Negative pressure wound therapy (NPWT) is utilized in patients presenting with chronic or complex acute wounds and acts to optimize wound-healing capacity. Currently available NPWT technologies are based on modifications of a device first evaluated by Argenta and Morykwas [1,2]. This early device involved placing and securing reticulated open-cell foam in the wound with an adhesive semipermeable dressing. An aperture made in the dressing was subsequently attached to an external subatmospheric pressure source via plastic tubing, enabling the application of continuous or intermittent negative pressure to the wound. The mechanisms underlying the effectiveness of NPWT are complex and explored in detail elsewhere [3▪,4]. In brief, NPWT facilitates wound closure via five key mechanisms: promotion of wound contraction, resulting in reduced wound area ; improving tissue perfusion by reducing tissue oedema ; ensuring constant removal of wound debris, exudate and infectious materials that may inhibit healing ; encouraging wound bed granulation  and optimizing the wound environment by providing thermoregulation and ensuring the retention of moisture .
NPWT systems have been successfully utilized to treat a spectrum of wound types and technologies are constantly being refined and adapted [10▪]. In 1998, a NPWT system incorporating fluid instillation [negative pressure wound therapy with instillation (NPWTi)] was described by Fleischmann et al.. This novel development combined two historical surgical principles, irrigation and suction, into one device, and although evidence assessing the efficacy of NPWTi systems is limited compared with that available for NPWT, experience with their use continues to widen, especially in difficult-to-treat wounds [12▪▪].
NPWT is often an important component of the comprehensive treatment plan devised for patients with diabetic foot ulcers (DFUs) or postoperative diabetic wounds. There is good evidence to support the use of NPWT in these patients from randomized controlled trials (RCTs) [13–15]. In a recent systematic review, Guffanti [16▪] concludes that NPWT, specifically using the vacuum assisted closure (VAC) system, results in more effective and faster wound healing, and may also reduce potential infective complications, when compared with standard moist wound therapy in patients with diabetic foot infections.
Evidence relating to the utilization of NPWTi in DFUs or postoperative diabetic wounds is less robust compared with that available for NPWT and is generally limited to case reports and case series. However, as the potential benefits of NPWTi continue to be realized, the use of this technology may become more commonplace.
The current review will focus on the evaluation of novel NPWTi therapies and assess in detail the evidence relating to its application as a therapeutic option in patients with DFUs, postoperative diabetic wounds and diabetic foot infections.
NEGATIVE PRESSURE WOUND THERAPY WITH INSTILLATION
NPWTi enables cyclical delivery of a topical solution to the wound bed. Following a predetermined dwell time, whereby the instilled solution is allowed to penetrate the tissues, any residual fluid is extracted through application of NPWT . Utilization of NPWTi systems has continued to expand since the first reports of their use in 1998 . However, the catalyst enabling wider clinical use was the introduction of commercially available NPWTi systems by KCI (V.A.C. Instil Wound Therapy System – delivers intermittent irrigation) and Innovative Therapies, Inc. (Svedman Wound Treatment Systems – delivers intermittent or continuous irrigation) in 2003 and 2007, respectively. Building on their initial success, both companies launched second-generation NPWTi systems in 2012 (V.A.C. Ultra Negative Pressure Wound Therapy System with V.A.C. Veraflo Therapy – KCI, and Quantum Wound Treatment System – Innovative Therapies, Inc.) [12▪▪].
Developing an evidence base to support the use of novel NPWTi therapy is challenging. To date, evidence relating to the clinical efficacy of NPWTi is derived from case reports, case series or small comparative studies that outline the experience of an individual clinician or centre. Theoretically, the use of intermittent or continuous instillation therapy offers to enhance standard NPWT by reducing bioburden and removing wound bed debris and exudate through regular irrigation, and enabling the direct delivery of topical solutions including antimicrobial agents to the wound bed. Additionally, the delivery of irrigation in a sealed environment reduces the risk of pathogen aerosolization and may therefore reduce patient-to-patient bacterial transmission events. This hypothesis was tested in a recent ex-vivo study by Allen et al.[18▪] who demonstrated a significantly reduced risk of cross-contamination on using NPWTi compared with traditional low-pressure wound lavage.
