Negative-pressure wound therapy (NPWT) is

WOU HEALING Negative-Pressure Wound Therapy: A Comprehensive Review of the Evidence Ersilia L. Anghel, BS, BA Paul J. Kim, DPM, MS, FACFAS Washington, D.C. Background: Negative-pressure wound therapy (NPWT) and its variations are an established adjunctive modality for the treatment of wounds. Since its introduction, there have been an increasing number of publications with periods of rapid increases in the number of publications after innovations to the technology. Its application in different wound types and varying clinical scenarios has also contributed to the growing number of publications. Methods: A comprehensive literature review (1998 2016) was performed using key words most relevant to NPWT using PubMed/Medline and OVID. Eligibility criteria included higher level evidence studies. Results: One thousand three hundred and forty-seven publications were identified. A total of 26 publications are included in this review: 16 comparing NPWT with standard wound dressing, 6 comparing variations of NPWT, and 4 for NPWT with instillation. The level of evidence, wound type studied, reported outcomes and impact, and key findings are tabulated and discussed. Conclusions: The number of publications has grown significantly since the inception of NPWT. In part, this reflects the variations of NPWT that have developed. However, a greater number of robust, randomized, prospective studies are needed to support its wide spread use. (Plast. Reconstr. Surg. 138: 129S, 2016.) Negative-pressure wound therapy (NPWT) is considered a standard adjunctive treatment option for the management of a variety of wound types and anatomical locations. Although there is a large volume of already published articles and a continuously increasing number of articles on this topic, some reviews, editorials, and commentaries report on the lack of evidence for NPWT. The objective of this review is to provide a comprehensive review of the literature with an emphasis on evidence from randomized controlled trials, summarize validated findings, and identify areas that could benefit from further study. In addition, we comment on the trends in publication on NPWT and the global distribution of articles. OVERVIEW OF NPWT NPWT is a powerful adjunct to surgical management of a wound or can be used in From the Division of Wound Healing and Hyperbaric Medicine, Department of Plastic Surgery, MedStar Georgetown University of Hospital; and Division of Wound Healing and Hyperbaric Medicine, Department of Plastic Surgery, Georgetown University School of Medicine. Received for publication February 5, 2016; accepted May 7, 2016. Copyright 2016 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000002645 circumstances where surgery is not possible. Once a wound is clean and well vascularized, NPWT can expedite healing by secondary intention. It is thought to aid in wound healing by a number of mechanisms, including macrodeformation, microdeformation, fluid removal, and optimization of the wound environment. 1 Macrodeformation is a gross reduction in wound size because of the centripetal forces of the negative-pressure dressing, in addition to an increase in wound bed tissue pressure caused by the negative pressure. It is worth noting that the effects of macrodeformation are highly depend on tissue type. 1 Microdeformation is specific to NPWT devices that use a porous foam at the wound interface and leads to increased cellular differentiation, thermoregulation, neurocutaneous activation, and inflammatory control. 1 Finally, NPWT optimizes the wound environment through fluid removal with some moisture retention and reduction of bacterial load. The molecular mechanisms by which NPWT acts on the wound bed continues to be controversial but is thought to include a modulation of Disclosure: P. J. Kim has received research and consulting funding from KCI, an ACELITY Company, a m anufacturer of negative-pressure wound therapy devices. E. L. Anghel has nothing to disclose. www.prsjournal.com 129S

