ORIGINAL ARTICLE. doi: /iwj Medicalhelplines.com Inc and John Wiley & Sons Ltd. International Wound Journal ISSN

Transcription

1 International Wound Journal ISSN ORIGINAL ARTICLE Improving wound healing and preventing surgical site complications of closed surgical incisions: a possible role of Incisional Negative Pressure Wound Therapy. A systematic review of the literature Alessandro Scalise 1, Roberto Calamita 1, Caterina Tartaglione 1, Marina Pierangeli 1, Elisa Bolletta 1, Matteo Gioacchini 1, Rosaria Gesuita 2 & Giovanni Di Benedetto 1 1 Department of Plastic and Reconstructive Surgery, Università Politecnica delle Marche, Ancona, Italy 2 Interdepartmental Centre of Epidemiology, Biostatistics and Medical Informatics (EBI Centre), Università Politecnica delle Marche, Ancona, Italy Key words Closed wounds; Incisional Negative Pressure Wound Therapy; Surgical incision; Surgical wound infection; Wound healing Correspondence to A Scalise Department of Plastic and Reconstructive Surgery Università Politecnica delle Marche Via Conca 71, Torrette Ancona 60126, Italy chiplast@univpm.it, alescalise1@gmail.com, a.scalise@univpm.it doi: /iwj Scalise A, Calamita R, Tartaglione C, Pierangeli M, Bolletta E, Gioacchini M, Gesuita R, Di Benedetto G. Improving wound healing and preventing surgical site complications of closed surgical incisions: a possible role of Incisional Negative Pressure Wound Therapy. A systematic review of the literature. Int Wound J 2016; 13: Abstract Advances in preoperative care, surgical techniques and technologies have enabled surgeons to achieve primary closure in a high percentage of surgical procedures. However, often, underlying patient comorbidities in addition to surgical-related factors make the management of surgical wounds primary closure challenging because of the higher risk of developing complications. To date, extensive evidence exists, which demonstrate the benefits of negative pressure dressing in the treatment of open wounds; recently, Incisional Negative Pressure Wound Therapy (INPWT) technology as delivered by Prevena (KCI USA, Inc., San Antonio, TX) and Pico (Smith & Nephew Inc, Andover, MA) systems has been the focus of a new investigation on possible prophylactic measures to prevent complications via application immediately after surgery in high-risk, clean, closed surgical incisions. A systematic review was performed to evaluate INPWT s effect on surgical sites healing by primary intention. The primary outcomes of interest are an understanding of INPWT functioning and mechanisms of action, extrapolated from animal and biomedical engineering studies and incidence of complications (infection, dehiscence, seroma, hematoma, skin and fat necrosis, skin and fascial dehiscence or blistering) and other variables influenced by applying INPWT (re-operation and re-hospitalization rates, time to dry wound, cost saving) extrapolated from human studies. A search was conducted for published articles in various databases including PubMed, Google Scholar and Scopus Database from 2006 to March Supplemental searches were performed using reference lists and conference proceedings. Studies selection was based on predetermined inclusion and exclusion criteria and data extraction regarding study quality, model investigated, epidemiological and clinical characteristics and type of surgery, and the outcomes were applied to all the articles included. 1 biomedical engineering study, 2 animal studies, 15 human studies for a total of 6 randomized controlled trials, 5 prospective cohort studies, 7 retrospective analyses, were included. Human studies investigated the outcomes of 1042 incisions on 1003 patients. The literature shows a decrease in the incidence of infection, sero-haematoma formation and on the re-operation rates when using INPWT. Lower level of evidence was found on dehiscence, decreased in some studies, and was inconsistent to make a conclusion. Because of limited studies, it is difficult to make any assertions on the other variables, suggesting a requirement for further studies for proper recommendations on INPWT Medicalhelplines.com Inc and John Wiley & Sons Ltd

2 A. Scalise et al. Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications Introduction Incisional wound healing is an orchestra of biological and molecular events such as cell migration, proliferation and of extracellular matrix storing and remodelling. Certain pathophysiological and metabolic conditions can alter this healing milieu and thereby impair or delay healing. The increase in number and the complexity of trauma and the improved techniques and technology that allow for surgical procedures on patients with a higher baseline risk of surgical site complications, have contributed to the escalating complexity of wounds, which surgeons are expected to manage (1). Often, the management of these patients remains challenging because of the high rate of post-operative wound complications development. Risk factors used to asses surgical wounds post-operative complications risk can be classified as trauma-related (soft tissue injury or fracture, type) surgery-related (incision placement, surgical site contamination, technique, operative time, estimated blood loss) or patient-related (morbid obesity, multiple significant comorbidities, drugs, nicotine abuse). Primary closed incisions with a high risk of complications include those from hip and knee arthroplasty (2), lower extremities bypass (3), abdominal laparotomy (4,5), and cardiothoracic procedures (6), in particular those performed during the harvesting of bilateral internal mammary arteries (7). In addition, surgical defects such as an excessive suture tension or a protracted hospital stay may adversely affect incisional healing. It has been shown that there is an increased risk of infection in patients presenting morbid obesity, diabetes mellitus, peripheral vascular disease or coronary artery disease, renal failure, severe chronic obstructive pulmonary disease, extended use of mechanical ventilation and preoperative malnutrition (8 11). All these comorbidities in addition to risk factors like nicotine abuse, radiation or chemotherapy, and use of steroid or immunosuppressive drugs, present potential challenges in maintaining incision closure after an open surgical procedure (12 14). Incisional closure complications can include post-operative superficial surgical site infection (SSI) (15 20), which accounted, as reported by Stannard et al., (15) for 17 22% of health care-associated infections (16 18), wound cellulitis (21), surgical wound separation or fascial dehiscence that range from 0 25% to 3% (post laparotomies), 1 6% to 42 3% (post-caesarean incisions) and 0 5% to 2 5% (after sternal incisions) (15,22 24), formation of haematomas or seromas, skin and fat necrosis, and can lead to delayed or impaired healing of the incision. Methods to close an incision may range from sutures (25) to nitinol staples, adhesive strips, liquid skin adhesive (26) or a combination thereof. Wilkes et al. (27) demonstrated that in patients with a higher baseline risk of surgical site complications, the use of suture and staples induces elevated stress concentrations that can cause ischemia, fibrosis, or other tissue injury. The management of clean, closed surgical incisions diversify from preoperative prophylactic precautions as well as microbial sealants (28), intra-operative devices like prophylactic gentamycin-collagen sponges (29) to post-operative measures. Post-operative measures range from conventional Key Messages underlying patient comorbidities in addition to surgical-related factors often make the management of surgical wounds primary closure challenging because of the higher risk of developing complications surgical incision complications include post-operative surgical site infections, surgical wound dehiscence, formation of hematomas and seromas, skin and fat necrosis and skin and fascial dehiscence or blistering Iincisional Negative Pressure Wound Therapy seems to be a useful prophylactic measure in the incidence of infection and sero-hematoma formation and in decreasing re-operation rates when applied over closed surgical incisions and so can be considered to be potentially cost saving especially in high-risk patients dressing of sterile dry gauzes (5), debriding agents and topical antimicrobial dressing, to more advanced wound dressings in an effort to stimulate the proliferative phase of wound healing, including hydrocolloids (5), topical application of autologous blood products (30), growth factors (31), cultured skin (32) and Negative Pressure Wound Therapy (NPWT) (3,6,33). The evidence that supports the benefits of Negative Pressure Wound Vacuum Therapy in improving healing, as an adjunctive therapy, in the management of difficult open wounds, has been widely described in literature (34 46); however, its application in closed incisions is not characterised so well. Since the introduction of this portable and practical device in clinical practise in the 1990s, the acute and chronic open wounds management s landscape has been dramatically revolutionised (44,47 51). NPWT involves the controlled application of intermittent or continuous sub-atmospheric pressure to the wound bed typically via a pressure-manifolding dressing. Two main mechanisms are proposed to explain the accelerated rate of wound healing: a fluid-based mechanism with the removal of the excessive interstitial fluid and toxic inflammatory mediators from the subcutaneous tissue and a wound surface s microdeformation mechanism, which is cited as a cellular proliferative mechanism (52). Besides, NPWT promotes a moist wound-healing milieu, decreases bacterial colony counts, reduces the permeability of blood vessels and increases granulation tissue, cutaneous blood flow to the wound margins (53) and angiogenesis (54 56). The formation and organisation of the platelet plug between skin edges, is also enhanced, probably for the increased vascular perfusion (57). Besides, NPWT acts by stimulating cell-mediated immune response and fibroblast viability, migration and proliferation already 48 hours after its application (58). Additionally, the mechanical friction of gauze (under negative pressure) on either side of the wound may contract and even act as a splint against tensile forces across the wound (57). This technology has been rapidly introduced into a wide array of conditions, such as open acute and chronic wounds, burns, pressure ulcers, skin grafts, large abdominal hernias and complex abdominal wall reconstruction (44,47,59). While NPWT technology is an established and accepted treatment for non-healing wounds and open surgical incisions following infection or breakdown, a small but growing 2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd 1261