Effect of negative pressure wound therapy with instillation on reducing wound bed bioburden
Presence of a high bioburden within the wound bed adversely affects healing [19▪,20,21]. Bacterial virulence factors (e.g. lipopolysaccharide and metalloproteinase enzymes) result in the activation of innate and adaptive immune components, and cytotoxic enzymes released by polymorphonuclear neutrophils, macrophages and monocytes result in subsequent host tissue damage [22,23]. Bacterial metabolism utilizes oxygen and nutrients available for wound healing, and cytokines released in the proinflammatory response cause localized vasoconstriction, thus further reducing wound healing capability [22,24].
Phillips et al. utilized an ex-vivo porcine skin explant model to assess the effects of NPWTi on reducing Pseudomonas aeruginosa biofilm and planktonic bacterial bioburden. A significant reduction in bacterial load was observed on using a number of antimicrobial solutions as instillation fluids compared with physiological saline instillation alone [1 or 10% povidone iodine, 0.05% chorhexidine gluconate, 0.1% polyhexamethylene biguanide and 0.2% polydiallyldimethylammonium chloride all significantly (P < 0.001) reduced the total number of colony-forming units]. In a small case–control study, Gabriel et al. compared the outcomes of 15 prospective patients (received NPWTi with instillation of silver nitrate) with 15 retrospective controls (received standard moist wound-care therapy). Patients receiving NPWTi cleared infection earlier (based on sequential quantitative culture) underwent earlier wound closure, and were discharged earlier than patients in the control group.
In a more recent cohort-controlled study comparing outcomes in patients undergoing NPWT alone with those receiving NPWTi (Prontosan instillation fluid – dwell time of 6 or 20 min), Kim et al.[27▪] failed to demonstrate a significant difference in bioburden reduction between groups. However, a significant reduction in wound bed Gram-positive bacterial colonizers in patients undergoing NPWTi (6-min dwell time), compared with NPWT alone (P = 0.0001), was observed following exclusion of Gram-negative colonizers, Corynebacterium and yeast [27▪]. Although the evidence relating to bioburden reduction and NPWTi therapy was unclear in this study, other findings were more convincing. The authors demonstrated that NPWTi was associated with a significant reduction in the number of operative visits (6-min and 20-min dwell time, P ≤ 0.05), a shorter time to final surgical procedure (6-min and 20-min dwell time, P ≤ 0.05) and a shorter inpatient stay (20-min dwell time only, P ≤ 0.05), compared with NPWT alone. Although this study demonstrates the potential benefits of NPWTi, the results must be interpreted with caution due to its retrospective nature and particular vulnerability to potential selection bias.
In a further small-scale pilot study, Goss et al.[19▪] assessed the effects of NPWT vs. NPWTi (0.125% sodium hypochlorite – Dakin's solution) on postdebridement wound bioburden in a prospective, nonrandomized cohort comprising 13 patients. A statistically significant reduction in absolute bioburden (P = 0.016) was observed in patients receiving NPWTi compared with those receiving standard NPWT [19▪].
Evaluation of negative pressure wound therapy with instillation fluids
A broad range of instillation fluids have been utilized in patients undergoing NPWTi therapy. In an attempt to provide clinical guidance in this area, international consensus guidelines were devised in 2013 by an expert panel utilizing a modified consensus process methodology [12▪▪]. There was strong consensus from the panel that Lavasept (polyhexanide 0.04%), Prontosan (polyhexanide 0.1% with betadine) and Microcyn/Dermacyn were appropriate instillation fluids to be used with NPWTi.
Polyhexanide 0.04% has broad-spectrum antimicrobial activity and proven efficacy in reducing bacterial bioburden in the oral cavity and chronic wounds [28–30]. In an in-vitro model with a broad range of pathogens, including methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, vancomycin-resistant Enterococcus and Acinetobacter baumannii, 0.1% polyhexanide combined with 0.1% betadine reduced viable bioburden by 5.3–5.8 log . Reports relating to the successful use of 0.1% polyhexanide with betadine as an NPWTi instillation fluid are numerous but mainly relate to prosthetic or orthopaedic infections [9,32]. In a retrospective case–control study, Timmers et al. compared debridement followed by NPWTi with polyhexanide instillation in patients with osteomyelitis to standard surgical debridement with implantation of gentamicin polymethylmethacrylate beads and intravenous antibiotics. A significant reduction in infection recurrence was observed in cases compared to controls (3/30 vs. 55/93 recurrence of osteomyelitis in NPWTi vs. control group, respectively, P < 0.0001) .
