Download Wounds and Scars - Tulane University

WOUNDS AND SCARS
George Broughton II MD PhD and Rod J Rohrich MD
WOUND HEALING
The ability to heal wounds by forming scar tissue
is essential to the survival of all higher species.
Indeed, wound healing is the very foundation of
our specialty. Although we can now intervene in
some chronic wounds to accelerate healing, a conservative and noninterventional approach is still the
standard of care of acute wounds in an otherwise
healthy person.
For more than three centuries after Paré’s observations, our understanding of the biologic processes
involved in the healing of wounds was limited to
John Hunter’s experiments with replantation and
his musings on the difference between wound contraction and contracture, Joseph Lister’s writings on
wound sepsis, and Alexis Carrel’s notes on organ
transplantation and tissue preservation. The cellular
changes in healing soft-tissue wounds were not elucidated until the scientific method was applied in
the 20th century.
HISTORY
The biology of wound healing has been a concern of physicians through the ages. The earliest
medical writings dealt extensively with wound
care—eg, 7 of 48 case reports in the Smith Papyrus
(1700 BC) are about wounds and their management.1
The ancient physicians of Egypt, Greece, India,
and Europe practiced gentle methods for dealing
with wounds and appreciated the importance of
foreign body removal, suturing skin edges, and protecting injured tissues from the environment with
clean materials. Following the invention of gunpowder and ever-more-frequent gunshot wounds,
however, a new philosophy of wound care emerged
that no longer relied on natural processes of softtissue repair supplemented with cleanliness, gentle
washing with warm boiled water, and applications
of mild salves. For the next 250 years, surgeons
aggressively treated persons who had open wounds
with the likes of boiling oil, hot cautery, and scalding water. This “let’s-do-something-about-it” attitude toward wounds produced disastrous results.
In the mid-1500s, the great French army surgeon Ambroise Paré by chance rediscovered the
value of gentle methods of wound care. During the
battle of Villaine the supply of oil was exhausted,
and Paré was forced to use milder measures on
amputation stumps. To his surprise, these wounds
healed rapidly without the expected complications,
and from this modest beginning the modern era of
wound care evolved.
CURRENT KNOWLEDGE
The following pages summarize our knowledge of
wound healing. Despite great advances, at present
there is no “magic bullet” that can be used in the
management of wounds. Indeed, our current understanding of the intricate dance of cellular populations, intracellular events, and extracellular factors
that are involved in a healing wound belies the existence of such a compound or procedure. The myriad
molecular events involved in wound healing are well
reviewed by McGrath,2 Moulin,3 and Martin.4
PHASES OF HEALING
A thorough understanding of the wound healing
process is a prerequisite for managing surgical wounds.
The three classic phases of wound healing are:
inflammation, fibroplasia, and maturation (Fig 1).5,6
Inflammatory Phase
The sequence of events begins with a stimulus to
inflammation that evokes a nonspecific inflammatory response. The stimulus may be physical injury,
an antigen-antibody reaction, or infection. Inflammation is a cellular and vascular response that serves
to clean the wound of devitalized tissue and foreign material.
The initial changes are vascular. After the injury
there is a transient 5–10-minute period of vasoconstriction that serves to slow the blood flow
through the area and to aid hemostasis. Vasocon-
SRPS Volume 10, Number 7, Part 1
Fig 1. Schematic concept of wound healing. (Annotated from
Hunt TK et al (eds): Soft and Hard Tissue Repair—Biological and
Clinical Aspects, 1st Ed. New York, Praeger, 1984, p 5.)
striction is followed by active vasodilation. Vessel
walls (particularly small venules) become lined with
leukocytes, platelets, and erythrocytes, and leukocytes begin migrating into the wound for the
debriding process. There is a simultaneous increase
in permeability of the vessel walls: Endothelial cells
swell and pull away from their neighbors, opening
gaps through which the serum gains entry into the
wound.
Histamine is responsible for the initial vasodilation as well as for the early permeability changes.
