Keywords
lower-limb reconstruction - lower-limb trauma - negative-pressure wound therapy -
tissue resurfacing
Introduction
Lower-limb reconstruction in the setting of trauma is challenging. With advances in
the understanding of wound healing physiology, there have been a large number of wound
healing aids that have been introduced. Negative-pressure wound therapy (NPWT) is
one such aid that has been increasing in popularity among clinicians and has changed
the way we now treat lower-limb injuries in trauma.
In this review article, we aim to look through the evidence behind the use of NPWT
in lower-limb reconstruction and how our current clinical practices have changed as
a result of NPWT and the cellular and tissue responses to NPWT.
History of Negative-Pressure Wound Therapy
History of Negative-Pressure Wound Therapy
Morykwas et al introduced the concept of a subatmospheric pressure method for the
treatment of wounds: vacuum-assisted closure (VAC).[1] This technique was developed as a means to expedite the rate of wound healing by
secondary intention. In his porcine model, they found that wounds treated with VAC
had increased blood flow levels, increased granulation tissue formation, decreased
tissue bacterial counts, and significantly increased survival rates of random pattern
flaps.
VAC was initially designed to aid the healing of chronic wounds, but it has progressively
been used for the management of all types of wounds, ulcers, and burns. Given the
increase in the usage of NPWT, there have been multiple advances in dressing technology
related to NPWT such as silicon interfaces, open-cell foam types with differing pore
densities, and an irrigation system to allow the instillation of fluids into the wound.
Given all the advances in NPWT, there has been a global increase in the number of
such devices being used and the market continues to grow.
Technique of Negative-Pressure Wound Therapy Application
Technique of Negative-Pressure Wound Therapy Application
The technique of NPWT application is relatively straightforward. After thorough debridement
of the wound, proper hemostasis, and coverage of all critical structures such as blood
vessels and nerves, the wound bed is ready for application of the NPWT[2] ([Fig. 1]). NPWT consists of continuous or intermittent subatmospheric pressure applied to
an open-cell foam that is sealed in an occlusive dressing ([Fig. 2]). This creates a sterile, closed, vacuum-sealed environment that is connected to
a vacuum pump. The negative pressure (50–175 mm Hg) and the mode used (intermittent
or continuous) can be customized according to the patient and wound type.
Fig. 1 An open trimalleolar ankle fracture with a critical defect over the lateral ankle
underwent external fixation and debridement. Antibiotic-laden cement beads were packed
into the critical defect during the second debridement and washout.
Fig. 2 These are the materials used when applying negative-pressure wound therapy—open-cell
foam, occlusive dressing, and the trackpad.
To prevent the surrounding intact skin from becoming macerated, the open-cell foam
should be cut smaller than the actual wound size and can be halved to reduce the thickness
of the foam ([Fig. 3]). In certain cases, the wound edge can be lined with a protective hydrocolloid dressing
to further prevent skin maceration ([Fig. 4]). Once the open-cell foam has been applied to the wound, occlusive dressing is placed
and a hole is cut into the dressing to allow for creation of the vacuum-sealed environment
by the application of the trackpad ([Fig. 5]). Once the machine is turned on, one should see the open-cell foam contract and
no leak should be noted on the machine ([Fig. 6]). NPWT should be changed ideally in the operating theater or by the bedside every
72 to 120 hours.
Fig. 3 For wounds that are shallow, the open-cell foam can be halved before application.
Ensuring that the foam is smaller than the actual wound size also prevents surrounding
skin maceration.
Fig. 4 The wound edges are further lined with a protective hydrocolloid dressing to prevent
surrounding skin maceration.
Fig. 5 After applying the occlusive dressing over the foam dressing, a hole is cut in the
dressings to allow for application of the trackpad to create the vacuum-sealed environment.
Fig. 6 On turning the negative-pressure wound therapy machine on, the open-cell foam is
seen to contract and the leak status can be observed from indicators on the machine.
Wounds that are contraindicated[3] for the use of NPWT include (1) actively bleeding wounds, (2) inadequately debrided
bone and soft tissue infections, (3) malignant wounds, (4) nonenteric and unexplored
fistulae, and (5) necrotic tissue with eschar present. Before the application of NPWT,
all wounds require a proper debridement, adequate hemostasis, and protection of neurovascular
structures.
Clinical Benefits of Negative-Pressure Wound Therapy
Clinical Benefits of Negative-Pressure Wound Therapy
Timing of Reconstruction
Previously according to Godina, early microsurgical reconstruction within 72 hours
from trauma increased flap survival, reduced infection, and shortened hospitalization
stay of patients.[4] However, this notion has been challenged by many authors. Some have found that reconstruction
can be performed up to 2 weeks from injury[5] and that flap survival is not time dependent.[6] Thus, the timing of lower-limb reconstruction in trauma is still controversial.
