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Keywords:

  • negative pressure therapy;
  • efficacy;
  • practice

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of Interest
  9. References

Negative pressure (wound) therapy, synonymous with topical negative pressure or vacuum therapy mainly cited as branded VAC® (vacuum-assisted closure) therapy, is a mode of therapy used to encourage wound healing. It is used both as primary treatment of chronic and complex wounds and as an adjunct for temporary closure and wound bed preparation preceding surgical procedures such as skin grafts and flap surgery. The device has come into wide and successful use, although the physiological basis of its effect is not yet fully understood, and with a delay, increasingly evidence-based data become available. A meta-analysis was made of peer-reviewed publications (PubMed–Medline) chosen on the basis of inclusion of the terms randomized clinical trial, vacuum-assisted closure, and topical negative pressure. Scientific data were evaluated from experimental animal studies, randomized clinical trials, observations of clinical applications, and case reports on all known effects of VAC therapy. Systematic analysis of the data shows efficacy concerning induction of wound healing mechanisms, especially in the early stage. Increased perfusion can be considered proven. Data analysis shows positive efficacy for treatment of infection. Although this therapy appears effective and its superiority to conventional techniques has been demonstrated, there are still some critical votes concerning efficacy. Because its mechanisms of action remain unclear, and because there is still some gap between evidence-based data and the excellent clinical results, further prospective, randomized, blinded studies are needed. Even so, we conclude that vacuum therapy, used when indicated and especially by experienced surgeons, is an excellent tool to support wound healing. Copyright © 2012 John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of Interest
  9. References

Treatment of wounds, especially hard-to-heal wounds, has been the working basis of plastic surgery since the start of this specialized discipline. Vacuum-assisted closure therapy was originally developed as an alternative treatment for debilitated patients with chronic wounds [1] at Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Vacuum-assisted closure therapy is an adjunct therapy using negative pressure to remove fluid from open wounds through a sealed dressing [reticulated open cell foam (ROCF)] and a specialized tubing that is connected to a collection container. Because this technology has been patented and cleared for marketing by the US Food and Drug Administration (registration of medical devices does not always require submission of data from controlled randomized efficacy trials), currently, the VAC® therapy system (KCI, San Antonio, TX, USA) has been widely spread throughout North America and Europe and is becoming more and more available in other parts of the world.

Contributions to leading journals nowadays require a peer review evaluation and selection. The first four submissions by Morykwas et al. [1] with the goal to publish about vacuum-assisted closure therapy were rejected until their report was published in 1997 [2, 3]. Resistance to new discoveries can affect even great scientists and very influential highly cited articles [4].

Stephen Lock [5], for example, felt that peer review ‘favours unadventurous nibblings at the margin of truth, rather than quantum leaps’. Gunter Stent [6], a molecular biology researcher, coined the term ‘premature discovery’ to describe a finding that is not fully appreciated at the moment of its announcement, because it cannot be connected by a series of simple logical steps to up-to-date or generally accepted knowledge. According to this, the authors of the first report described the concept of using a vacuum to treat an open wound and facilitate wound closure as a premature discovery [7]. Since the publications of Morykwas et al. [1], this technique has been used both as primary treatment of chronic and complex wounds such as diabetic foot wounds and as an adjunct for temporary closure and wound bed preparation, preceding surgical procedures, such as skin grafts and flap surgery. The device has come into wide and successful use, although the physiological basis of its effect is not yet fully understood, and with a delay, increasingly evidence-based data become available. Here, we describe a literature survey to study evidence for this therapy system.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of Interest
  9. References

A meta-analysis was made of peer-reviewed publications (PubMed–Medline) chosen on the basis of inclusion of the terms randomized clinical trial, vacuum-assisted closure, and topical negative pressure (TNP).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of Interest
  9. References

More than 660 peer reviewed articles are published on the basis of the terms used in our search. More than 800 abstracts were submitted and accepted for scientific events. The technique of TNP is described in more than 70 book reviews. The scientific data evaluating experimental animal studies, randomized clinical trials, observations of clinical applications, and case reports on all types of effects show mainly results reached with VAC® therapy. The evidence on clinical efficacy, however, is often discussed, because the scientific level of evidence, in the opinion of the reviewers, is not always the most ideal level [8]. Aside from the discussion on (the level of) evidence, the mode of action is often seen as not completely clear; however, dependent on the mechanism described, different levels of evidence are available.