Hemostatic factors released from the activation of
platelets, kinin components, complement components, and the prostaglandin system all participate
in sending cellular control signals to initiate the
inflammatory phase. At another level, fibronectin, a
major constituent of granulation tissue, seems to
promote the adhesion and migration of neutrophils,
monocytes, fibroblasts, and endothelial cells into
the wound region. Fibronectin is abundant in the
first 24–48 hours of injury, gradually disappearing
as protein synthesis and chronic inflammation
changes become predominant. The inflammatory
response of the injured tissues, then, is mediated
2
by local substances within the wound, culminating
in a a dynamic cellular milieu at the site of injury.
The precise role that each type of inflammatory
cell plays in the wound healing process remains
obscure. Both polymorphonuclear leukocytes
(PMNs) and mononuclear leukocytes (MONOs)
migrate into the wound in numbers directly proportional to the circulating concentrations.7 Although
the initial wound exudate contains mainly PMNs,
within the wound environment PMNs have a shorter
lifespan than MONOs, so that with prolonged
inflammation the exudate becomes predominantly
mononuclear.
Studies using specific anticellular sera suggest that
wound healing proceeds normally in the absence
of both PMNs and lymphocytes, but monocytes must
be present to trigger normal fibroblast production
and subsequent invasion of the wound space.
The early wound exudate also contains fragments
of cells disrupted during the initial injury, together
with foreign material and a continued bacterial challenge. There is also a variety of enzymes, both proteolytic and collagenolytic, and a number of biologically active substances.
Fibroblastic (Proliferative) Phase
Beginning on day 2 or 3 after wounding, fibroblasts begin to move into the wound along a framework of fibrin fibers established during initial
hemostasis. This fibrous scaffolding is essential to
fibroblast migration from their usual, mostly perivascular habitat8 in the tissues surrounding the wound.9
Once in the wound proper, fibroblasts produce
several substances essential to wound repair,
beginning with glycosaminoglycans and ending with
fibrillar collagen.10 Glycosaminoglycans are repeating disaccharide units attached to a protein core.
Hyaluronic acid is synthesized first, followed in short
order by chondroitin-4 sulfate, dermatan sulfate,
and heparin sulfate. As these are secreted by the
fibroblasts, they are hydrated into an amorphous
gel—ground substance—that plays an important role
in the subsequent aggregation of collagen fibers.7
The conversion of tropocollagen into fibrillar collagen is mediated by the action of two enzymes
and calcium.11 Collagen fibrils begin to appear as
ground substance accumulates, and over the ensuing 2–3 days are synthesized at a highly accelerated rate. Collagen levels rise continuously for
SRPS Volume 10, Number 7, Part 1
approximately 3 weeks,12 but as increasing quantities of collagen accumulate in the wound, the number of synthesizing fibroblasts begins to decrease,
until the rates of collagen degradation and synthesis
are equivalent—collagen homeostasis.
The increase in wound tensile strength that takes
place during the fibroblastic phase corresponds to
the increasing levels of collagen within the wound.
Gains in tensile strength are thus most rapid while
the collagen-building curve is climbing, although the
wound will continue to get stronger for some time.
In summary, the true fibroblastic phase begins
on or about the 4th day after injury and lasts
approximately 2 to 4 weeks, depending on the site
and size of the wound (Fig 2). Toward the end the
glycoprotein and mucopolysaccharide content of
scar tissue and the number of synthesizing fibroblasts will be markedly diminished, although the
region around the wound will remain more cellular
than the surrounding connective tissue for a period
of many months.
Maturation (Remodeling) Phase
The classic maturation phase of wound healing
begins approximately 3 weeks after injury. At this
time collagen synthesis and degradation are accel-
erated (no net increase in collagen content), large
numbers of new capillaries growing into the wound
regress and disappear, and collagen fibers initially
deposited in a haphazard fashion gradually become
more organized and arranged into a pattern determined by local mechanical forces. The maturation
phase is then fully under way.
During this phase the formerly indurated, raised,
and pruritic scar becomes a mature scar, while the
wound continues to gain tensile strength.12 Most of
the embryonic Type III collagen laid down early in
the healing process is replaced by Type I collagen,13
until the normal skin ratio of 4:1 Type I:Type III
collagen14 is obtained. The macromolecules of the
intercellular matrix are progressively degraded, the
hyaluronic acid and chondroitin-4 sulfate levels
decrease to resemble those of normal dermis, and
the water content of the tissues gradually returns to
normal.15 As new collagen is deposited during this
phase, more stable and permanent crosslinks are
established.