3 Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications A. Scalise et al. number of clinical studies have been published based on the hypothesis that negative pressure dressings improve healing of closed (sutured) wounds. These studies evaluated a novel application of NPWT immediately after surgery to high-risk surgical closed incisions (Incisional Negative Pressure Wound Therapy, INPWT) as delivered by Prevena (Incision Management System, Kinetic Concepts Inc. USA, San Antonio, TX) and Pico systems (Smith & Nephew Inc, Andover, MA) as a prophylactic measure specifically designed to help prevent the development of wound healing complications like infection or dehiscence (15). Prevena Incision Management system consists of a vacuum therapy suction unit that is connected to a dressing tube by a canister for fluid collection, and a precut peel-and-place reticulated open-cell foam dressing specifically designed for use over closed surgical incisions that are at high risk for post-surgical complications. To provide flexibility for application to anatomical contours, the dressing has a plated non-adherent layer surrounding the foam and a semi-permeable adhesive drape. The dressing contains ionic silver (0 019%) to prevent bacterial growth and the system is supplied with a carrying case to minimise the effects on patient mobility. In particular, the use of Prevena intends to provide an innovative and effective negative pressure dressing to improve incisional healing by protecting the wound from external contamination through the maintenance of a closed and sterile environment, keeping the wound edges together, equalising the strain in the tissue and off-loading midline tension on the skin incisions, thus diminishing resistance and tension on the wound overall as well as via the application of the beneficial effects of NPWT (removing fluids and components in these fluids by the application of negative pressure therapy preset at 125 mmhg, stimulation of cell proliferation, reduction of inflammatory mediators, increasing arterial and subcutaneous oxygen partial pressure, reduction of the wound stress), which have been already demonstrated over the past 15 years of clinical experience. Pico systems is canister-free, the pump generates an effective negative pressure of 80 mmhg (for 7 days of therapy) and is connected to a dressing that manages the fluid away from the wound or closed incision through a unique combination of absorbency and evaporation. Patients can be safely discharged with PICO in place. Although the exact criteria for INPWT initiation are still being defined, patients with a clean, closed post-operative incision and multiple surgical wound s post-operative complications risk factors were however considered candidates for INPWT. Previous reviews visited the topic: Webster et al. (60) evaluated the efficacy of INPWT on surgical incisions healing but due to the poor number of studies included and the small samples size, INPWT could not be considered to play an effective role in primary surgical wounds healing. Ingargiola et al. (61) have recently made a systematic review to evaluate the effect of INPWT on preventing surgical sites complications. Both reviews measured the efficacy of INPWT basing it properly on the incidence of surgical site complications; however there were no primary clinical outcomes of interest from animal and biomedical engineering studies that provided a direct explanation of the possible mechanisms of action of INPWT, but no interest was direct to an explanation of INPWT possible mechanisms of action or to animal and engineering studies. Besides, since the release of these review articles, several new studies have been published assessing the effect of INPWT on high-risk surgical incisions so we considered it to be appropriate to re-examine the topic. We performed a systematic review to evaluate the effect of INPWT on surgical sites healing by primary intention. The primary clinical outcomes of interest from animal and biomedical engineering studies are an explanation of the possible mechanisms of action of INPWT on surgical incision and of its potential benefits on healing milieu. Human studies have been investigated in order to evaluate the influence of INPWT not on the cosmetic appearance of the incisions, which was regarded as a subjective evaluation parameter, unreliable and not reproducible, but on the incidence of post-operative complications (infection, dehiscence, seroma, hematoma, skin and fat necrosis, skin and fascial dehiscence or blistering) as well as on other variables (re-operation and re-hospitalization rates, time to dry wound, cost saving). Materials and methods Research methodology A search was conducted for published articles in various databases including the Medline/PubMed (MeSH database), Google Scholar and Scopus databases from 2006 to March The search was performed in April 2014 using the key words incisional negative pressure wound therapy, incisional wound therapy, Prevena, Pico, negative pressure wound therapy, vacuum therapy, negative pressure dressing, topical negative pressure, negative pressure therapy, VAC, vacuum-assisted closure, vacuumpressuredressing, vacuum-assisted closure therapy, each one of these combined with closed incision(s), closed wound(s), surgical incision(s), wound healing, wound complication(s), surgical wound dehiscence, surgical wound infection, surgical site infection, wound cellulitis, haematoma, seroma, skin necrosis, fat necrosis and blistering. Further articles were collected for inclusion from conference proceedings. Additional citations review and references review of identified articles was performed and if a new article contained at least one key word from the above, it was included. Inclusion and exclusion criteria, extrapolation data and quality valuation The collected studies were reviewed and each study abstract and the full-text version were evaluated for inclusion on the basis of set inclusion and exclusion criteria (Table 1). No filter was put on the design of study and on the model investigated (human, animal or engine) but data extraction was performed in a standardised and reproducible form, separating the articles on animal and engineering models from those on human models because the purpose of these types of studies were different. Otherwise, only articles in which INPWT was used as a preventive measure on a closed (sutured) incision and applied immediately in the post-operative phase were included Medicalhelplines.com Inc and John Wiley & Sons Ltd