Plastic and Reconstructive Surgery September Supplement 2016 cytokines to an anti-inflammatory profile and signaling mediated through mechanoreceptors and chemoreceptors. 2 This culminates in angiogenesis, extracellular matrix remodeling, and finally deposition of granulation tissue. 2 TYPES OF NPWT NPWT systems require a vacuum source, dressing, and drainage tubing. The dressing is usually secured with adhesive tape to seal the wound. Typically, the NPWT system is changed every 2 to 3 days, making the wound less susceptible to cross contamination when compared with the normal level of contamination that occurs when the dressing is changed 2 or 3 times each day. This negative-pressure system can be applied to the open wound bed directly (standard NPWT or NPWT) or to a closed incision, which is known as incisional NPWT (inpwt). Redon bottles (highvacuum drainage bottles) were one of the early vacuum sources used for vacuum therapy, but this approach is limited by decline in negative pressure as the canister is filled. 3 Forming a seal using foam or using moistened gauze is needed to evenly distribute the negative pressure throughout the wound. Systems using foam have the added benefit of microdeformation. NPWT system devices can be portable [ie, SMART NEGATIVE PRESSURE Therapy (SNAP Therapy; KCI, an ACELITY Company, San Antonio, Texas)] or fixed [ie, VAC- UUM ASSISTED CLOSURE Therapy (V.A.C. Therapy; KCI, an ACELITY Company, San Antonio, Texas)] for inpatient use only. An additional variation is the use of NPWT with instillation (NPWTi), which allows for irrigation with an assortment of solutions from antibiotics to normal saline. NPWTi is a relatively novel variation to traditional therapy that combines negative pressure ( 125 to 150 mm Hg) with automated, intermittent instillation of a topical wound solution of set volume (until sponge is visibly saturated), dwell time (10 20 min), frequency (every 1.5 2 h), and duration (2 10 d). Other variations to NPWT are currently being explored, including the use of different pore sizes in systems that use foam and incorporation of dermal scaffold materials. 1 METHODS A comprehensive search was conducted for indexed published articles extracted from the following databases: PubMed/Medline and OVID from 1998 to January 2016 by a medical digital information librarian. The following search terms were used: negative pressure wound therapy, negative pressure wound therapy with instillation, negative pressure dressing, incisional negative pressure wound therapy, and vacuum pressure dressing. A review of citations from source documents was completed, and those articles that contained search terms were also included barring exclusion criteria. All search results were exported to a spreadsheet for organized review. Collected articles were read in abstract form to screen for the inclusion and exclusion criteria (Table 1). Quality evaluation was performed by noting the study type, model, and cohort numbers. Articles scientific merit and the accuracy of statistical analysis were not evaluated. There was no distinction made between industry-sponsored studies and investigator-initiated studies. Human studies were considered for further review. Of those, only randomized controlled trials with total cohorts greater or equal to 30 individuals were included. Articles achieving this criterion were reviewed in full. Articles were categorized by those that discussed: NPWT compared with standard wound dressing, NPWT variations, and NPWTi. Data items extrapolated from clinical studies included wound type, cohort size, control therapy, experimental therapy, primary aims, primary outcomes, and summary statement (Table 2). Each study s level of evidence for therapeutic studies was rated per the American Society of Plastic Surgeons Guidelines. 4 Table 1. Inclusion and Exclusion Criteria Inclusion Exclusion 1. Application of NPWT (with or without instillation, any solution) after primary incision 1. Non-English language articles closure immediately at the end of the surgical procedure 2. Application of NPWT (with or without instillation, any solution) after debridement to 2. Sample of <30 patients temporize definitive wound closure, immediately at the end of the surgical procedure 3. Articles in English 3. Articles published before 1998 4. Articles published from 1998 to December 2015 4. Cost effectiveness studies 5. Human studies, experimental animal or bioengineering studies 5. Technique articles 6. Sample of 30 patients if it is a human study 6. Articles lacking abstracts 7. Randomized control trial study design 130S