How long the maturation phase lasts depends
upon many variables, including the patient’s age
and genetic background, type of wound, specific
location on the body, and length and intensity of
the inflammatory period.
Fig 2. Time sequence of classical wound healing.
3
SRPS Volume 10, Number 7, Part 1
IMMUNE RESPONSE
The inflammatory response to tissue injury is characterized by the accumulation of polymorphonuclear leukocytes as well as macrophages. Macrophages appear at the site of injury within 48–96
hours, so that they actively participate in the
inflammatory and debridement phases.16 Activated
macrophages release two monokines known to have
angiogenic properties in vitro: interleukin-1 (IL-1)
and tumor necrosis factor-α/cachectin (TNF-α).17
IL-1 also promotes fibroblast proliferation through
the induction of protein-derived growth factor. Both
IL-1 and TNF-α stimulate and inhibit collagen synthesis and deposition under various conditions.16,17
A chemical factor in macrophages is necessary
for proper angiogenesis in early wounds.18,19 Fibrin
breakdown products may provide the signal for
development of vasculature at the appropriate time
in the healing process.20,21 Because their halflife
within the wound is longer, macrophages achieve
peak levels somewhat later than PMNs. Neutrophils in the wound are not necessary for chemotaxis of fibroblasts nor for eventual fibroplasia.22
T-lymphocytes migrate into wounds following the
influx of macrophages and other inflammatory cells,
and produce several lymphokines that influence
the endothelial cells of the wound through their
angiogenic and modulatory properties. These lymphokines both inhibit and stimulate fibroblast
recruitment and induce fibroblast proliferation via
fibroblast-activating factor (FAF). Some can also
inhibit collagen synthesis.16 Depletion of T-lymphocytes before or up to 1 week after wounding
results in decreased breaking strength of the wound
and impaired collagen synthesis and deposition.23
EPITHELIAL REPAIR
The epithelial portion of wound repair begins
with cell mobilization and migration across the
wound. Cellular numbers are thereafter augmented
by mitosis and cellular proliferation, while cellular
differentiation accounts for maturation into the normal epithelial appearance.
The epithelial cells immediately adjacent to the
wound initially undergo a mobilization process during which they enlarge, flatten, and detach from
neighboring cells and the basement membrane. As
the cells flatten they tend to flow in a direction
away from adjoining epithelial cells. The stimulus
4
to migration is an apparent loss of contact inhibition. As the marginal cells begin their migration, the
cells immediately behind them also tend to flatten,
break their cellular connections, and drift along;
epithelium thus flows across the gap of the wound.
The epithelial stream continues until the advancing
cells meet cells coming from the opposite side of
the wound, whereupon motion stops abruptly—
contact inhibition.
During their migration across the wound cellular
numbers are maintained by mitosis. Fixed basal
cells away from the wound edge begin mitosis to
replace the migrating cells, and as resurfacing of
the wound proceeds, the cells that have migrated
in turn start to divide and multiply. Increasing numbers of cells thicken the new epithelial layer.
Upon reepithelialization of the wound, the
orderly progression from basal mitotic cells through
layers of differentiated keratinocytes to stratum corneum is again established. In other words, once the
wound gap is bridged by advancing cells from the
perimeter, the normal cellular differentiation from
basal to surface layers resumes.
Cell receptors called integrins are said to “maintain integral cell contact through a bridge between
the extracellular structural protein matrix and the
cell’s internal cytoskeleton.”24 Integrins bind to specific extracellular proteins by recognizing a region
with a certain amino acid sequence. The integrinmatrix bond can be inhibited by monoclonal antibodies and synthetic peptides, which block the
receptors or the sites to which they attach.
SKIN METABOLISM AND PHYSIOLOGY
The blood supply of the skin is far greater than it
requires metabolically. Blood vessels in the skin
are capable of carrying 20–100X the amounts of
oxygen and nutrients that are needed for cellular
survival and function. (Cells above the basal layer of
the epidermis have largely lost their mitochondria
and respire mainly through glycolysis, contributing
little to the metabolic needs of the skin.) Despite
the abundant blood supply, skin perfusion is insufficient to support wound healing, which requires
granulation tissue.
