Wounds in infection and sepsis

• Wound healing is an integral step to the

restoration of tissue after injury
• The majority 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.
 initial phase of healing
• 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.
• 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.
 second phase of wound healing
• 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.
• 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.
• 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.
 wound healing in sepsis
• 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.
• 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.
• 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.
• 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.