The availability of NPWT has allowed us to stretch the duration till definite lower-limb
reconstruction. Exposed fractures may predispose to increased rates of wound infection
and adverse outcomes, and this has driven the need for urgent coverage.[7] NPWT allows for temporary coverage of the wound in a sterile environment while applying
negative pressure at the wound bed to reduce tissue edema, promote granulation tissue,
and enhance bacterial clearance. This has resulted in an increase in NPWT being used
for open lower-limb fractures before reconstruction.[4]
Effect on Infection Rates
The initial work by Morykwas et al showed that NPWT increased bacterial clearance
in the porcine model with a reduction in the daily quantitative bacterial counts over
a 5-day treatment period.[1] These results were replicated in a subsequent human study that they conducted on
300 wounds, ranging from acute and subacute to chronic.[8]
Since then, there has been conflicting evidence in the literature regarding the effect
of NPWT on infection rates. There have been multiple studies published showing no
significant difference between infection rates in wounds treated with NPWT and conventional
dressings.[9]
[10] Yet, there has also been more recent evidence showing that NPWT has helped significantly
decrease the rate of infection when used in the treatment of open tibial fractures.
Joethy et al conducted a retrospective analysis of Gustilo IIIB tibial fractures between
two periods of time: 2003–2004 and 2008–2009.[11] All patients underwent free flap reconstruction, with the earlier cohort being treated
with occlusive dressings as compared with the later cohort who had NPWT. There was
a statistically significant difference in infection rates, with the NPWT cohort having
roughly one-third the rate of infection (10% [5/51] vs. 33% [6/18], p = 0.029).
This study was further supported by a prospective randomized study by Stannard et
al, which found a significantly lower deep infection rate in open fractures covered
with NPWT compared with conventional dressings.[12] Similar results were also found by Blum et al who concluded that NPWT substantially
decreases deep infection when used in the soft tissue management of open tibial fractures.[13]
Effect on Flap Failures and the Need for Complicated Reconstructive Procedures
NPWT has been reported to increase granulation tissue formation and blood flow to
the wound bed. It has also shown to improve the survival of random patterned flaps
in its original animal study.[1] When used in the management of open Gustilo IIIB tibia fractures, Joethy et al found
a lower rate of flap failures as compared with when occlusive dressings were used
(6% [3/51] vs. 11% [2/18]).[11] However, in this study, this result was not noted to be statistically significant.
Lower-limb trauma wounds with exposed tendon, bone, and implants would usually require
flap reconstruction. However, with the increased use of NPWT in the management of
such cases, there has been a growing number of publications showing a reduction in
the need for free tissue transfers. DeFranzo et al looked at the use of NPWT in wounds
with critically exposed structures in 75 patients.[14] All wounds were closed with delayed primary closure, split-thickness skin grafts,
or regional flaps without the need for free tissue transfer.
Herscovici et al prospectively studied the use of NPWT in 21 high-energy soft tissue
wounds where flap reconstructive procedures would have originally been performed.
After an average of 4.1 sponge changes over an average of 19.3 days (5–84 days), further
reconstructive surgery was avoided for 57% of the wounds.[15] Other than the decrease in the overall need for flap reconstructive procedures,
it has also provided an alternative option for otherwise non-salvageable wounds in
medically unfit patients. Despite all the benefits of NPWT, it is important to remember
that it does not replace the need for formal wound debridement.
In the below clinical scenario, an open wound was sustained over the left anterior
tibia, which eventually became infected and broke down ([Fig. 7]). After a proper debridement, the tibia devoid of periosteum ([Fig. 8]) was exposed, and the use of NPWT allowed us to delay the need for flap reconstruction
until the wound was clear of infection. A bipedicled perforator flap ([Fig. 9]) based on the posterior tibial artery was performed to resurface the anterior tibial
wound with split-thickness skin grafting ([Fig. 10]) applied over the gastrocnemius muscle.
Fig. 7 The left distally based anterior tibia wound was initially sutured. It subsequently
became infected 2 weeks later and the patient required readmission for surgical debridement
and intravenous antibiotics.
Fig. 8 Post-debridement, the critical defect over the tibia devoid of periosteum was 10
cm (L) × 6 cm (W). The wound was covered with negative-pressure wound therapy thereafter
until intraoperative cultures were negative.
Fig. 9 A bipedicled flap based on the perforators of the posterior tibial artery was raised
to resurface the critical defect over the anterior tibia.