Basic research suggests the following effects:

  • extracellular effects, such as increased blood flow and oedema reduction; local wound environment is positively influenced; it has a barrier function and creates tissue fixation;
  • cellular effects, such as granulation tissue formation and cellular synthesis;
  • complex effects, such as bacterial clearance, infection control, fluid analysis, immunologic response, systemic effects, matrix function, and flap survival.

Extracellular effects

Blood flow

Several studies with somewhat differing results were found. The first animal study by Morykwas et al. [2] described a maximal increase of perfusion measured by laser Doppler using 125 mmHg negative pressure lasting for 5–7 min, followed by a decrease to baseline. Levels of 400 mmHg negative pressure resulted in a decrease of blood flow. Using the intermittent mode led to a repetitive maximal increase [2], but there was no investigation concerning the permanence of this effect. Wackenfors et al. [8] could find an area of hypoperfusion close to the wound edges (<1.5 cm) but increased perfusion slightly removed from the border of artificial wounds in swine. Distances >3.5 cm from the edges remained uninfluenced. Increased perfusion >50% remained for 10 min, followed by decrease under baseline. Negative pressure higher than 50 mmHg led to increase of the hypoperfusion area. The author concluded lower negative pressures and intermittent mode to avoid hypoperfusion [8]. Rejzek and Weyer [10] found an increase in perfusion in seven patients experiencing venous ulcer treated by vacuum therapy (VT) without control group. Unfortunately, no statement was made concerning vacuum level and permanence of effect. An increase in blood flow was found by Zöch et al. [11] using vacuum-assisted closure therapy (VAC®) in diabetic foot wounds measured by IC-View perfusography. Both Kamolz et al. [12] and Schrank et al. [13] investigated superficial to deep dermal burn injuries treated by VAC®. They found an increase in perfusion and concluded efficacy to prevent burn wound progression by reducing the zone of venous stasis. Chen et al. [14] observed an increase in blood flow in wounds experimentally created in the ears of white rabbits and subsequently treated with vacuum-assisted closure technology. Microscopic examination and image pattern analysis revealed that increased blood flow showed to be the result of increased vascular diameter, blood flow velocity, and blood volume, as well as increased angiogenesis and endothelial proliferation. All studies found an increase in perfusion for a short period and in different wound areas. Some studies described small sample sizes, all with different kinds and depths of wounds; others described a lack of control group. Timmers evaluated the response of cutaneous blood flow in healthy intact forearm skin in a prospective randomized trial in response to various negative pressure levels (25–500 mmHg) using two foam types using in-foam-incorporated laser Doppler probes. Significant increase of cutaneous blood flow was seen up to −300 mmHg; however, no decrease below baseline was seen during the whole experiment. These authors concluded that a higher level of negative pressure will have a longer, consistent effect on increase in blood flow [15]. The questions for ideal subatmospheric pressure levels, mode of action, and duration of increase remain unanswered until now.

Oedema reduction

Many references described that VAC therapy can reduce oedema [1, 2]; however, this is only based on clinical observations. Until now, no publications were found measuring oedema quantitatively. Kamolz et al. [12] investigated the volume of drained fluid; however, he could only find a weak, indirect conclusion for oedema reduction because of the fact that drained fluid also could include fluid from open lymphatic vessels or from blood vessels. In spite of the fact that oedema reduction was present, no conclusion could be drawn concerning the foam, level of vacuum, and mode of suction, intermittent or continuous.

Local wound environment

It is proven that a wet wound environment increases the process of wound healing. Wound healing is assumed to be the result of balance between promoting cytokines and inhibiting proteases [16]. Some believe that TNP can lead to a higher reduction in proteases than in cytokines. The effect, however, still remains unclear, because cytokines were shown to be eliminated, too [17].

Barrier function

Several authors have described a kind of safety barrier as advantage for VT. The polyurethane (PU) foil was shown to be a border between the wound and surrounding environment. It is limitedly permeable for vaporized water although impervious for air and bacteria. This barrier effect is assumed to be bidirectional. Fleischmann et al. [18, 19] found an effective protection of acute traumatic wounds in retrospective as well as in prospective clinical trials. Unfortunately, until now, there is no evidence that VAC therapy reduces bacterial contamination from the environment.