Volume 138, Number 3S Negative-Pressure Wound Therapy Review Table 2. Data Extrapolation from Clinical Studies Data Point Publication date Authors Country Journal Study design Level of evidence Patient wound type Control treatment Experimental treatment NPWT device type NPWTi solution type Outcomes Infection/dehiscence Length of hospital stay Time to wound healing % granulation tissue Reoperation Recurrence Complications Duration of treatment application STSG take Time to final closure RESULTS After the screening process was performed, a total of 23 publications are included in this review: 16 comparing NPWT with standard wound dressing, 6 comparing variations of NPWT, and 1 comparing solutions for NPWTi (Fig. 1). An additional 3 retrospective cohort-controlled studies are included in the discussion of NPWTi because of the relative novelty of this technology. All studies received a grade of I or II for the level of evidence per American Society of Plastic Surgeons Guidelines (Tables 3 5). 4 The geographic distribution of publications is global with the majority of publications occurring in the United States (43%), England (29%), Fig. 1. Scheme of this review performed. The Netherlands (7%), and Germany (5%) (Fig. 2). The number of annual publications on NPWT, before exclusion by screening, showed a significant rise in output in 2007 to 2008 and 2015 (Fig. 3). The number of publications range from 1 to 4 between 1998 and 2006, escalated to 26 in 2007, and range from 116 to 182 between 2008 and 2014. In 2015, there are 269 publications on this topic. NPWT versus Standard Wound Dressing There are a total of 16 randomized controlled trials that compare NPWT with standard wound dressing (Table 3). Three studies specifically investigated the use of inpwt in the management of surgically closed wounds. 15,16,19 Seven studies investigated the complicated wounds in diabetic patients, either following amputations, significant surgical intervention, or chronic stable ulcers. 8 14 The consensus was that NPWT is safe, effective, and reduces operative interventions for complicated wounds in diabetic patients. Although, in another study, patients with more than 2 comorbidities and closed surgical wounds did not have a reduction in infection after treatment with inpwt when compared with standard dressing changes. 15 Four studies evaluated the use of NPWT for split thickness skin graft (STSG) retention, with 3 specifically investigating the use in acute injury or burn patients. 5 7 All found that NPWT pressure resulted in better outcomes than standard dressing, whether used for wound bed preparation for STSG or post-stsg application. The use of NPWT after skin-grafted free muscle flaps resulted in reduced inflammatory response and edema formation. 20 Two studies commented on the use of inpwt over closed posttraumatic wounds and in open high-risk traumatic fractures and found decreased rates of infection. 16,17 The use of standard NPWT in damage control laparotomy, abdominal compartment syndrome, and the use of inpwt status post elective hip arthroplasty was not found to be superior to standard treatments. 18,19 NPWT Variations A total of 6 randomized controlled trials compared variations of NPWT (Table 4). Two studies compared VACUUM ASSISTED CLOSURE Therapy (V.A.C. Therapy; KCI, an ACELITY Company, San Antonio, Texas) and SMART NEGATIVE PRESSURE Therapy (SNAP Therapy; KCI, an ACELITY Company, San Antonio, Texas). 21,22 In noninfected lower extremity diabetic and venous wounds, both treatments 131S