Fig. 10 Split-thickness skin graft was harvested from the left medial thigh and meshed 1:1.5.
Negative-pressure wound therapy was placed over the skin graft recipient site and
removed after 5 days once 100% graft take was established.
Our Current Understanding of Basic Science
Our Current Understanding of Basic Science
Although widely used in clinical practice, the mechanisms by which NPWT promotes wound
healing remain under investigation.[16]
[17]
[18] Its beneficial result appears to be the consequence of multiples effects triggered
at the tissue and cellular levels supporting the healing mechanism.[16]
[17]
Macro- and Micro-deformation–Induced Angiogenesis
The earliest effects that were investigated were related to the mechanical stress
that NPWT applied to the wound as it was suspected to be an important factor in the
positive effects observed on the healing process. One of the mechanical effects imposed
by NPWT on the wound edges is macro-deformation[17]: this results in the application of a compressive force on the tissues that promote
wound contraction[19] and can potentially reduce edema by pushing fluids away.[20] Although not considered as the major contributor of wound healing promoted by NPWT,
the effect of macro-deformation plays a part in its efficiency.[16]
The second type of mechanical effect triggered by NPWT is micro-deformation: This
results from the interface created between the wound bed and the foam material used
to apply a uniform negative pressure on the wound bed.[21] This effect has been directly correlated with an improvement in blood perfusion,
angiogenesis, and cell proliferation.[22]
[23]
[24]
[25] Although poorly understood, it has been shown to stimulate basic fibroblast growth
factor upregulation and the downstream activation of ERK1/2, indicating cell proliferation
stimulated through mitogen-activated kinase pathway.[24]
[26] In addition, micro-deformation stimulates angiogenesis and vascular remodeling through
upregulation of vascular endothelial growth factor (VEGF), which is critical in the
elongation and proliferation of endothelial cells, and also plays an important role
in the regulation of inflammation.[22]
[26]
[27] Other proteins upregulated with NPWT treatment include intercellular adhesion molecule
1—a glycoprotein expressed on the surface of endothelial and immune cells that play
a role in inflammation and transmigration of immune cells through the endothelial
barrier.[28] Macrophage migration inhibitory factor is also upregulated, and this proinflammatory
lymphokine has the ability to regulate macrophage migration, function, and regulation
of the antioxidant response elements system.[28]
[29]
[30]
Hypoxia Signaling and Angiogenesis
NPWT has a positive impact on angiogenesis, and this has been linked to the modulation
of the hypoxic response. Hypoxia-inducible factor 1α, a master regulator of hypoxia
signaling, has been observed to have decreased expression[31] whereas angiogenic factors such as VEGF and angiopoietin 2 are observed to increase.
These events cause the regulation of hypoxia within the wound bed, optimizing the
shape and function of neovascularization. NPWT may destabilize blood vessels in the
early phase of wound healing and allow for the formation of new vessels at the later
phases of wound healing, allowing the establishment of mature blood vessels.[32] Other factors involved in angiogenesis such as platelet-derived growth factor and
epidermal growth factor (EGF) have also been shown to increase with NPWT.[33] Angiogenesis is critical in the promotion of wound healing and is also an important
parameter in the formation of granulation tissue.
Hypoxia Signaling and Lactate Production
Another effect induced by hypoxia is lactate production, which is an important metabolite
involved in wound healing.[34] As lactate is able to act as a surrogate to hypoxia and stimulate the hypoxic pathyways,[35]
[36] it is able to modulate angiogenesis and promote collagen deposition for granulation
tissue formation.[34]
[37]
The major mechanisms modulated by NPWT comprise pathways regulating inflammation,
angiogenesis, and extracellular matrix formation.[37] Whereas these are the major pathways that have been identified in the cellular mechanisms
triggered by negative pressure, gaps remain to be filled and new questions arise about
how all these events are interconnected to fully assess the impact of NPWT on tissue
repair.[16]
[17] Mechanotransduced signals, energetic metabolism modification regulated by NPWT,
are among the most interesting but still poorly understood mechanisms involved in
NPWT. By understanding them, it may be possible to further modify them, with the eventual
goal of further aiding wound healing.
Conclusion
The use of NPWT in the management of complex lower-limb wounds has been increasing
over the past two decades since its initial introduction. There has been a growing
body of evidence to show its efficacy, how it has changed current treatment practices
in multiple centers globally as well as an evolving understanding of the science behind
it. NPWT has proven to be a useful adjunct in the treatment of lower-limb trauma,
and its use has been included in our institution's standardized guidelines for the
management of open lower-limb fractures. At present, better evidence is required to
further justify the growing use of NPWT in lower-limb reconstructions.
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