Tissue fixation

Von Lübken et al. [20] found a uniform negative pressure distribution when using negative pressure over the whole wound area in his in vitro and in vivo studies. Saxena et al. [21] found microdeformations of tissue and a fixed tissue–foam gearing when using VAC therapy. Advantages of this effect are used for securing skin grafts, as well as supporting flap surgery and chest wall stabilization in patients with sternal osteomyelitis. Until now, there is a shortness of data describing negative pressure values for optimizing tissue fixation.

Cellular effects

Granulation tissue formation and cell proliferation

In his experiments, Morykwas et al. [2] found an increase of granulation tissue formation in an animal model. He investigated the influence of different modes of negative pressure on artificial wounds using a swine model. A second wound on the same animal treated with saline gauze acted as a control group. He found a significant increase in tissue formation, in case of intermittent mode (5 min of negative pressure, on; 2 min of negative pressure, off), more obvious than in continuous mode (negative pressure continuous on). This was performed in a prospective, nonrandomized, and nonblinded study design. One of his other experiments described the effects of varying levels of subatmospheric pressure in experimental wounds in swine [22]. The authors found a maximum of granulation tissue formation and increase in wound healing using −125 mmHg subatmospheric pressure, whereas lower levels (−25 mmHg) and higher values (−500 mmHg) led to increase in wound surface. Fabian et al. [23] observed a significant increase of granulation tissue with vacuum-assisted closure therapy in an ischemic wound model in rabbits. A contralateral ear wound treated by foam without suction acted as a control group. A clinical trial in eight animals investigated tissue biopsies taken from wound base and edge before and after 5 days of TNP. The authors found a 200% increase in endothelial cell proliferation based on immunohistochemical methods [24]. A prospective randomized trial in a swine wound model described no difference in granulation tissue formation using histological analysis between a TNP group and a saline gauze group, both equally overcoming the foil dressing [25]. Isago et al. [26] described a significant reduction in wound size of 50 Wistar rats after 2 weeks of TNP, equally treated with lower levels (50–125 mmHg) of negative pressure compared with the group without suction or with −25 mmHg suction. Another trial investigated the epithelialization of split thickness skin graft donor sites with different depth treated with TNP as in a swine model as well as in a clinical setting with 15 patients [27]. A second donor site treated with Opsite® foil acted as a control group. Histological analysis of punch biopsy specimens described a significant and earlier increase of epithelialization in the negative pressure group.

Cellular synthesis

Kremers et al. [28] investigated in vitro fibroblasts cultured out of arterial walls, exposed to stress of mechanical stretching (VT, 5 min on; 2 min off mode), and showed a significant increase of p38 protein kinase and appendant transcription factor, representing markers of cell proliferation. Fibroblasts not exposed to mechanical stretching acted as a control group. No direct conclusions could be drawn because of the differences in targets of the used biaxial stretch stimulation versus VT producing positive pressure values, too. In a controlled randomized trial in 30 diabetic foot ulcer patients, Kopp et al. [29] showed a higher increase of growth factors [e.g. platelet-derived growth factor; vascular endothelial growth factor; transforming growth factor β (TGF-β) measured on days 0, 2, 4, 6, and 8] in wound fluid in the VT group versus the hydrocolloid group. Platelet-derived growth factor effects an increase of mitosis in fibroblasts and smooth muscle cells; TGF-β is considered to stimulate collagen and elastin production and inhibit metalloproteinases. Premature conclusions should not be drawn because efficacy of cytokines can be depressed by proteases. VT potentially can interact in wound healing by eliminating proteases. Until now, no conclusion could be drawn defining which effect is predominating: the synthesis of cytokines or the inhibition of proteases. Shi et al. [30] found a decrease in metalloproteinases by analysing wound fluid in five patients with chronic wounds treated by vacuum-assisted closure therapy. The authors concluded that the minor expression of MMP1, MMP13, and MMP2–mRNA was a result of VT resulting in a better wound healing. There was no control group; furthermore, the role of metalloproteinases in wound healing is seen differently.