Plastic and Reconstructive Surgery September Supplement 2016 Table 3. Summary of Randomized Controlled Trials on NPWT versus Standard of Care* Reference LOE Wound Type (n) Outcomes Findings P Key Finding Apelqvist et al 8 II Diabetic: postamputation (up to TM level) in diabetic patients (162) Armstrong I Diabetic: et al 9 diabetic foot ulcers, particularly secondary to amputation (162) Sajid I Diabetic: et al 13 diabetic foot ulcer (278) Blume I Diabetic: et al 11 diabetic foot ulcers (342) Tuncel et al 10 II Infected draining venous, diabetic, traumatic ulcers (50) Vaidhya II Diabetic: et al 14 diabetic foot ulcers (60) Karatepe et al 12 II Diabetic: chronic diabetic foot ulcers (67) Petkar II STSG: postet al 6 STSG in burn patients (100) Saaiq et al 7 II STSG: pre-stsg in acute traumatic injury: 10 d wound bed preparation (100) Bloemen et al 5 I STSG: post- STSG with dermal substitute in burn patients (86) Eisenhardt et al 20 II STSG: postoperative skin-grafted free muscle flaps (30) Hospital stay Operative interventions (n) Dressing changes (n) Healed Granulation tissue (d) Adverse events Reamputation Wound surface area at 2 wk (cm 2 ) Complete ulcer closure Secondary amputations Complications (infection, cellulitis, and osteomyelitis) Size reduction at 3 wk (cm 2 ) Recurrence at 12 mo (n) Culture negative at 12 mo (n) Mean (n) dressing Ready for closure with STSG or suturing (d) Quality of life (SF-36) Healing time (wk) Continued dressings after surgery (d) Graft take at 9 d Graft take (>95%) Wound healing time (2 wk post STSG) Regrafting Hospital stay (<3 wk) Graft take Epithelialization Postop contamination Skin elasticity (12 mo) Inflammation: CD68 + IL1-β TNF-α Interstitial edema Apoptotic cells 10.6 NPWT vs 9.9 C 43 NPWT vs 120 C 41 (range: 6 140) NPWT vs 118.0 (range: 12 226) C 56% NPWT vs 39% C 42 NPWT vs 84 C 52% NPWT vs 54% C 0.225 RR for NPWT vs C 11.5 ± 2.8 NPWT vs 13.7 ± 2.9 C 43.2% NPWT, vs 28.9% C 4.1% NPWT, vs 10.2% C 2.4% NPWT, vs 0.6% C 72.1 ± 75.8 NPWT vs 98.4 ± 100.9 C 2 NPWT vs 14 C 22 NPWT vs 16 C 7.5 ± 2.3 NPWT vs 69.8 ± 11.9 C 17.2 ± 3.55 NPWT vs 34.9 ± 5.96 C NPWT > C in MCS and PCS 5.3 ± 1.4 NPWT vs 4.2 ± 1.9 C 8 ± 1.48 NPWT vs 11 ± 2.2 C 96.7 ± 3.55% NPWT vs 7.5 ± 8.73% C 90% NPWT vs 18% C 90% NPWT vs 18% C 0% NPWT vs 8% C 10% NPWT vs 74% C 94.8% NPWT vs 92.4% C 91.7% NPWT vs 85.3% C 71% NPWT vs 76% C 0.80 NPWT vs 0.51 C 2 NPWT vs 2.8 C 11 NPWT vs 16.5 C 8 NPWT vs 10.5 C 3% NPWT vs 9% C 25 NPWT vs 40 C < 0.0001 0.040 0.010 (0.875) 95% CI (0.5 1.1) NPWT reduces operative interventions (including debridement) and dressing changes NPWT is a safe and more effective treatment for DFU than standard dressing and reduces the RR for reamputation There is evidence for the superiority of NPWT in diabetic foot ulcer healing 0.007 0.035 (0.371) 0.047 0.03, 0.004 < < N/A (0.552) (0.433) 0.042 0.027 <0.01 < <0.01 <0.01 NPWT is more efficacious than control and equally safe in achieving complete diabetic foot ulcer closure NPWT is safe and superior in managing challenging infected wounds compared to standard dressing Rate of healing is faster with NPWT and fewer dressing changes are required NPWT is effective in treatment of DFU and improves quality of life NPWT improves graft take in burn patients and reduces number of dressing changes post-op NPWT improves graft take when used as pretreatment of wound bed and reduces rates of regrafting along with hospital stay NPWT reduces post-op contamination after STSG and results in greater skin elasticity at 12 mo post-op NPWT leads to a reduced inflammatory response following ischemia/reperfusion, and reduced edema formation (Continued) 132S

Volume 138, Number 3S Negative-Pressure Wound Therapy Review Table 3. (Continued) Reference LOE Wound Type (n) Outcomes Findings P Key Finding Stannard et al 17 I Trauma: severe high-energy open fractures (59) Stannard et al 16 I Trauma: highrisk fracture types in lower extremity blunt trauma (249) Masden I Other: surgical et al 15 incision in patients with >2 comorbidities (81) Gillespie I Other: postoperative et al 19 elec- tive primary hip arthroplasty (70) Bee et al 18 I Other: damage control laparotomy/ abdominal compartment syndrome (48) Acute infection Delayed infection Deep infection Total infection Dehiscence Infection Wound Infection Dehiscence Reoperation Surgical site infection Wound complications Delayed primary fascial closure rates Fistula rates 0% NPWT vs 8% C 5.4% NPWT vs 