4 A. Scalise et al. Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications Table 1 Inclusion and exclusion criteria Inclusion criteria 1. Application of NPWT to surgical incisions after primary incision closure immediately at the end of the surgical procedure. 2. Incisions healing by primary intention. 3. Sample of 10 patients if it is a human study. 4. Articles in English language. 5. Article published from 2006 to March Human studies, experimental animal or biomedical engineering studies. Exclusion criteria 1. Application of NPWT to open chronic non-healing wounds or open surgical incisions following infection or breakdown. 2. Incision healing by secondary intention. 3. Sample 10 patients if it is a human study. 4. Non-English language articles. 5. Articles published prior to NPWT, Negative Pressure Wound Therapy. Table 2 Data item extrapolated from animal and biomedical engineering studies Publication date Model investigated Testers used to perform the simulations Study design Epidemiology (age, gender) Intervention Surgical incision simulation NPWT type, time and pressure setting Dressing configuration in the controls Discontinuation criteria Possible mechanisms of action of INPWT Outcomes Infection Dehiscence Seroma and hematoma Skin breakdown (necrosis, blister) Re-operation Time to dry wound INPWT, Incisional Negative Pressure Wound Therapy. If it was a human study, this had to have a sample of at least ten patients. Additional filters included articles in the English language from 2006 to March Non-English language articles and articles published prior to 2006 were excluded. Data items extrapolated from animal and biomedical engineering studies incorporated study design, model investigated, testers used to perform the simulations, clinical characteristics of the animals, surgical incision simulation, type of INPWT used and dressings used in the control group (CG), and an explanation of the possible mechanism of action of INPWT (Table 2). Data items extrapolated from human studies comprehended study design, epidemiology and patients comorbidities, surgical viewpoint, INPWT type and standard dressings used in the CG, influence of INPWT on surgical wound complications and on potential cost savings (Table 3). Results Search results and study selection The search was performed on April 2014 and, after application of filters of inclusion criteria and citation review of identified articles, a total of 18 studies remained: 1 biomedical engineering study (prospective cohort study (27)), 2 animal studies Table 3 Data item extrapolated from human studies Publication date Study design Statistical test used Epidemiology (age, gender) Patient comorbidities Obesity, diabetes mellitus, vascular or respiratory disorders, immunosuppression, nicotine abuse Type of surgery, number and placement of surgical incisions Intervention INPWT type and pre-setting INPWT discontinuation criteria Dressing configuration in CGs Outcomes Average follow-up weeks Total wound complications Infection Dehiscence Seroma and hematoma Skin breakdown (necrosis, blister) Re-operation, re-hospitalization Time to dry wound INPWT potential cost savings Contraindications Complications of INPWT use INPWT, Incisional Negative Pressure Wound Therapy. (prospective cohort studies (57,62)) and 15 human studies (6 randomized controlled trials (3,33,63 66), 2 prospective cohort studies (67,68), 7 retrospective analyses (6,69 74)). Study design and publication date of each study are reported in Table 4a for animal and biomedical engineering studies and in Table 5a for human studies. Study characteristics, intervention groups, and quality In total, the systematic review investigated the outcomes of 1133 incisions on 2 Finite Element Analysis (FEA) models, 1 Benchtop model, 6 Yorkshire Pigs, 8 Domestic Pigs and 610 patients (see Table 4 for models investigated by animal and engineering studies). The most common study designs were as follows: retrospective observational studies (38 8%) (6,69 74), Randomized Controlled Trials (RCTs) (33 3%) (3,33,63 66) and prospective observational studies (27 7%) (27,57,62,67,68). 100% of the animal studies (57,62), 100 % of the biomedical engineering studies (27) and 87% of human studies 2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd 1263

5 Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications A. Scalise et al. Table 4 Animal and biomedical engineering studies (a) Reference (in publication order) Publication date Model investigated Testers used to perform the simulations Study design Age range, mean (years) Gender, % (male; female) N 0 animals or engineering models/n 0 incisions Wilkes et al. (27) 2012 March FEA-1 (simulator of epidermis and adipose tissue), FEA-2 (multiple layers of tissue that included the non-linear mechanical behaviour of epidermis 0 2 mm, dermis 2 9 mm, fat layer above the fascial separation 9 9 mm, fat layer below fascial separation 10 mm, muscle 10 mm), Benchtop Modelling (mixture of room-temperature-vulcanized liquid silicone and PlatSil Gel 10 Deadener simulating 2 mm skin, 10 mm fat, 10 mm muscle) Abaqus/Explicit version 6.7 and 6.9 (Dassault Systèmes Simulia Corp, Providence, RI) Meeker et al. (57) 2011 December Yorkshire Pig (weight range: pounds) Tensile strength testing performed by servohydraulic materials testing apparatus (MTS model 812, Eden Prairie, MN), data collected by an analog to digital conversion setup (Instron 8500 Plus, Norwood, MA), and ImageJ (National Institution of Health, Bethesda, MD) digital imaging software Kilpadi and Cunningham (62) 2011 September Domestic Pig: 50% Great White, 25% Landrace, 25% Yorkshire (weight range: kg) PC ND ND 3/3 PC ND Female 6/56 (28 pairs) ND PC ND Female 8/32 (b) Reference (in publication order) Surgical incision simulation INPWT type MmHg presetting, Time of INPWT Control group Post-op intervention group(s) (N 0 of incisions) Possible INPWT s mechanisms of action Wilkes et al. (27) Open incision 25 mm deep 2mm wide in FEA-1; vertical incision to the upper fat layer,2 mm wide by applying skin tension 0 to 150 kpa over 0 2 s to the dermis and epidermis exposures at the model sides in FEA-2; incisions of 9 inches down to the muscle layer closed alternatively with sutures or staples in Benchtop model Prevena * 125inFEA-1,NDinFEA-1; 125inFEA-2,startingat 0 4 s and attaining target negative pressure at 1 s; 125 in Benchtop model, ND in Benchtop model ND in FEA-1; simulated closure of the incisions with suture without dressings in FEA-2; simulated closure of the incisions with suture or staples without dressings in Benchtop model ND 50% of the lateral stress around the incision and in the fat layer; normalisation of the stresses direction; the force required to disrupt the incision by 43% to 51% as compared with closure alone Medicalhelplines.com Inc and John Wiley & Sons Ltd