Complex effects

Bacterial clearance and infection control

Morykwas et al. [2] found a significant reduction of bacteria on day 5 in artificial wounds in a swine model, treated for 2 weeks by vacuum-assisted closure therapy versus saline gauze in the control group. After day 5, no further reduction occurred. This trial was prospective and controlled but not randomized or blinded. Mouës et al. [31] measured the bacterial concentration in chronic wounds of 29 patients treated by vacuum-assisted closure therapy versus a saline gauze group as control. The clinical trial was controlled, randomized, and blinded. The results showed no differences in concentration between both groups. Although the amount of Staphylococcus aureus cultures increased, the amount of Gram-negative cocci decreased significantly in the vacuum-assisted closure group. Weed et al. [32] found equal bacterial rates in chronic wounds in the course of VT. Both authors observed better wound healing despite constant or increased bacterial count [31, 32]. Fleischmann et al. [33] and, later, von Fritschen et al. [34] used the combination of vacuum-assisted closure therapy with instillation of antiseptics or antimicrobial agents in wounds. Fleischmann et al. [33] investigated different kinds of wounds, whereas von Fritschen et al. [34] studied those with tissue defects and exposed orthopaedic hardware. All wounds healed after obtaining sterile swabs. One case of recurrent infection of an endoprosthesis appeared during the first trial. Von Fritschen et al. [34] used sufficient flap coverage for maintenance of orthopaedic hardware. Both authors concluded that instillation therapy led to elimination of infection by gaining sterile swabs, followed by successful wound coverage. Ngo et al. [35] described the effects of combined TNP and antiseptic instillation on Pseudomonas biofilm. In an in vitro model of chronic wounds, he found an approximately 100-fold enhancement of bacteriocidal effect when povidone iodine, as instillation solution, was combined with TNP in comparison with povidone iodine alone. Outcome parameters measured in this study included viable bacterial count, fluorescent microscopy, and electron microscopy. Until now, there is a lack of evidence-based data, showing efficacy of VT and antibiotic or antiseptic instillation. The VAC-Instill® therapy system (KCI) seems to be a promising approach concerning reduction of bacteria and control of infections; however, aside from this, surgical debridement is still essential.

Fluid analysis

Gouttefangeas et al. [36] investigated chronic wounds immunohistochemically by studying the infiltration of foam by leukocytes after 5 days of VT. He was able to detect neutrophils, macrophages and lymphocytes, and especially activated T-cells in high concentrations. Bischoff [37] however tried to prove the bactericidal effect of drained wound fluid against S.aureus, Sepidermidis and Ecoli. In an invitro test 93% bactericidal activity in the group treated with antimicrobial agents was reduced 66% treated without them. The authors concluded there seems to be an anti-infective potency with. In both studies a control group is lacking and results of bactericidal activity in wound fluid with or without administered antibiotics really surprising.

Immunologic response

Banwell et al. [38] found in a prospective clinical trial a significant reduction of extravasation of neutrophils by immunohistochemical analysis in second-degree human burns treated by vacuum therapy versus a conventional control group. He concluded the attenuation of burn depth progression by TNP via selective modulation of neutrophil extravasation. Similar results were described by Adams et al. [39] in treatment of burns and skin graft donor sites. Both authors investigated extravasation of inflammatory cells and found a decrease. Concerning acute burns, VT seems to decrease burn depth progression by diminishing interstitial inflammatory cells, whereas concerning contamination in chronic wounds, VT seems to boost immunologic reaction. In conclusion, until now, these situations are only presumptions.

Systemic effects

Morykwas et al. [40] investigated the influence of vacuum-assisted closure therapy on crush injury after 2, 4, and, 6 h, in a standardized rabbit model. He measured serum myoglobin and found a significant decrease in the VT group versus the ‘foam alone’ control group. In a randomized clinical trial, Buttenschoen et al. [41] investigated the effect of VT on systemic inflammatory infection TGF-β. He compared patients with fractures of the talocrural joint. One group was surgically treated by primary wound closure versus another one treated by VT. Half an hour after surgical closure, he found a significant increase in endotoxins in comparison with the VT group. Other parameters such as haptoglobin, transferrin, C-reactive protein IL-6, and α-1-antitrypsin, and complement factors C3 and C4 remained equal. The authors concluded minor systemic effect of VT concerning the small size of wound surface. In an animal study with artificial 15% body surface area burns, Kremers et al. [42] observed a decrease in thromboxane XA2-stimulating vasoconstriction and an increase in prostaglandin 12-stimulating vasodilation in mesenterial perfusion 30–180 min after trauma in the VT group versus the ‘foam alone’ group.