Ryan25 summarizes this paradox as follows:
. . . the skin can resist many hours of compression and obliteration of its blood supply and . . .
[yet] nonhealing of the skin is one of the most
SRPS Volume 10, Number 7, Part 1
common of problems and is often blamed on
impairment of blood supply. . . .The dilemma is
explained by the fact that exchange between blood
vessels and the supplied tissue services the functions of that tissue, and, although it is often stated
that richness of the skin vasculature exceeds
nutritional need, this statement is a misconception.
. . . The frequent stimuli of scratching, stretching,
compressing, heating, or cooling of the skin requires
restoration of skin stiffness to a status quo. In
restoring itself to the status quo, the mechanical
properties of the skin must be instantly repaired and
this repair requires a luxurious blood supply to
maintain not merely cell metabolism but the
physical properties of the interstitium.
Ryan (1995)
COLLAGEN
Collagen is the principal building block of connective tissue, accounting for one third of the total
protein content of the body. Collagen is an unusual
protein in that it is almost devoid of the sulfurcontaining amino acids cysteine and tryptophan. In
their stead, collagen contains hydroxyproline and
hydroxylysine, two amino acids with very limited
distribution otherwise—only in collagen, elastin, the
C1q subcomponent of the complement system, and
the tail structure of acetylcholinesterase.26 Collagen
has a very complex tertiary and quaternary
molecular structure consisting of three polypeptide
chains, each chain wound upon itself in a lefthanded helix and the three chains together wound
in a right-handed coil to form the basic collagen
unit. The polypeptide chains are held in their relative configurations by covalent bonds. Each triple
helical structure is a tropocollagen molecule. Tropocollagen units associate in a regular fashion to
form collagen filaments; collagen filaments in turn
aggregate as collagen fibrils, and collagen fibrils
unite to form collagen fibers, which are visible under
the light microscope (Fig 3).
Five types of collagen have been identified in
humans on the basis of amino acid sequences. Their
relative distribution in connective tissues varies, hinting at individual properties valuable for specific functions (Table 1). Type I collagen is abundant in skin,
tendon, and bone. These tissues account for more
than 90% of all collagen in the body. Normal skin
contains Type I and Type III collagen in a 4:1 ratio,
the latter mainly in the papillary dermis. In hyper-
Fig 3. Molecular and fibrillar structure of collagen.
5
SRPS Volume 10, Number 7, Part 1
Table 1
Types and Distribution of Collagen
Fig 4. Collagen synthesis and site of action of common inhibitors.
(Annotated from Prockop DJ et al: The biosynthesis of collagen and
its disorders. N Engl J Med 301:13, 1979.)
trophic and immature scars the percentage of Type
III collagen may be as high as 33% (a 2:1 Type I:III
ratio).27
Collagen synthesis takes place extracellularly as
well as intracellularly. Certain substances inhibit
the formation of collagen either by interfering with
its synthesis or activating its degradation (Fig 4).
Normal connective tissue is in a state of dynamic
equilibrium balanced between synthesis and degradation, and this makes it vulnerable to local stimuli
such as mechanical forces on the tissue. While
excessive collagen degradation results from
unchecked collagenase synthesis, not enough collagenase gives rise to tissue fibrosis. Homeostasis is
achieved through activation of collagenase by parathyroid hormone, adrenal corticosteroids, and
colchicine; and inhibition of collagenase synthesis
by serum alpha-2 macroglobulin, cysteine and
progesterone.28
6
THE MYOFIBROBLAST
AND WOUND CONTRACTION
Contraction is an essential part of the repair
process by which the organism closes a gap in
the soft tissues. Contracture, on the other hand,
is an undesirable result of healing, at times due to
the process of contraction and at other times due
to fibrosis or other tissue damage.29
In 1971 Gabbiani, Ryan, and Majno 30 first
noted a type of fibroblast in granulation tissue
that bore some structural similarities to smooth
muscle cells. Myofibroblasts differ from ordinary
fibroblasts by having cytoplasmic microfilaments
similar to those of smooth muscle cells. Within
the filamentous system are areas of “dense bodies” that serve as attachments for contraction.
