, systematic reviews, or RCTs

with a high risk of Bias. 2++ High quality systematic reviews of case

control or cohort or Studies. High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal.

2+ Well-conducted case control or cohort

studies with a low risk of confounding or bias and a moderate probability that the relationship is causal.

2- Case control or cohort studies with a high

risk of confounding or bias and a significant risk that the relationship is not causal.

3 Non-analytic studies, e.g. case reports, case

series, OR in vivo or in vitro studies. 4 Expert opinion.

Based on SIGN system for EBR development: A (Must) - At least one meta-analysis, systematic

review, or RCT rated as 1++, and directly applicable to the target population; or A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results.

B (Should) - A body of evidence including studies rated

as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+.

C (May) - A body of evidence including studies rated as

2+, directly applicable to the target population and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 2++.

D (Possible) - Evidence level 3 or 4; or Extrapolated

evidence from studies rated as 2+. GPP

b - Good practice point. A basic requirement of

application consistent with manufacturer’s instructions and in agreement with the NPWT-EP.

IDSA, 20125

Based on Systematic Weighting of Evidence Using GRADE:

“Strong recommendation, high-quality evidence: o Desirable effects clearly outweigh undesirable effects, or vice versa. o Consistent evidence from well-performed RCTs or exceptionally strong evidence from unbiased

observational studies. o Recommendation can apply to most patients in most circumstances. Further research is unlikely

to change our confidence in the estimate of effect.

Strong recommendation, moderate-quality evidence: o Desirable effects clearly outweigh undesirable effects, or vice versa. o Evidence from RCTs with important limitations (inconsistent results, methodological flaws,

indirect, or imprecise) or exceptionally strong evidence from unbiased observational studies. o Recommendation can apply to most patients in most circumstances. Further research (if

performed) is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.


Table 9: Levels of Evidence and Grading of Recommendationsa

Quality of Level of Evidence Grading/Strength of Recommendation

Strong recommendation, low-quality evidence: o Desirable effects clearly outweigh undesirable effects, or vice versa. o Evidence for at least 1 critical outcome from observational studies, RCTs with serious flaws or

indirect evidence. o Recommendation may change when higher-quality evidence becomes available. Further

research (if performed) is likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Strong recommendation, very low-quality evidence (very rarely applicable): o Desirable effects clearly outweigh undesirable effects, or vice versa. o Evidence for at least 1 critical outcome from unsystematic clinical observations or very indirect

evidence. o Recommendation may change when higher-quality evidence becomes available; any estimate of

effect for at least 1 critical outcome is very uncertain.

Weak recommendation, high-quality evidence: o Desirable effects closely balanced with undesirable effects. o Consistent evidence from well performed RCTs or exceptionally strong evidence from unbiased

observational studies. o The best action may differ depending on circumstances or patients or societal values. Further

research is unlikely to change our confidence in the estimate of effect.

Weak recommendation, moderate-quality evidence: o Desirable effects closely balanced with undesirable effects. o Evidence from RCTs with important limitations (inconsistent results, methodological flaws,

indirect, or imprecise) or exceptionally strong evidence from unbiased observational studies. o Alternative approaches likely to be better for some patients under some circumstances. Further

research (if performed) is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Weak recommendation, low-quality evidence: o Uncertainty in the estimates of desirable effects, harms, and burden; desirable effects, harms,

and burden may be closely balanced. o Evidence for at least 1 critical outcome from observational studies, RCTs with serious flaws, or

indirect evidence. o Other alternatives may be equally reasonable. Further research is very likely to have an

important impact on our confidence in the estimate of effect and is likely to change the estimate.

Weak recommendation, very low-quality evidence: o Major uncertainty in the estimates of desirable effects, harms, and burden; desirable effects may

or may not be balanced with undesirable effects or may be closely balanced. o Evidence for at least 1 critical outcome from unsystematic clinical observations or very indirect

evidence. o Other alternatives may be equally reasonable. Any estimate of effect, for at least 1 critical

outcome, is very uncertain.” page e134 EBR = evidence-based recommendation; IDSA = Infectious Disease Society of America; GPP – good practice point; GRADE = Grading of Recommendations Assessment, Development and Evaluation; NPWT-EP = International Expert Panel on Negative Pressure Wound Therapy; RCT = randomized controlled trial; SIGN = Scottish Intercollegiate Guidelines Network. a Verbatim from the guidelines.

b Additional grade provided by Bruhin et al., 2014

8

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TITLE: Negative Pressure Wound Therapy for …...Negative Pressure Wound Therapy for Infected Wounds 2 other treatments are required. NPWT or NPWTi are supported by some evidence in