Matrix function

Vacuum-assisted closure therapy is used with either PU (PU foam or ROCF) or polyvinyl alcohol foam in vivo. ROCF)-related materials are still used in tissue engineering (TE). TE is a relatively new, interdisciplinary, and multidisciplinary field that has seen intense development in recent years. One of the main motivations for TE research is the chronic shortage of organ donors and other limitations related to organ and tissue transplantation. The idea that tissues and, ultimately, organs can be ‘engineered’ to be used in patients requiring transplantation is, at the same time, revolutionary and stimulating. However, TE is a discipline still at its infancy, an intricate puzzle far from being completed. One key piece of this puzzle is the scaffold that provides temporary support for cell proliferation and differentiated function, allowing neotissue formation and initial remodelling. Vacuum-assisted closure therapy, when using matrix materials, will increase cell proliferation and angiogenesis, and increasing depth of penetration could be the key point of further studies in the future.

Flap survival

Morykwas et al. [2] described in a swine model the effect of vacuum-assisted closure therapy (−125 mmHg) on critically perfused random pattern flaps (width–length ratio, 1 : 4). He found a significant increase in flap survival and less tissue loss compared with the VT group. Holle et al. [43] described in a clinical trial a 100% tissue survival in seven random pattern flaps with critical tip perfusion after VT. He used −100 mmHg subatmospheric pressure in an intermittent mode.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of Interest
  9. References

Analysis of all these studies showed that effects of vacuum-assisted closure therapy seem to take place in the early stage of wound healing and seem to be terminable. VT seems to aim physiological processes of per secundam healing respectively supporting them. Regarding infection control, VT is a useful tool in case of acute processes and short treatment intervals, whereas chronic infections might benefit from instillation with antiseptics or antibiotics.

The increase of blood flow seems to be proven, whereas the mode of action, as well as the therapy continuation time as the amount of affected tissue, remains still unclear. Oedema reduction, environment, wound protection, and stabilization are still investigated in studies until now, however, without convincing evidence. Until now, there is a lack of data concerning the required duration of VT. Only in a few studies the complete healing after VT could be observed. Large wounds and soft tissue defects stay as plastic surgery domains. Primary wound closure by tissue replacement should always be aspired, particularly to avoid masses of granulation tissue followed by scar formation and functional impairment. The risk of fibrosis, recurrent infection, and scar cancer is not inestimable, although there is a lack of data. Many patients with chronic wounds are not optimal candidates for reconstructive procedures. If treated with VT, their wounds can stabilize and comorbidities can be controlled, allowing for definitive closure under elective conditions with skin grafts or flaps. By analysing data according Cochrane Collaboration 2001, AWMF 2006, Augustin and Herberger [44] found 269 original articles among 674 publications on VT online; he described the effectiveness and benefits of VT on chronic wounds: diabetic foot ulcer – level Ib (24 studies), chronic venous ulcer – level Ib (32 studies), and pressure sores – level Ib (27 studies). Concerning acute wounds, he stated level II for trauma tissue defects (73 studies), level IV for burns (12 studies), level IV for surgical site infections (94 studies), level IV for noninfected postoperative wounds (20 studies), level II for fistula and sinus pilonidalis (24 studies), and level Ib for securing skin grafts (33 studies).

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of Interest
  9. References

Although TNP appears effective and its superiority to conventional techniques has been demonstrated, there are still some critical votes concerning efficacy. Because its mechanisms of action remains partly unclear and because there are still some gaps between evidence-based data and the excellent clinical results, further prospective, randomized, ideally blinded studies are needed. Even so, we may conclude that TNP, when used on the right indication and especially by experienced healthcare professionals (e.g. surgeons), is an excellent tool to support wound healing and even to save lives.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of Interest
  9. References
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  • 38
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  • 41
    Buttenschoen K, Fleischmann W, Haupt U, et al. The influence of vacuum-assisted closure on inflammatory tissue reactions in the postoperative course of ankle fracture. Foot Ankle Surg 2001; 7: 165173.
  • 42
    Kremers L, Wanner M, Argenta JA, et al. Effects of subatmospheric pressure on PG12 and TBX-βA2 and control of visceral blood flow post burn. Wound Repair Reg 2003; 11(5): 0.008.
  • 43
    Holle G, Peek A, Fritschen v. U, Exner K. 2002. Von der komplizierten Wunde zum Tissue-engineering. Besondere Indikationen für die VAC. Therapie. Abstractband, 33. Jahrestagung Vereinigung der Deutschen Plastischer Chirurgen, 2002, S 48.
  • 44
    Augustin M, Herberger K. Benefits and limitations of vacuum therapy in wounds. Hautarzt 2007; 58(11): 945951.