20% C 5.4% NPWT vs 28% C NPWT < C; RR, 0.199; 95% CI, 0.045 0.874 for NPWT 8.6% inpwt vs 16.5% C 1% inpwt vs 18.8% C 1.9 RR for C vs inpwt 6.8% inpwt vs 13.5% C 36% inpwt vs 29.7% C 21% inpwt vs 22% C 5.7% inpwt vs 8.6% C 1.6 RR for inpwt vs C 31% NPWT vs 26% MESH 21% NPWT vs 5% MESH 0.024 0.044 0.049 95% CI (1 3.6) (0.46) (0.54) (0.89) (0.65) 95% CI (1 2.5) NPWT used as prophylactic treatment in traumatic open fractures reduces infection overall when compared with standard dressing inpwt decreases the risk for infection and dehiscence when used as prophylactic treatment inpwt does not reduce post-op infection or dehiscence in patients with >2 comorbidities These is uncertainty around the benefit of inpwt after elective hip arthroplasty MESH and NPWT are equivalent. J-tubes are recommended to avoid fistulas with NPWT C, standard of care; CI, confidence interval; DFU, diabetic foot ulcer; IL, interleukin; J-tube, nasojejunal tube; LOE, level of evidence; MCS, mental component summary;, no difference; TM, transmetatarsal; PCS, physical component summary; RR, relative risk; SF-36, SF-36 questionnaire; TNF, tumor necrosis factor. *Standard of care included: moist and dry dressings. Polyglactin mesh, hydrogels, alginates, and petroleum gauze. resulted in similar outcomes, 21 although SNaP was found to be superior in treating patients with venous leg ulcers in another study. 22 Two studies compared wall suction applied to sealed gauze dressing with VAC in patients with acute wounds and post-stsg; both found wall suction applied to sealed gauze dressing to be noninferior to VAC. 23,24 Patients with infected diabetic foot wounds had similar results whether they were treated with low- or high-pressure NPWT. 25 Finally, bulb suction drains were incapable of maintaining negative pressure in grade III or IV decubitus ulcers compared with VAC; thus, the trial was terminated before its completion. 26 NPWTi There is only 1 randomized controlled trial that has evaluated NPWTi; because of this, retrospective cohort-controlled studies were included in our findings (Table 5). Two studies compared moist dressing with NPWTi in trauma patients with osteomyelitis and complex infected wounds; both found NPWTi superior, citing a reduction in inpatient care requirements and surgical interventions. 27,28 NPWTi with normal saline compared with standard NPWT was found to be superior in patients with infected wounds requiring hospitalization. 29 Finally, the benefits of NPWTi were equivalent whether normal saline or antiseptic solution (0.1% polyhexanide + 0.1% betaine) was used in infected wounds requiring hospitalization. 30 DISCUSSION The prevalence of articles on the topic of NPWT has grown exponentially in the past decade. The first appreciable raise in publications was in 2007 to 2008 (Fig. 3); this may be related to the pivotal randomized controlled trial published by Armstrong et al 9 on the use of NPWT for partial diabetic foot amputation in 2005. This contribution to the literature validated the use of NPWT in complex wounds and opened the door for investigation of this therapy in other surgical specialties. Another jump in publications occurred in 2015, likely because of the article published by Kim et al 29 in 2014 comparing standard NPWT with NPWTi. This article showed improved outcomes and decreased infected wounds requiring hospitalization being treated with NPWTi. 29,30 133S

Plastic and Reconstructive Surgery September Supplement 2016 Table 4. Summary of Randomized Controlled Trials on NPWT Variations Reference LOE Armstrong I Diabetic: noninfected et al 21 lower extremity diabetic and venous wounds (132) Lavery II Diabetic: infected et al 25 diabetic foot wounds (40) Dorafshar II Traumatic: acute wounds et al 23 Wound Type (n) Treatment groups Outcomes Findings P s from trauma, dehiscence, surgery (87) A: SNaP B: VAC A: 75 mm Hg NPWT SCD B: 125 mm Hg NPWT PFD A: GSUC B: VAC Nguyen I STSG: post-stsg (104) A: GSUC et al 24 B: VAC Marston et al 22 ulcers (40) I Other type: venous leg Wild II Other type: pressure et al 26 ulcers grade III or IV (10*) A: SNaP B: VAC A: Redon drains B: VAC Wound reduction (%) (4, 