Microcyn and Dermacyn are pH neutral water-based super-oxidized solutions with varying oxychlorine concentrations. Microcyn has proven in-vitro activity against a broad range of pathogens including bacterial endospores, pseudomonas biofilms and yeasts [34–36]. Aragón-Sánchez et al. outlined the effectiveness of Dermacyn as a daily irrigation fluid in 14 patients with diabetic foot osteomyelitis. In all cases, limb salvage was successfully achieved and, importantly, there were no reports of side effects associated with Dermacyn treatment . The efficacy of topical Microcyn was evaluated in patients with mildly infected DFUs in a prospective, randomized study by Landsman et al.. Although the study was not adequately powered, the authors demonstrated that Microcyn wound irrigation was well tolerated and could be as effective as oral levofloxacin therapy along with saline wound irrigation. Despite evidence that Microcyn and Dermacyn are well tolerated and effective when utilized as topical irrigation agents, there is limited published evidence relating to their use with NPWTi systems. One case series does however demonstrate five cases where Microcyn instillation fluid was successfully utilized with NPWTi in a variety of complex wounds .
Other instillation fluids that have been utilized with NPWTi systems include normal saline [40▪▪], Dakin's solution (0.125% sodium hypochlorite) [19▪], diluted acetic acid or iodine solutions [12▪▪], and a variety of antibiotic [11,41,42], silver nitrate  and insulin-based  solutions.
Prior to utilizing a solution for instillation purposes it is important to consider the potential safety implications. Adverse reactions relating to wound instillation fluids have included temporary coma and ST-segment elevation secondary to oxygen microbubble embolization to the cerebral and coronary arteries following the use of 3% hydrogen peroxide as an irrigation solution , iodine toxicity resulting in death following the use of continuous postoperative wound irrigation with betadine , and intraoperative anaphylaxis following mediastinal irrigation with bacitracin solution . It is also imperative that manufacturer guidelines are checked to confirm that any proposed instillation solution is compatible with the NPWTi device components, for example device tubing and dressing materials.
The safety and effectiveness of physiological saline as an NPWTi instillation fluid were assessed in a prospective cohort of 131 patients with complex wounds by Brinkert et al.[40▪▪] They observed favourable outcomes in 98% of cases and postulated that, in patients who had initially failed to progress with traditional NPWT, NPWTi with physiological saline in combination with surgical debridement encouraged previously stalled granulation tissue formation. Dakin's solution has been used historically in NPWTi systems  and, as previously discussed, has been demonstrated to significantly reduce bioburden when used in the NPWTi setting [19▪].
The use of antibiotic-based solutions for NPWTi is attractive as it enables an identified organism to be targeted directly. Topical instillation with antibiotics such as doxycycline may also provide additional benefits based on their antiinflammatory properties . Data relating to the use of antibiotics as NPWTi instillation fluids are limited, and therefore the associated risks are not well understood. However, as with all topical antibiotics, potential risks include hypersensitivity reactions and serum-concentration-related toxicity [47,48].
APPLICATION OF NEGATIVE PRESSURE WOUND THERAPY WITH INSTILLATION IN DIABETIC FOOT INFECTIONS
The estimated prevalence of diabetes globally is 3%; however, in the West this figure is significantly higher, mainly as a result of the obesity epidemic . DFUs occur in 15–25% of diabetic patients over their lifetime and are associated with numerous infective complications ranging from mild cellulitis or paronychia, to osteomyelitis/septic arthritis and life-threatening necrotizing fasciitis [50,51]. A systematic approach that promptly controls spreading infection and ensures maximal tissue preservation must be utilized in patients with diabetic foot infections to prevent the need for amputation .
Evidence from RCTs supports the utilization of NWPT in patients with DFUs or postamputation diabetic wounds, and demonstrates that NPWT results in faster and more effective wound healing compared with traditional methods [13–15]. Furthermore, the use of NPWT in these patients is associated with significant cost savings . However, these studies do not directly support the use of NPWT in infected diabetic wounds as they all actively excluded patients with evidence of clinical infection, including cellulitis or underlying osteomyelitis, prior to randomization.