6 A. Scalise et al. Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications Table 4 Continued (b) Reference (in publication order) Surgical incision simulation INPWT type MmHg presetting, Time of INPWT Control group Post-op intervention group(s) (N 0 of incisions) Possible INPWT s mechanisms of action Meeker et al. (57) Five pairs of elliptically shaped excisional incisions down to paraspinous muscular fascia; to simulate muscle injury and bleeding, a 3 cm long and 2 cm deep incision through the fascia and perpendicular to the fibers of the paraspinous muscle was made, the dermal edges was undermined 2 cm on both sides and UI heparin was administered. Perpendicular to the longitudinal axis of the animal on each side of the midline of the spine, spaced from each other by at least 7 cm. Kilpadi et al. (62) Two 5 cm incisions per side cranial and caudal on the abdomen abutting mammary tissue, 3 5 mm deep down to the level of underlying muscle, and creating underlying dead spaces. Incisions closed by simple interrupted sutures prior to the introduction of the nanospheres. ND 125; 3 days Ordinary gauze dressing Prevena incision dressing* 125; 4 days SFD (Tegaderm Dressing, 3 M, St. Paul, MN) ND of 142% wound s tensile resistance for maximum load at failure (0 470 versus of thecg); of 176% energy to failure (0 85 mj/mm in controls versus 1,128); wound appearance SFD (n = 16) INPWT (n = 16) Remodelling and enhancing macromorphological change of lymph structures resulting in an increased clearance (c) Reference (in publication order) Infection, (%) Dehiscence, (%) Seroma; hematoma (%) Skin necrosis; skin blistering, (%) Re-operation, (%) Time to dry wound (days) Wilkes et al. (27) ND ND ND ND ND ND Meeker et al. (57) ND ND 15% hematoma cross-sectional areas (1 31 cm 2 of ND ND ND controls versus cm 2 of NPWT) Kilpadi et al. (62) ND ND 25 (mean) ± 8 g (SE) less hematoma/seroma ( 63% of ND ND ND hematoma/seroma mass: 15 ± 3 g versus 41 ± 8g) FEA, finite element analyses; ND, not defined; INPWT, Incisional Negative Pressure Wound Therapy; PC, prospective cohort; SFD, semipermeable film dressing;, decrease;, increase. *Prevena Incision Management System, Kinetic Concepts Inc., San Antonio, TX Medicalhelplines.com Inc and John Wiley & Sons Ltd 1265

7 Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications A. Scalise et al. Table 5 Human studies (a) Reference (in publication order) Publication date Study design Age range; mean, years Gender, % (male; female) Mean BMI (Kg/m 2 ) DM, % PVD; CAD, % Immuno -compromised, % Smoking; COPD, % Lewis et al. (69) 2014 March R ND 0; (median 33 6)* ND ND; ND ND ND; ND 13 8*; 4 6* Condé-Green et al. (70) Blackham et al. (71) Grauhan et al. (63) 2013 October R CG 23 81; 55 INPWT 21 72; June R CG ND; 57 1 ± 13 4 INPWT ND; 57 1 ± 12 7 P = 0 980* 2013 May RCT CG 54 81; 67 INPWT 44 84; 68 P = 0 59 Tauber et al. (72) 2013 March R CG ND; 59 8 ± 10 4* INPWT ND; 60 5 ± 11 9* P = ;33* CG 36 1 INPWT 36 4* ND CG 26 8 ± 5 5 INPWT 28 3 ± 5 7 P = 0 072* CG 32; 43 INPWT 26; 49 P = 0 40 CG 36 (30 45) INPWT 37 (30 62) P = 0 22 ND CG 26 5 ± 4 4* INPWT 28 9 ± 8 0* P = * ND; 10 8* 3 1 (immunosuppression drugs)* CG n = 12 (14) INPWT n = 17 (16) P = 0 624* CG n = 40 (53) INPWT n = 41 (55) P = 0 25 ND; ND ND CG n = 22 (26) INPWT n = 16 (15) Ex-smoker: CG n = 18 (21) INPWT n = 16 (15) ND; LVEF < 30%: CG n = 5(7) INPWT n = 8(11) P = 0 56 ND ND; CG n = 22 (29) INPWT n = 15 (20) P = 0 25 ND ND; ND ND ND; ND Vargo (73) 2012 December R ND; ND ND ND ND ND ND ND CG 13 5*INPWT 18 2* Masden et al. (64) 2012 June RCT CG 38 86; 61 3* INPWT ; 61 3* P = 0 98 Pachowsky et al. (65) Stannard et al. (33) Colli and Camara (67) 2012 April RCT ND; CG 70 0 ± INPWT ± CG 23;14*INPWT 31;13* P = 0 43 CG 32 1*INPWT 31 0* P = 0 63 CG 64 9* INPWT 79 6* P = 0 12 CG 54 0* INPWT 47 7* P = 0 57; CG 16 2* INPWT 11 4* P = 0 53 CG 8 1* INPWT 9 1* P = 1 00 ND ND ND ND ND ND 2012 January RCT 18 80; 43* 65;35* ND 3 3 ND; ND ND 52*; ND 2011 December PC 55 78; ;5 ND n = 9 (90%) n = 9 (90%); n = 8 (80%) Howell et al. (66) 2011 March RCT CG 55 73; 66 CG 50;50 CG 50% with BMI INPWT 100% with BMI > 30 Goldstein et al. (68) CG ND INPWT0 CG 90 INPWT ND; CG 100 INPWT ND P = 0 57; ND ND ND; n = 3 (30%) ND ND; CG 30 INPWT ND 2010 November PC 40 83; 59 60;40 ND 40 ND; ND ND ND; ND Reddix et al. (74) 2009 September R 20 72; 41 21; ND ND; ND ND ND; ND Atkins et al. (6) 2009 June R ND; ; ;100 ND ND; ND Stannard et al. (3) 2006 June RCT 19 78; 41 73;27 ND ND ND; ND ND ND; ND Medicalhelplines.com Inc and John Wiley & Sons Ltd