8, 12, and 16 wk) Infection Wound closed surgically 50% area, volume reduction (4 wk) Wound reduction (%) Application (min) Pain Full take POD 4 5 Mean graft take Wound closure 30 d (n) Wound closure 90 d (n) Granulation tissue Fibrin tissue Necrosis B > A at time 0 A: 33, 44.6, 49.5, 52.9 B: 23.7, 40.7, 39.6, 42.7 A: 3.1%, B: 7.4% A: 50% B: 60% A: 65%, 95% B: 80%, 90% A: 4.5/d, B: 4.9/d A: 19, B: 31 A: 0.50, B: 1.73, 0.96 A: 80%, B: 78% 0.80 A: 96.12%, B: 96.21% 0.80 0.98 A: 52.6%, B: 23.8% A: 57.9%, B: 38.2% A: 7.1%, B: +54% A: +21.8%, B: 27% A: 15%, B: 0.3%, 0.60 0.01 0.02 0.03 0.035, 0.598 Similar wound healing outcomes are found between SNaP and VAC systems There is no difference between low pressure SCD and high pressure PFD NPWT. GSUC is noninferior to VAC with respect to wound area, easier to apply, and less painful GSUC is noninferior to VAC in securing STSG and results in a comparable outcome Supports the use of SNaP in venous leg ulcers Redon drains are not a good alternative for commercial NPWT GSUC, wall suction applied to sealed gauze dressing; LOE, level of evidence;, no difference; PFD, polyurethane foam dressing at 125 mm Hg; POD, postoperative day; SCD, silicone-covered dressing at 75 mm Hg; STSG, split thickness skin graft. *Post hoc analysis revealed need to terminate study because Redon bottle was significantly inferior to commercial NPWT. Table 5. Summary of Trials on NPWT with Instillation Reference LOE Wound Type (n) Treatment Groups Outcomes Findings P Key Finding Gabriel et al 27 * Kim et al 29 Kim et al 30 Timmers et al 28 * II Complex infected wounds (30) II Infected wounds requiring hospitalization (142) I Infected wounds requiring hospitalization (100) II Osteomyelitis in traumatology (124) A: Moist dressing B: NPWTi A: NPWT B: NPWTi, 6 min C: NPWTi, 20 min NPWTi with: A: normal saline, B: antiseptic* A: Moist dressing B: NPWTi with Antiseptic *Retrospective cohort-case study. Randomized controlled trial. 0.1% polyhexanide + 0.1% betaine. FSP, final surgical procedure; LOE, level of evidence;, no difference. Treatment (d) Inf. resolved (d) Wound closed (d) Hospital stay (d) Surgical interventions (n) Hospital stay (d) Time to final surgery (d) Surgeries (n) Hospital stay (d) Time to FSP (d) Closed/covered at 1 mo Surgeries(n, range) Hospital stay (d) Recurrence A: 36.5 ± 13.1, B: 9.9 ± 4.3 A: 25.9 ± 5.4, B: 6 ± 1.5 A: 29.6 ± 6.5, B: 13.2 ± 6.8 A: 39.2 ± 12.1, B: 14.7 ± 9 A: 3.0 ± 0.9, B: 2.4 ± 0.9, C: 2.6 ± 0.9 A: 14.92 ± 9.23, C: 11.4 ± 5.1 A: 9.23 ± 5.2, B: 7.8 ± 5.2, C: 7.5 ± 3.1 A: 2.5 ± 0.9, B: 2.8 ± 0.9 A: 13.6 ± 12, B: 14.5 ± 9 A: 5.7 ± 3.8, B: 7.7 ± 5.5 A: 69% vs B: 65% A: 5 (1 4), B: 2 (2 42) A: 73, B: 36 A: 58%, B: 10%, 0.19, 0.68 0.04, 0.83 0.0001 0.0001 0.0001 NPWTi may reduce inpatient care requirements for complex infected wounds NPWTi with normal saline is better than standard NPWT for infected wounds Normal saline maybe be as effective as an antiseptic for NPWTi in infected wounds Posttraumatic osteomyelitis treated with NPWTi reduces surgical interventions 134S

Volume 138, Number 3S Negative-Pressure Wound Therapy Review Fig. 2. Pie chart of the global distribution of articles published on negative-pressure wound therapy from 1998 to 2016. The global distribution of publications on NPWT is broad and includes many countries that have contributed less than 10 articles to the literature (Fig. 2). From this, one can gather that the use of NPWT is widespread internationally, although no article exists discussing the usage prevalence of NPWT globally. Interestingly, the United States and England have the greatest volume of literature on the topic, likely reflecting their pervasive use of this therapeutic modality. The use of this technology in countries with fewer publications cannot be taken at reflect their usage, as this review was limited to English and Medline indexed articles only. NPWT has evolved from an inpatient therapy to a portable therapeutic modality and most recently includes the use of instillation. Throughout the last 10 years, the safety and efficacy of NPWT have been evaluated in burn patients and trauma patients, along with diabetic