An array of case reports and case series outline the successful use of NPWTi in patients with complex diabetic foot infections. Bernstein et al. describe the successful application of NPWTi (instillation fluid – 500 000 units of polymyxin B and 50 000 units of bacitracin in 2 l of 0.9% saline; 6 h of NPWT followed by 90 s instillation and 5-min dwell time) in five patients with complex diabetic foot infections with underlying osteomyelitis. In all cases, adequate granulation tissue formation was noted with postoperative use of NPWTi following initial debridement and localized amputation . More recently, Dalla Paola  described how, in his opinion, NPWTi (instillation fluid – polyhexamethylene biguanide; 15 min dwell time followed by 2 h of NPWT) was an important factor in ensuring complete wound healing in two patients initially presenting with lower limb gangrene.
In a prospective study assessing the effectiveness of NPWTi utilizing physiological saline in patients with infected wounds or wounds at significant risk of infection (24% of cohort had diabetes mellitus), Brinkert et al.[40▪▪] achieved complete wound closure in 98% of cases. Interestingly, in 35% of the cohort, initial use of NPWT without saline instillation following debridement had failed to promote adequate granulation tissue formation. In a further retrospective study inclusive of 24 patients, Fluieraru et al.[55▪] assessed the effectiveness of NPWTi using normal saline in patients with deep inaccessible or infected wounds, or in wounds that had failed to heal with traditional NPWT. Although diabetes was only a comorbidity in 33% of the cohort, positive outcomes were observed in 23 of 24 patients who received NPWTi with normal saline [55▪].
Two key retrospective cohort-controlled studies compare NPWT with NPWTi in the treatment of acutely or chronically infected wounds [27▪,56▪]. The first study by Kim et al.[27▪] included 142 patients (58% with diabetes mellitus) and demonstrated statistically significant outcomes relating to reduced length of hospital stay, reduced number of operative visits and reduced time to final surgical procedure with NPWTi utilizing Prontosan wound irrigation solution compared with NPWT alone. The second study by Gabriel et al.[56▪] retrospectively compared outcomes in 82 patients with infected or critically colonized wounds treated with NPWTi (physiological saline or Prontosan instillation fluid) or traditional NPWT. Unfortunately, this study did not outline the prevalence of diabetes in either cohort. However, patients in the NPWTi group underwent fewer operative debridements (P < 0.0001), had faster wound healing (P < 0.0001) and required fewer days in hospital (P < 0.0001) compared with those receiving NPWT. Furthermore, cost analysis demonstrated that the overall cost of care was reduced in patients in the NPWTi cohort [56▪]. Although findings from these studies appear promising, they are both particularly vulnerable to selection bias due to their retrospective, nonrandomized designs. Consequently, the associated findings must be interpreted with caution.
The benefits of NPWT are well documented in the treatment of a variety of complex acute or chronic wounds, including noninfected postoperative diabetic wounds and DFUs [10▪,13–15]. Combining intermittent wound irrigation with NPWT may offer additional benefits to NPWT alone including further reduction of wound bed bioburden [19▪,25,26,27▪], increased granulation tissue formation [40▪▪,57,58] and the ability to provide wound irrigation in a sealed environment, thus preventing potential cross-contamination events [18▪].
Management of diabetic foot infections requires a multidisciplinary approach and involves systemic antimicrobial therapy, surgical debridement and intensive postoperative wound management. High-quality evidence relating to the utilization of NPWTi in diabetic foot infections is limited; however, it has been utilized successfully as a component in the management of these complex infections [27▪,40▪▪,53,54,55▪]. A particular strength of NPWTi is its ability to encourage the formation of wound granulation tissue compared with NPWT [55▪]. Although not exclusively inclusive of diabetic patients, a recent prospective cohort-controlled study concludes that NPWTi with Prontosan was superior to NPWT alone in the treatment of acutely infected wounds [27▪]. This evidence is promising and should now prompt the design and development of high-quality, adequately powered RCTs to compare NPWT with NPWTi in this patient group.
Instillation fluids utilized with NPWTi must be compatible with the device used and potential risks, including hypersensitivity reactions and serum-concentration-related toxicity, must be fully evaluated prior to use. Good-quality evidence relating to the use of instillation fluids in NPWTi systems is lacking, however, consensus statements devised by an expert panel are available for guidance [12▪▪].
Although evidence relating to the use of NPWTi in patients with diabetic foot infections is limited, findings to date appear promising. Challenges in this area relate to the potential difficulty in standardization of practice, especially in relation to the available variety of instillation fluids and treatment protocols. As well as exploring the efficacy of available instillation fluids, well designed, randomized studies are required to confirm or refute the benefits of NPWTi vs. NPWT in diabetic foot infections.
The authors have not received any financial support and/ or sponsorship from any organization.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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