8 A. Scalise et al. Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications Table 5 Continued (b) Reference (in publication order) N 0 patient / N 0 incisions Area of surgical incision; Type of surgery INPWT type Lewis et al. (69) ND Abdomen; laparotomy for endometrial cancer Condé-Green&& et al. (70) Blackham et al. (71) Grauhan et al. (63) 56/56 Abdomen; abdominal wall reconstruction after initial (40% of patients), recurrent (58%) or incarcerated recurrent (1 5%) ventral hernia 189/191 Abdomen; laparotomy for colorectal cancer, pancreatic cancer, or peritoneal carcinomatosis 150/150 Sternum; median sternotomy for coronary artery bypass grafting or valve surgery in high-risk group of obese patients Prevena (Prevena Incision Management System, Kinetic Concepts Inc., USA, San Antonio, TX), Pico System (Smith & Nephew Inc, Andover, MA) Vac Therapy (KCI USA, Inc., San Antonio, TX) with non adherent dressing (Adaptic, Johnson & Johnson, New Brunswick, NJ) VAC system (Kinetic Concepts, Inc, San Antonio, TX) with nonadhesive, permeable Dressing (Adaptic, Johnson & Johnson) Prevena, KCI, Wiesbaden, Germany Tauber et al. (72) 24/45 Groin; uni- or bilateral inguinal LND for penile cancer or cancer of the urethra Vargo (73) 30/30 Abdominal; Skin flaps after complex abdominal reconstruction Polyvinyl alcohol dressing (V.A.C. White Foam Dressing, KCI Medizinprodukte GmbH, Wiesbaden, Germany) connected to ActiVAC Vac Therapy (KCI USA, Inc., San Antonio, TX) mmhg Presetting (type of suction), time of INPWT CG Average follow up (weeks) Postoperative intervention group(s) (N 0 of incisions) Statistical test used ND, 7 days Routine care ND ND ND 125, 5 days Conventional dressing of dry gauze 60 CG (n = 33) INPWT (n = 23) χ 2 for categorical variables, t-test for continuous variables with statistical significance for p < (continuous), 4 days Standard sterile dressing ND CG (n = 87) INPWT (n = 104) t-tests or Mann Whitney U-tests for continuous variables, χ 2 or Fisher exact tests for categoric variables 125, 6 7 days Conventional sterile dry wound dressing 100 (continuous, intensity +++), 7 days Compression dressing 12 8 CG (n = 75) INPWT (n = 75) 11 7 CG (n = 30) INPWT (n = 15) Mann Whitney U-test and Fisher exact test for dichotomous data; freedom from infection by Kaplan Meier analysis, log-rank test to compare patient groups t-tests, Mann Whitney U-tests, Fisher s exact test with a significance level for α = (continuous), 5 6 days (range 5 7 days) ND 4 ND χ2 analysis 2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd 1267

9 Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications A. Scalise et al. Table 5 Continued (b) Reference (in publication order) N 0 patient / N 0 incisions Area of surgical incision; Type of surgery INPWT type mmhg Presetting (type of suction), time of INPWT CG Average follow up (weeks) Postoperative intervention group(s) (N 0 of incisions) Statistical test used Masden et al. (64) 81/81 Abdomen, groin, trunk, back, lower extremities; Closure of vascular bypass wounds and Lower extremities amputations proximal to the forefoot Pachowsky et al. (65) Stannard et al. (33) Colli and Camara (67) 19/19 Lower extremities; THA for osteoarthritis of the hip 263/263 Lower extremities; ORIF for lower extremities trauma reconstruction 10/10 Sternum; sternal surgical incision for CABG and/or AVR and/or MVR V.A.C. KCI,San Antonio, Tx 125, 3 days Standard dry dressingconsisting of a non adhesive silicone Layer (Mepitel, M lnlycke Health Care AB, G teborg, Sweden) and a bacterostatic single silver layer (Acticoat, Smith & Nephew, Hull, UK) 16 1 CG (n = 37) INPWT (n = 44) Prevena 125, 5 days Dry wound coverage 1 4 CG (n = 10) INPWT (n = 9) ND 125, 2 days Standard dry dressing ND CG (n = 122) INPWT (n = 141) Prevena 125, 5 days ND 4 INPWT (n = 10) ND Howell et al. (66) 51/60 Lower extremities; TKA ND 125, 2 days Sterile gauze dressing Goldstein et al. (68) 10/17 Lower extremities; local random fasciocutaneous flap for reconstruction of complex ankle wounds Reddix et al. (74) 19/19 Lower extremities; ORIF acetabular fractures ND 125; 4 days Standard dry dressing ND 75; ND Standard dry dressing Atkins et al. (6) 57/57 Sternum; CABG ND 125; 4 Standard dry dressing Stannard et al. (3) 44/44 Lower extremities; ORIF for lower extremities trauma reconstruction ND ND; 2 Standard dry dressing 48 CG (n = 36) INPWT (n = 24) χ2, Fischer Mann Whitney U-test ND ND 22 INPWT (n = 17) ND 84 INPWT (n = 19) ND ND INPWT (n = 57) ND ND CG (n = 24) INPWT (n = 20) ND Medicalhelplines.com Inc and John Wiley & Sons Ltd

10 A. Scalise et al. Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications Table 5 Continued (c) Reference (in publication order) Total wound complications (%) Infection, (%) Dehiscence, (%) Seroma; hematoma, (%) Skin necrosis; skin blistering, (%) Re-operation; re-hospitalization (%) Time to dry wound (days) INPWT cost saving Lewis et al. (69) Condé-Green et al. (70) Blackham et al. (71) n = 134 (31), (36 9 among patients with BMI > 30; 41 among patients with BMI > 40) CG n = 21 INPWT n = 5 P = CG n = 31 (35 6) INPWT n = 25 (24 0) P = OR 0 51, 95% CI Among CCCs: CG n = 28 (45 2) INPWT n = 24 (24 0) P = OR 0 46, 95% CI n = 87 (64 9) ND ND; ND ND; ND n = 11;n = 16 ND Ata relative risk of wound complications of 0 5: $104 for the full cohort, $163 in the obese cohort and $203 in the morbidily obese cohort CG n = 1(4 3) INPWT n = 2(6) Total CG n = 23 (26 4) INPWT n = 17 (16 3) P = 0 065, OR 0 48, 95% CI superficial incisional SSIs CG n = 17 (19 5) INPWT n = 7(6 7) P = 0 019, OR 0 29, 95% CI Incisional SSIs CG n = 17 (19 5) INPWT n = 12 (11 5) P = OR 0 48, 95% CI Among CCCs: total CG n = 22 (35 5) INPWT n = 16 (16 0) P = OR 0 40, 95% CI superficial incisional SSIs CG n = 17 (27 4) INPWT n = 6(6 0) P = OR 0 23, 95% CI incisional SSIs CG n = 17 (27 4) INPWT n = 11 (11 0) P = OR 0 40, 95% CI CG n = 13 (39) INPWT n = 2(8 7) P = CG n = 24 (27 6) INPWT n = 17 (16 3) P = OR 0 45, 95% CI Among CCCs: CG n = 22 (35 5) INPWT n = 16 (16 0) P = OR 0 41, 95% CI CG n = 4(12) INPWT n = 0 P = 0 14; CG n = 0 INPWT n = 0 CG n = 3(3 4) INPWT n = 4(3 8) P = 0 867, OR 0 85, 95% CI Among CCCs: CG n = 3(4 8) INPWT n = 4(4 0) P = 0 867, OR 0 85, 95% CI ; CG n = 2(2 3) INPWT n = 0 Among CCCs: CG n = 1(1 6) INPWT n = 0 CG n = 6(18) INPWT n = 2 (8 7); ND P = 0 45 CG n = 3 INPWT n = 1 P = 0 63; ND ND ND ND; ND ND; ND ND ND 2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd 1269