and medically complex patients, in both acute and chronic wounds. There remains some controversy over the use of NPWT for complicated wounds in diabetic patients. Although several randomized controlled trials showed superiority of NPWT over standard dressing, Masden et al 15 found that NPWT applied over closed incisions was nonsuperior to standard dressings in reducing infection or reoperation in wounds belonging to patients with more than 2 comorbidities. Although the body of literature on NPWT has grown to validate safety and effectiveness in a range of patient and wound types, there still remain gaps in knowledge. Portable NPWT has only been evaluated in 2 randomized controlled trials, one presenting equal outcomes to standard NPWT in noninfected lower extremity diabetic and venous wounds 21 and, in contrast, the other stating superiority of portable NPWT for venous leg ulcers. 21,22 Recent studies have shown promising findings for the superiority of NPWTi in infected wounds. 27 30 Unfortunately, 75% of the reported studies were retrospective cohort-controlled and hold less weight Fig. 3. Line graph representing the prevalence of articles on negative-pressure wound therapy over time. 135S

Plastic and Reconstructive Surgery September Supplement 2016 than randomized controlled trials. There is a need for more prospective randomized controlled trials comparing NPWTi with NPWT and standard dressing to develop the existing evidence. CONCLUSIONS NPWT has a role in managing chronic, complex, and infected wounds. Here we cite randomized controlled trials validating superiority of NPWT in certain patient populations along with some articles that describe equivalency of this therapeutic modality. Clearly, NPWT has changed the approach to the management of wounds. Technological advances in the interface dressings, occlusive drapes, the user interface, solution delivery, and portability have triggered spikes in the number of publications in the past and will similarly result in a greater number of future publications. A concerted effort is needed to publish research focused on identifying the mechanism of action and cost-effectiveness of this technology. Paul J. Kim, DPM, MS, FACFAS Division of Wound Healing and Hyperbaric Medicine Department of Plastic Surgery Georgetown University School of Medicine 3800 Reservoir RD NW Washington, DC 20007 paul.j.kim@gunet.georgetown.edu REFERENCES 1. Huang C, Leavitt T, Bayer LR, et al. Effect of negative pressure wound therapy on wound healing. Curr Probl Surg. 2014;51:301 331. 2. Glass GE, Murphy GF, Esmaeili A, et al. Systematic review of molecular mechanism of action of negative-pressure wound therapy. Br J Surg. 2014;101:1627 1636. 3. Scientific basis, indications for use, case reports, advice. In: Willy C, ed. The Theory and Practice of Vacuum Therapy. Ulm, Germany: Lindqvist Book Publishing; 2006:405. 4. Sullivan D, Chung KC, Eaves FF 3rd, et al. The level of evidence pyramid: indicating levels of evidence in plastic and reconstructive surgery articles. Plast Reconstr Surg. 2011;128:311 314. 5. Bloemen MC, van der Wal MB, Verhaegen PD, et al. Clinical effectiveness of dermal substitution in burns by topical negative pressure: a multicenter randomized controlled trial. Wound Repair Regen. 2012;20:797 805. 6. Petkar KS, Dhanraj P, Kingsly PM, et al. A prospective randomized controlled trial comparing negative pressure dressing and conventional dressing methods on split-thickness skin grafts in burned patients. Burns 2011;37:925 929. 7. Saaiq M, Hameed-Ud-Din, Khan MI, et al. Vacuum-assisted closure therapy as a pretreatment for split thickness skin grafts. J Coll Physicians Surg Pak. 2010;20:675 679. 8. Apelqvist J, Armstrong DG, Lavery LA, et al. Resource utilization and economic costs of care based on a randomized trial of vacuum-assisted closure therapy in the treatment of diabetic foot wounds. Am J Surg. 2008;195:782 788. 9. Armstrong DG, Lavery LA; Diabetic Foot Study Consortium. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial. Lancet 2005;366:1704 1710. 10. Tuncel U, Erkorkmaz Ü, Turan A. Clinical evaluation of gauze-based negative pressure wound therapy in challenging wounds. Int Wound J. 2013;10:152 158. 