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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Wounds in infection and sepsis - role of growth factors and mediators

, M.D. and , M.D.

Departments of Surgery, Sinai Hospital and the Johns Hopkins Medical Institutions, Baltimore, Maryland, U.S.A.

Wound healing is an integral step to the restoration of tissue after injury. Surface wounds are often the only external evidence of surgical intervention and as such are the patients' visual link to their procedures. The major`ity of wounds heal without difficulty. However, wound complications such as infection, disruption, or delayed closure can be devastating.

Phases of normal healing

Although wound healing is a dynamic cascade of events initiated by injury and extending well beyond the restoration of tissue continuity, it may be divided into distinct phases as characterized by both the predominant cellular population and cellular function.

Tissue disruption causes bleeding and initiates the coagulation cascade. Platelet activation, in the form of degranulation and adhesion, leads to hemostasis and chemotaxis of inflammatory cells. These are the hallmarks of the initial phase of healing. The inflammatory phase of healing (injury to 5 days) is defined by neutrophil infiltration with subsequent replacement by macrophages and lymphocytes. Each population of cells acts in response to specific cytokines that are temporally released as the normal healing process progresses. Neutrophils function primarily to clean the wound environment by production of superoxides that kill bacteria and by phagocytosis of necrotic material. Although optimal healing requires that all different populations of cells be present, only macrophages are an absolute necessity. The fibroplastic phase is the second phase of wound healing (days 4 through 12). Macrophages produce growth factors and other cytokines which then promote fibroblast migration, proliferation and collagen synthesis. It is during this phase that tissue continuity is restored; angiogenesis and epithelialization are also achieved. The maturation and remodeling of the scar begins during the fibroplastic phase and is characterized by reorganization of the previously synthesized collagen. Collagen is broken down by matrix metalloproteinases (MMPs) and net collagen in the wound is the result of a balance between collagenolysis and collagen synthesis.

Role of growth factors in normal healing

Growth factors are polypeptide substances which function to stimulate cellular migration, proliferation and function (table I). They are often named for the cells from which they were first derived (i.e. platelet-derived growth factor, PDGF) or for their initially identified function (i.e. fibroblast growth factor, FGF). These names are at times misleading because growth factors have multiple functions (and their functions continue to be defined). Most growth factors are extremely potent and produce their effects naturally in nanomolar concentrations. They may act in an autocrine manner (where the growth factor acts on the cell producing it), a paracrine manner (by release into the extracellular environment where it acts on the immediately neighboring cells) or in an endocrine manner (where the effect of the substance is distant to the site of release and the substance is carried to the effector site through the blood). Temporal release of growth factors may be as important as concentration in determining effect. As these polypeptides exert their effects by cell-surface receptor binding, the appropriate receptor on the responding cells must be present at the time of release in order that the effect occur.

Table I. Origin and action of growth factors.

Table I

Origin and action of growth factors.

Impaired healing in sepsis

The global physiologic changes characteristic of sepsis or septic inflammatory response are governed by a heightened production and release of inflammatory cytokines with their concomitant dysregulation. This extended production of acute phase proteins may be likened to a light switch stuck in the on position. Frequently the most readily identifiable cause is a focal infection (or septic source), but the hyper-dynamic state of inflammatory response may be the result of overwhelming injury as well. Excessive inflammatory mediators are responsible, either directly or indirectly, for fever, hypotension, elevated cardiac output, depressed tissue perfusion and continued protein catabolism.

There are several ways in which wound healing is impaired during sepsis. The key to survival following severe traumatic or infectious insult is the maintenance of blood flow to essential organs. This occurs at the expense of non-essential structures such as viscera, skeletal muscle and cutaneous tissue. Prolonged insult results in impaired cellular oxygen perfusion (tissue hypoxia) in the setting of an increased metabolic state; ultimately there is progression to multiple organ failure. Locally, hypoxia is exacerbated by the edema which results from leaky capillaries. Hypoxia itself is a powerful stimulant of the healing response. The accumulation of toxic metabolites and excessive inflammatory cytokines are a direct result. Macrophages activated by the hypoxic stimulus produce pro-inflammatory cytokines (such as TNF-α; and IL-1β). These then lead to altered of MMP synthesis with increased collagenolysis and decreased collagen synthesis; the resultant decreased wound collagen content physically weakens the wound leading to acute wound failure. Hypoxia also impairs leukocyte killing of bacteria, angiogenesis, collagen synthesis and thus contributing to depression of healing. It is important to recognize that growth factors influence normal cellular function, but do not correct deficits caused by inadequate oxygen delivery.