11 Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications A. Scalise et al. Table 5 Continued (c) Reference (in publication order) Total wound complications (%) Infection, (%) Dehiscence, (%) Seroma; hematoma, (%) Skin necrosis; skin blistering, (%) Re-operation; re-hospitalization (%) Time to dry wound (days) INPWT cost saving Grauhan et al. (63) ND CG n = 12 (16) INPWT n = 3(4) P = 0 026; OR 4 57; 95% CI, G+: CG n = 10 INPWT n = 1 P = 0 009; OR 11 39; 95% CI, Tauber et al. (72) Fewer patients with INPWT experienced inguinal wound complications compared with CG. P = Vargo (73) n = 2(3) (0) P < 0 05 Masden et al. (64) CG n = 13 (35 1) INPWT n = 18 (40 9) P = 0 59 Pachowsky et al. (65) Stannard et al. (33) Colli and Camara (67) CG n = 4 INPWT n = 2 P = 0 061; ND ND LPC: CG (62) INPWT (20) LPR: CG (45) INPWT (7) LPE: CG (46) INPWT (0); ND CG n = 5(13 5) INPWT n = 3(6 8) P = 0 46 (not statistically significant); no difference in the development time ND CG n = 23 (18 9) INPWT n = 14 (9 9) P = ND; ND ND; ND CG n = 5(7) INPWT n = 3(4) P = 0 72; ND ND; ND CG n = 7/30 wounds (23) INPWT n = 1/15 wounds (7) P = 0 631; ND ND ND CG (25%-Pe: 6; 50%-Pe: 7; 75%-Pe: 18) INPWT (25%-Pe: 5; 50%-Pe: 7; 75%-Pe: 8) P = ND n = 1(3 3); ND (0); ND ND; ND ND ND CG n = 11 (29 7) INPWT n = 16 (36 4) P = 0 53 (not statistically significant); no difference in the development time P = 0 45 ND ND CG n = 9 (90) mean volume 5 08 ml INPWT n = 4(44) mean volume 1 97 ml P = 0 021; ND CG n = 20 (16 5) INPWT n = 12 (8 6) P = ND; ND ND; ND CG n = 8 (22) INPWT n = 9(20 9) of the total wound complication P = 0 89; ND ND 4 3 ND ND; ND ND; ND ND ND ND; ND ND; ND ND; ND CG n = 3 INPWT n = ND; ND ND; ND 0;0 5 ND Howell et al. (66) ND CG n = 1(2 8) INPWT n = 1(4 2) ND ND; ND ND; CG n = 3(12) INPWT n = 15 (63) CG 0 INPWT 0; ND CG 4 1 INPWT 4 3 ND ND Medicalhelplines.com Inc and John Wiley & Sons Ltd

12 A. Scalise et al. Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications Table 5 Continued INPWT cost saving Time to dry wound (days) Re-operation; re-hospitalization (%) Skin necrosis; skin blistering, (%) Seroma; hematoma, (%) Total wound complications (%) Infection, (%) Dehiscence, (%) (c) Reference (in publication order) Goldstein et al. (68) ND 0 n = 2(11 8) ND; ND ND; ND ND; ND ND ND Reddix et al. (74) ND; ND ND; ND ND; ND ND ND Atkins et al. (6) 0 0 ND ND; ND ND; ND 0;ND ND ND ND ND; ND ND; ND CG 3 1 INPWT 1 6 P = 0 03 CG 4 8 days INPWT 1 8 days P = 0 02 CG n = 4(16 7) INPWT n = 4 (20) Stannard et al. (3) ND CG n = 3(12 5) INPWT n = 3(15) AVR, aortic valve replacement; BMI, body mass index; CABG, coronary artery bypass graft; CAD, coronary artery disease; CCCs, clean-contaminated cases; CG, control group; CI, confidence interval; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; G+, gram-positive skin flora; INPWT, Incisional Negative Pressure Wound Therapy; LVEF, left ventricular ejection fraction; LND, lymphadenectomy; LPC, lymphoceles; LPE, lymphoedema of the lower extremities; LPR, lymphorrhoea; MVR, mitral valve replacement; ND, not defined; OR, odds ratio; ORIF, open reduction internal fixation; P, P-value; Pe, percentile; PC, prospective cohort; PVD, peripheral vascular disease; R, retrospective; RCT, randomized controlled trial; SSIs, surgical site infections; THA, total hip arthroplasty; TKA, total knee arthroplasty. *No significant difference between control group and INPWT group. To compare treatment groups for symmetrically distributed quantitative data (age, body, BMI). To compare treatment groups for duration of drainage and maximal drained fluid. To compare binary data. Days of drainage from incision greater than minimal (>2 quarter-sized drops of drainage). (3,6,33,63 66,68 72,74) have a control intervention group for comparison of outcomes with those from the INPWT group (Tables 4b and 5b). Risk factors used to asses surgical wound s post-operative complications risk can be associated with any of three factors such as trauma (soft tissue injury or fracture, type), surgical procedure (incision placement, surgical site contamination, technique, operative time, estimated blood loss) or patient-related (morbid obesity, multiple significant comorbidities, drugs). Of these factors, INPWT use has been investigated most prevalently with respect to injury or fracture. Forty-six percent of the human studies (n = 7) evaluated the effect of INPWT on lower extremity high-risk incisions after reconstructive joint or fracture surgery (3,33,64 66,68,74). Twenty percent of the human studies (n = 3) evaluated the effect of INPWT on laparotomy for abdominal or genital malignancies (64,69,71). Two articles evaluated its use for abdominal incisions, one after abdominal wall reconstruction of recurrent ventral hernias (70) and the other after skin flaps for complex abdominal reconstruction (73). Three studies (20%) (6,63,67) used INPWT for sternal incisions after coronary arteries bypass grafting, and one experimented INPWT in the inguinal incision after lymphadenectomy for penile cancer or cancer of the urethra (72). Areas of surgical incision and type of surgery performed, are schematised in Table 5b for human studies. In terms of the duration and pre-setting of INPWT, animal experimental studies applied a negative pressure of 125 mmhg for a mean time of 3 5 days (57,62) (Table 4b). Among human studies, seven applied INPWT for a predetermined 4 6 days at 125 mmhg and then removed the dressing (6,63,65,67,68,70,71). Two studies used INPWT for 7 days (one at 125 mmhg (63), the other at 100 mmhg (72)) and one study for 3 days (64). In three studies (3,33,66) it was applied for 2 days and then removed and re-applied for a length of time depending on the amount of drainage noted in the suction canister, and in one study, INPWT was at 75 mmhg and continued until there was no fluid suctioned into the canister for 12 consecutive hours (typically in place for 1 3 days) (74). Mean follow-up ranged from 1 4 to84 weeks. INPWT pre-setting (mmhg, type of suction and time of application) and average follow-up weeks of each study are reported in Table 4b for animal and biomedical engineering studies and in Table 5b for human studies. Epidemiology and patients comorbidities In total, 13 studies (72%) provided data regarding the sex ratio of the study population (3,6,33,57,62 64,67,68,66,69,70,74) and 13 studies reported mean age ranging from 54 to 70 years in the CGs and 41 to 68 years in the INPWT groups (3,6,33,63 68,70 72,74). Mean Body Mass Index (BMI), diabetes mellitus, coronary artery disease, peripheral vascular disease, immunocompromised status, nicotine abuse and chronic obstructive pulmonary disease were reported with variability. Post-incision use of NPWT with respect to high-risk factors, including obesity and diabetes, has been investigated by several studies (6,67,74). All epidemiological and clinical characteristic data for each study are reported in Table 4a for animal studies and in Table 5a for human studies. Nearly all human 2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd 1271