11. Blume PA, Walters J, Payne W, et al. Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial. Diabetes Care 2008;31:631 636. 12. Karatepe O, Eken I, Acet E, et al. Vacuum assisted closure improves the quality of life in patients with diabetic foot. Acta Chir Belg. 2011;111:298 302. 13. Sajid MT, Mustafa Qu, Shaheen N, et al. Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers. J Coll Physicians Surg Pak. 2015;25:789 793. 14. Vaidhya N, Panchal A, Anchalia MM. A new cost-effective method of NPWT in diabetic foot wound. Indian J Surg. 2015;77(Suppl 2):525 529. 15. Masden D, Goldstein J, Endara M, et al. Negative pressure wound therapy for at-risk surgical closures in patients with multiple comorbidities: a prospective randomized controlled study. Ann Surg. 2012;255:1043 1047. 16. Stannard JP, Volgas DA, McGwin G 3rd, et al. Incisional negative pressure wound therapy after high-risk lower extremity fractures. J Orthop Trauma 2012;26:37 42. 17. Stannard JP, Volgas DA, Stewart R, et al. Negative pressure wound therapy after severe open fractures: a prospective randomized study. J Orthop Trauma 2009;23:552 557. 18. Bee TK, Croce MA, Magnotti LJ, et al. Temporary abdominal closure techniques: a prospective randomized trial comparing polyglactin 910 mesh and vacuum-assisted closure. J Trauma 2008;65:337 342. 19. Gillespie BM, Rickard CM, Thalib L, et al. Use of negativepressure wound dressings to prevent surgical site complications after primary hip arthroplasty: a pilot RCT. Surg Innov. 2015;22:488 495. 20. Eisenhardt SU, Schmidt Y, Thiele JR, et al. Negative pressure wound therapy reduces the ischaemia/reperfusionassociated inflammatory response in free muscle flaps. J Plast Reconstr Aesthet Surg. 2012;65:640 649. 21. Armstrong DG, Marston WA, Reyzelman AM, et al. Comparative effectiveness of mechanically and electrically powered negative pressure wound therapy devices: a multicenter randomized controlled trial. Wound Repair Regen. 2012;20:332 341. 22. Marston WA, Armstrong DG, Reyzelman AM, et al. A Multicenter randomized controlled trial comparing treatment of venous leg ulcers using mechanically versus electrically powered negative pressure wound therapy. Adv Wound Care (New Rochelle) 2015;4:75 82. 23. Dorafshar AH, Franczyk M, Gottlieb LJ, et al. A prospective randomized trial comparing subatmospheric wound therapy with a sealed gauze dressing and the standard vacuumassisted closure device. Ann Plast Surg. 2012;69:79 84. 24. Nguyen TQ, Franczyk M, Lee JC, et al. Prospective randomized controlled trial comparing two methods of securing skin grafts using negative pressure wound therapy: vacuum-assisted closure and gauze suction. J Burn Care Res. 2015;36:324 328. 25. Lavery LA, La Fontaine J, Thakral G, et al. Randomized clinical trial to compare negative-pressure wound therapy approaches with low and high pressure, silicone-coated 136S

Volume 138, Number 3S Negative-Pressure Wound Therapy Review dressing, and polyurethane foam dressing. Plast Reconstr Surg. 2014;133:722 726. 26. Wild T, Stremitzer S, Budzanowski A, et al. Definition of efficiency in vacuum therapy a randomised controlled trial comparing with V.A.C. therapy. Int Wound J. 2008;5:641 647. 27. Gabriel A, Shores J, Heinrich C, et al. Negative pressure wound therapy with instillation: a pilot study describing a new method for treating infected wounds. Int Wound J. 2008;5:399 413. 28. Timmers MS, Graafland N, Bernards AT, et al. Negative pressure wound treatment with polyvinyl alcohol foam and polyhexanide antiseptic solution instillation in posttraumatic osteomyelitis. Wound Repair Regen. 2009;17:278 286. 29. Kim PJ, Attinger CE, Steinberg JS, et al. The impact of negative-pressure wound therapy with instillation compared with standard negative-pressure wound therapy: a retrospective, historical, cohort, controlled study. Plast Reconstr Surg. 2014;133:709 716. 30. Kim PJ, Attinger CE, Oliver N, et al. Comparison of outcomes for normal saline and an antiseptic solution for negative-pressure wound therapy with instillation. Plast Reconstr Surg. 2015;136:657e 664e. 137S