The nuclei demonstrate numerous surface irregularities such as those of smooth muscle cells but
unlike those of ordinary fibroblasts. Myofibroblasts
are also different from normal fibroblasts in that
they have well-formed intercellular attachments
such as desmosomes and maculae adherens.31–34
Myofibroblasts are the source of contraction
within a wound.31–34
SRPS Volume 10, Number 7, Part 1
Rudolph35,36 found a direct relationship between
the rate of wound contraction and the number of
myofibroblasts within a wound.35 Rudolph36 also
demonstrated the presence of myofibroblasts
throughout the wound, not just adjacent to the
wound margins. McGrath and Hundahl37 confirmed
the parallel paths of wound contraction and number of myofibroblasts in the wound and the relatively even distribution of myofibroblasts in granulation tissue except at the wound bed (fewer) and
adjacent to foci of inflammation (more). Their findings support the “pull theory” of wound contraction, which holds that the entire granulating surface
of the wound acts as a contractile organ. This concept implies contraction of individual myofibroblasts
to shorten the wound, followed by collagen deposition and crosslinking to maintain the shortening, in
a lock-step mechanism.
Prostaglandin inhibitors do not inhibit myofibroblast production, therefore wound contraction is
not altered.38 Although present in a number of contracture disorders like Dupuytren’s disease, 39
Peyronie’s, and lederhosen disease,32 myofibroblasts
have not been implicated in their etiology.
TENSILE STRENGTH
The tensile strength of a wound is a measurement of its load capacity per unit area. A wound’s
breaking strength is defined as the force required
to break it regardless of its dimensions. Depending
solely on different skin thicknesses, breaking strength
can vary severalfold; tensile strength, on the other
hand, is constant for wounds of similar size.
Experimental studies give evidence that collagen
fibers are largely responsible for the tensile strength
of wounds.13,40 The rate at which a healing wound
regains strength varies not only among species, but
also among individuals and even among different
tissues in the same individual.29 The healing pattern
of the various tissues, however, is remarkably similar within a philogenetic family.
All wounds gain strength at approximately the same
rate during the first 14–21 days, but thereafter the
curves may diverge significantly according to the
tissue involved. In skin, the peak tensile strength is
achieved at approximately 60 days after injury41 (Fig
5). Given optimal healing conditions, the tensile
strength of a wound never reaches that of the original, unwounded skin, leveling off at about 80%.
Fig 5. Tensile strength of a healing skin incision as a function of
time. (Reprinted with permission from Levenson SM et al: The
healing of rat skin wounds. Ann Surg 161:293, 1965.)
FACTORS IN WOUND HEALING
Numerous local or systemic, physical conditions
or chemical agents either enhance collagen remodeling or impair wound healing. Some of these are
discussed below.
Oxygen. Hunt and Pai42 showed that fibroblasts
are oxygen-sensitive: At partial pressures of 30–
40mmHg, fibroblast replication is potentiated.
Because collagen synthesis cannot take place unless
the PO2 is >40mmHg, both myofibroblast and collagen production can be stimulated by maintaining
the wound in a state of hyperoxia.43 Oxygen also
converts regenerating epithelial cells to aerobic
metabolism.44
The most common cause of wound infection or
failure of wounds to heal properly is deficient
wound PO2.45 Adequate tissue oxygenation implies sufficient inspired oxygen as well as component transfer of oxygen to hemoglobin, ample
hemoglobin for oxygen transport, satisfactory vascularity of the tissues to keep oxygen diffusion distances small, etc. The arterial pressure of oxygen
alone is not indicative of tissue oxygenation; despite
supplemental inspired oxygen, the wound itself may
remain ischemic if perfusion is inadequate. Most
healing problems associated with diabetes mellitus,
irradiation, small vessel atherosclerosis, chronic
infection, etc. can be ascribed to a faulty oxygen
delivery system at some point.45
7
SRPS Volume 10, Number 7, Part 1
Hematocrit. The quantity of hemoglobin that is
available to carry oxygen to the tissues would be
expected to be a critical factor in maintaining tissue
oxygenation, yet the data regarding the effect of
anemia on the tensile strength of a wound are contradictory.29 When the hematocrit is reduced to
50% of normal as a result of hemorrhage and the
blood volume has been replaced by plasma, some
investigators report a marked decrease in tensile
strength46 while others report no change.47,48
Mild or moderate anemia does not appear to be
detrimental to healing in a well-perfused wound,
with collagen deposition being proportional to tissue oxygenation and perfusion.48 The reperfusion
of injured tissue itself can be deleterious to wound
healing, however, with release of anaerobic
metabolites and reactive oxygen species creating
additional oxidative stresses.