13 Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications A. Scalise et al. studies, except one (68), selected a sample of patients whose surgical incisions were considered by the investigators to be at high risk for complication because of both a large amount of comorbidities and/or by the type of the injury, incision placement, and known propensity for surgical site complications development. Outcomes Outcomes and complications are reported in Table 4c for animal and biomedical engineering studies and in Table 5c for human studies, with number and percentage rate listed by the study group. Infection Infection of the surgical incision was the commonly reported complication (72% of studies reviewed) (3,6,33,63,64,66 71,73,74). NPWT s rationale to prevent SSIs includes completely eliminating dead space, removing fluid and blood, improving blood flow and preventing the formation of subcutaneous seromas/hematomas that become secondarily infected. All the human studies included in the review investigated the incidence of SSIs except two (65,72). Three of the 7 retrospective studies (6,73,74) and 2 of the 2 observational studies (67,68) documented a 0% incidence of infection in their study population using INPWT. None of these studies had CGs to be compared with. Stannard et al. (3) randomised 88 orthopaedic trauma patients with draining hematomas or high-energy fractures to receive a standard dry dressing or INPWT over closed incisions. INPWT was associated with a shorter drainage time; however, there was no statistically significant difference in the rates of infections. A subsequent study from the same group (43) randomised 262 patients with high-energy lower-extremity fractures to standard dry dressings or INPWT and reported a lower incidence of SSIs (9 9% versus 18 9%, P value [P] = 0 049) with the use of INPWT. INPWT has also been associated with fewer SSIs compared with standard dry dressings (1 27 versus 6 15%, P = ) in patients who underwent acetabular fracture repair (75). In addition to the orthopaedic experience using INPWT, Atkins et al. (6) reviewed 57 high-risk cardiac procedures in which NPWT was used on closed sternotomy incisions for 4 days. Based on the risk assessment model developed by Fowler, three post-operative sternal wound infections were anticipated; however, none were observed. During the same time period, 213 patients who were not at high risk for sternal wound infections were treated with standard post-operative wound care, and 1 patient in this group developed a sternal wound infection. They concluded that NPWT was well tolerated and may prevent sternal wound complications in high-risk patients. Blackham et al. (71) reported that NPWT was associated with fewer surgical site complications when compared with standard sterile dressing, in patients undergoing colorectal, pancreatic, or cytoreductive surgery (Table 5c): 16 3% versus 26 4% for global infection incidence, 6 7% versus 19 5% (P = 0 015) for superficial incisional SSIs incidence and 11 5% versus 19 5% for incisional SSIs incidence. In particular, clean-contaminated operations appear to benefit the most from INPWT: 16 0% versus 35 5% for global infection incidence, 6 0% versus 27 4% for superficial incisional SSIs incidence and 11 0% versus 27 4% for incisional SSIs incidence. Condé-Green et al. (70) demonstrated no significant difference in the rate of infection between the INPWT (one infection, 4 3%) and the conventional dressing of dry gauzes (two infections, 6%) groups. In contrast with the previous studies, Howell et al. found a higher percentage of infections in the INPWT group (4 2%) versus sterile gauze dressing (66). In an RCT, Masden et al. demonstrated a lower incidence of infection in the INPWT group as compared with standard dry dressing but the results did not reach a level of statistical significance; no differences were noted in the infections development time between the two groups (64). In a prospective study, Grauhan et al. (63) analysed the role of NPWT in median sternotomy in a high-risk group of 150 consecutive obese patients (BMI 30). Three of 75 patients (4%) with continuous negative pressure wound dressing treatment had post-sternotomy wound infections compared with 12 of 75 patients (16%) with conventional sterile wound dressing (P = ). The breakdown of skin sutures with subsequent seepage of bacteria into the deeper layers emerged as the key event in the development of the majority of wound infections after sternotomy, and Gram-positive bacteria were the most commonly isolated organisms in up to 80% of cases (76 78). This pathogenesis may explain why the risk of wound infections is especially elevated in obesity, because shear and traction forces on skin sutures are high and there is ample scope for colonization of skin flora within skin folds. By considering wound infection by only Gram-positive skin flora, infections were found in only one patient in the NPWT treatment group compared with ten patients in the CG (P = ; OR, 11 39; 95% CI, ) indicating a considerable impact of prophylactic NPWT dressing treatment in reducing the likelihood of wound infection over clean, closed incisions for the first 6 7 post-operative days. Besides, in the NPWT group, the incision was primarily closed in 71 of the 75 patients (95%) and not a single wound infection occurred during the further course, indicating that wound closure already represented a sufficient barrier to external infectious sources. Thus, the key event of most infectious complications, which was skin breakdown and subsequent seepage of skin flora into deeper layers, could be prevented in most cases by prophylactic NPWT (76,77). In contrast, in the CG, 9 of 12 wound infections (75%) occurred beyond the first post-operative week and up to post-operative day 35. This indicated that with conventional wound dressing (in the CG) an adequate barrier to external infectious sources is considerably established later, which in turn underlined the positive impact of wound secretion drainage (hematoma, seroma) as well as the improved microcirculation during the course of wound healing that was observed with NPWT in previous studies (3,43,65). Other investigators evaluated the efficacy of NPWT in preventing surgical site complications. Gomoll et al. used INPWT on 35 orthopaedic trauma patients who were at high risk for SSIs and reported that no SSIs developed (2) Medicalhelplines.com Inc and John Wiley & Sons Ltd