As wound healing is a restorative process, tissue repair is anabolic and requires an adequate nutrient supply. Sepsis induces an overwhelmingly catabolic state where nutrient allocation is detrimental to healing tissues. Additionally, poor nutritional status significantly impairs immune response, which in itself is closely linked to the wound healing cascade.

It is still unclear the degree to which local or systemically produced inflammatory cytokines result in wound impairment. Excessive or prolonged inflammation enhances scarring; conversely, anti-inflammatory therapy (such as steroids and NSAIDs) adversely effect wound healing. There are no studies examining the effects of inflammatory cytokine modulation and clinical wound outcomes in humans. Nor are there consistent data to support modulation of the inflammatory responses seen in septic syndromes by monokine (or anti-monokine) therapy that correlate with positive outcome.

Dietary enhancement with immunomodulators such as arginine, nucleic acids and omega-3 fatty acids have demonstrated some benefit in decreasing ICU stay and total ventilator days, but does not appear to benefit mortality. Its role in wound healing or failure has not been examined. Supplemental dietary arginine, which is known to both qualitatively enhance wound collagen deposition and T-cell reactivity in normal and physiologically stressed humans, has not been assessed for affect on clinical wound outcome.

Optimization of oxygen delivery, providing adequate nutrition and treating proven infected sources are the therapeutic mainstays for the septic patients. They are also appropriate for reducing the effect of sepsis on the healing wound. At present, the greatest benefit to wound healing during sepsis is to eliminate the sepsis. Concerns about wound healing in septic or inflammatory states are directed most frequently towards the acute post-surgical wound. Wound failures in these patients (i.e. abdominal dehiscence or anastomotic disruption) are devastating and frequently fatal occurrences. Unfortunately it is difficult to predict which wounds will become clinically significant prior to the event.

Surgical site infection

Surgical site infection inhibits healing by maintaining an inflammatory state in the healing tissues. Additionally, the inflammatory response may be especially damaging secondary to excessive neutrophil accumulation, superoxide and protease release, tissue necrosis and pus formation. This also contributes to acute wound failure. Appropriate wound care consisting of debridement of necrotic tissues and drainage of purulent collection combined with systemic antibiotic therapy remain the most important therapies for surgical site infection.

Current clinical strategies for growth factor therapy

The concept is to flood the wound with a growth factor (or mix of growth factors) in order to stimulate cellular proliferation and decrease time to re-epithelialization. Table II lists a number of current and potential delivery systems of growth factors to wounds.

Table II. Current and potential methods of growth factor delivery to wounds.

Table II

Current and potential methods of growth factor delivery to wounds.

Growth factors for clinical therapy are retrieved from recombinant or homologous/-autologous sources. Recombinant sources allow the production and purification of high concentrations of individual growth factors which may then be combined with the delivery vehicle of choice. Autologous growth factors are harvested from the patient's own blood; this method results in a combination of factors (a “soup”) which is then applied to the wound. Platelet-derived wound healing factor (PD-WHF) which is derived from the alpha granules of platelets and contains PDGF, TGF-β, platelet factor 4, platelet-derived angiogenesis factor and platelet-derived epidermal growth factor is an example of autologously obtained growth factors. This approach allows treatment with patient-specific factors at a physiologic ratio of growth factor concentrations.

Only PDGF-BB is currently approved by the US Food and Drug Administration for treatment of diabetic foot ulcers. Once daily application to diabetic lower extremity ulcers of recombinant human PDGF-BB in a gel suspension both increases the incidence of total healing and decreases the time to healing (grade A). Several other growth factors have been tested clinically and show mixed promise, but are currently available as treatment in wound centers as clinical trials.

Although there is a large body of work outlining the effects of growth factors on wounds in animals, this data is not directly translatable to humans. The paradigm for assessing growth factors in human wound healing has been either chronic wounds (such as diabetic, pressure, or venous stasis ulcers) or split-thickness skin graft donor sites. At present, it is left to the individual physician to translate this information to other wounds such as the acute incisional wound failure or wounds in the septic host. Additionally, most growth factor studies use a topical delivery methodology which may not be appropriate for all problem wounds.

Conclusion

Regardless of growth factor or the mechanism of delivery, this type of therapy requires concomitant good wound care. The gold standard for treatment of complex wounds remains appropriate local management by eliminating infection, debridement of devitalized tissue and optimizing oxygen delivery. Control of systemic pathology (such as sepsis and diabetes) is vital.

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Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6957

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