14 A. Scalise et al. Surgical wound healing: role of Incisional Negative Pressure Wound Therapy in reducing complications Hematoma and seroma Seroma development was the second most commonly reported complication (55% of studies reviewed) (3,6,53,57,62,65,70 73). Hematomas and seromas result from the accumulation of blood and serum, respectively, in internal spaces. Even with an excellent surgical technique, bleeding and inflammation, and consequently serum extravasation, may occur, resulting in patient discomfort, increased probability of infection, slower healing, additional clinic visits and surgical re-interventions. Recent in vivo studies have provided evidence of improved fluid flow with four days of continuous INPWT (Prevena Incision Dressing) under 125 mmhg over clean, closed incisions, showing that its application, when compared with semi-permeable film dressing (Tegaderm Dressing, St. Paul, MN, USA), significantly decreased the amount of porcine subcutaneous dead spaces beneath superficial closed incisions indicating reduced haematoma/seroma (62). Kilpadi and Cunningham (62) demonstrated that NPWT reduced the mass of hematoma/seroma by 63% in domestic pigs (NPWT: 15 ± 3 g, control: 41 ± 8 g, P = 0 002) with minimal, if any, removal of fluid into the canisters but through an increased lymph clearance from the subcutaneous dead space, as measured by the significantly greater incidence in peripheral lymph nodes of both 30- (P = 0 04) and 50-nm (P = 0 05) neutron-activated nanospheres from NPWT-treated sites compared with control-treated sites, and an enhanced macromorphological change of lymph structures. Meeker et al. (57) investigated the role of NPWT in post-operative primary wound treatment and closure in a porcine model. They found that blinded measurements of wound hematoma cross-sectional areas were 15% smaller for NPWT-treated wounds as compared with controls (1 31 cm 2 versus cm 2 ; P = 0 02) (57). Among human studies the RCT of Pachowsky et al. (65) found a significant reduction in the incidence and mean size of post-operative seromas when measured by ultrasound with prophylactic INPWT (n = 4, 44%, 1 97 ml) versus conventional dry wound coverage (n = 9, 90%, 5 08 ml) to total hip arthroplasty incisions for osteoarthritis of the hip in 19 obese subjects (P = 0 021) (65). Stannard et al. (3) reported the incidence of minor to marked drainage from the surgical incision. Unfortunately, they did not specify if the drainage represented seroma or hematoma fluid; however, they found a substantial reduction in the number of days with greater than mild drainage from incisions with INPWT versus Standard dry dressing (1 8 versus 4 8 days, respectively; P = 0 02). Vargo, in his retrospective review of prospectively collected data in 30 patients with high-risk wounds treated with NPWT after complex abdominal reconstruction, reported only one case of seroma (3 3%) (73). In addition, Timmers et al. reported data regarding the incidence of seroma (53). Tauber et al. (72)found in 24 lymphadenectomy for penile or urethra malignancies, that patients treated with conventional wound care showed a slight tendency to higher values of maximum drained fluid per day (25%-percentile: 30 ml; median: 68 ml; 75%-percentile: 200 ml versus 25%-percentile: 35 ml; median: 55 ml; 75%- percentile: 78 ml; P = with no statistical significance) and duration of drainage (25%-percentile: 6 days; median: 7 days; 75%-percentile: 18 days versus 25%-percentile: 5 days median: 7 days; 75%-percentile: 8 days; P = with no statistical significance). While drainages had to be kept in place for more than 7 days in only 1/15 (8%) inguinal LND wounds treated with epidermal VAC, 15/30 inguinal conventional wound care treated wounds (50%) required a drainage time longer than 7 days. In comparison with only 1/8 (13%) patients of the VAC treated group, 4/16 (25%) patients of the CWC group were discharged with indwelling drainages (P = 0 631). Besides, Epidermal VAC treatment resulted in significantly fewer complications such as formation of lymphoceles (62% versus 20%), persistent lymphorrhoea (45% versus 7%) or lymphoedema of the lower extremity (46% versus 0%) (P = 0 032) (72). Condé-Green et al. (70) and Blackham et al. (71) were the sole authors to report the incidence of hematoma too. Condé-Green et al. reported a zero occurrence of hematoma in both the INPWT group and the CG, and a zero occurrence of seroma in the INPWT group versus 12% (n = 4) in the CG (70). In contrast with the previous studies, Blackham reported three cases (3 4%) of seroma in the CG versus four cases (3 8%) in the INPWT group (P = 0 867, OR 0 85, 95% CI ) while among clean-contaminated cases they reported seromas in 4 8% (n = 3) for CG and in 4% (n = 4) in INPWT group (P = 0 867, OR 0 85, 95% CI ). Incidence of hematoma was 2 3% (n = 2) in CG and 0 in INPWT group while among clean-contaminated cases 1 6% (n = 1) in CG and 0 in INPWT group (71). Dehiscence Among studies reviewed, the rate of dehiscence ranged from 8 6% to 36 4% in the INPWT groups versus 16 5% to 39% in the CGs. Among the four studies with treatment and CGs that reported the incidence of dehiscence, two studies found a statistically significant difference (6,67). Condé-Green et al. (70) demonstrated an 8 7% (n = 2) dehiscence rate with INPWT compared with 39% (n = 13) with standard dry dressing (OR = 6 83, 95% CI: , P = 0 014) and Stannard et al. (33) demonstrated a 8 6% (n = 12) percent dehiscence rate with INPWT versus 16 5% (n = 20) with conventional dressing (Relative Risk = 1, 95% CI: , P = 0 044). According to the results of Grauhan et al., after median sternotomy one patient in the NPWT group and three patients in the CG had sternum dehiscence (P = 0 061). In the NPWT patient, the skin incision was closed after 7 days of NPWT, but sternum dehiscence was diagnosed after 3 weeks and sterile re-osteosynthesis could be performed. In contrast, in the CG, 3 of 12 wound infections showed sternal bone involvement and skin flora as causative. One may surmise that these three infections could have been prevented by prophylactic NPWT (63). Blackham et al. (71) reported that NPWT was associated with fewer surgical site dehiscence in patients undergoing colorectal, pancreatic or cytoreductive surgery (Table 5c): in total, 24 patients (27 6%) required wound opening after being treated with standard sterile dressings, whereas 17 patients (16 3%) developed open incisions after receiving NPWT dressings (P = 0 043, OR 0 45, 95% CI ). After adjusting for the demographic and clinical differences between the two groups, the rate of wound opening for any reason was significantly better after using NPWT (P = 5 043) (71) Medicalhelplines.com Inc and John Wiley & Sons Ltd 1273