Steroids and Vitamin A. One of the more frequent disorders of wound healing is arrest of
inflammation as a result of the administration of
steroids. The steroid seems to inhibit wound macrophages and also interferes with fibrogenesis,
angiogenesis, and wound contraction.45,49
Through a poorly understood mechanism, both
vitamin A and anabolic steroids will restore monocytic inflammation that has been retarded by antiinflammatory steroids.50,51 The exact dose of vitamin A required is not known, but oral ingestion of
25,000IU/d or topical application of 200,000IU ointment q. 8h is effective in most cases.
Vitamin A deficiency retards repair.52 Conversely,
ingestion of vitamin A stimulates collagen deposition and contributes to increased breaking strength
of wounds, while topically applied vitamin A accelerates wound reepithelialization. Hunt52 hypothesizes that retinoids are particularly important in
macrophagic inflammation to initiate reparative
behavior in tissue.
Supplemental estrogen applied topically improves
healing in elderly women.53
Vitamin C. Ascorbic acid is an essential cofactor
in the synthesis of collagen, a fact known since the
sailing days of the 16th century. Vitamin C is the
main vitamin associated with poor healing due to
its influence on collagen modification.54 L-arginine
is required in a variety of metabolic functions,
wound healing, and endothelial function. It is
8
important in the synthesis of nitric oxide, and deficiency is linked to immune dysfunction and failure
of wound repair. The effects of vitamin C deficiency on healing wounds include proliferation of
immature fibroblasts; failure of formation of mature
extracellular material; production of alkaline phosphatase; and formation of defective capillaries that
can lead to local hemorrages. Even healed wounds
deprived of vitamin C for long periods show diminished tensile strength. Nevertheless, high concentrations of ascorbic acid do not promote supranormal
healing.
Vitamin E. Although vitamin E has been used to
control various problems of wound overhealing,55,56
its therapeutic efficacy and indications remain to
be defined. Large doses of vitamin E inhibit healing, as reflected by decreased tensile strength and
lower accumulations of collagen.57 The mechanism
by which vitamin E exerts this effect is related to its
membrane-stabilizing properties. Vitamin E does
not reverse the delaying action of glucocorticoids
on wound healing and is in turn reversed by vitamin A.
Vitamin E increases the breaking strength of
wounds exposed to preoperative irradiation.58 As
an antioxidant, vitamin E neutralizes the lipid
peroxidation caused by ionizing radiation, thus limiting the levels of free radicals, peroxidases, and
other products of lipid peroxidation that are known
to cause cellular damage.
Zinc and Other Minerals. Many trace metals
including manganese, magnesium, copper, calcium, and iron are cofactors in collagen production and deficiencies in these minerals impair collagen synthesis.54 Zinc is essential for normal
wound healing. Zinc influences reepithelialization
and collagen deposition.59 Epithelial and fibroblastic proliferation is impaired in patients with
low serum zinc levels.60 Zinc also influences B
and T lymphocyte activity, but many other nutrients including copper and selenium have been
implicated in immune system dysfunction.61 Zinc
accelerates healing only when there is a preexisting zinc-deficiency state, otherwise it is of no benefit.62
Tissue Adhesives. Logic dictates that fibrin-based
tissue adhesives might be useful in wound healing,
SRPS Volume 10, Number 7, Part 1
since deposition of the fibrin network during clotting has been implicated in many aspects of cellular
events after injury. A report on mechanical properties of rat skin wounds treated with a fibrin glue
notes increased breaking strength, energy absorption, and elasticity of the healing wounds.63
Antiinflammatory Agents. Nonsteroidal antiinflammatory drugs (aspirin and ibuprofen) have
been shown by Kulick et al64,65 to decrease collagen
synthesis an average of 45% even at ordinary therapeutic doses. The effect is dose-dependent and
mediated through prostaglandins.66
Smoking. Smoking is harmful to a healing
wound.67–73 The mechanism of action is likely to
be multifactorial. Nicotine is a vasoconstrictive substance that decreases proliferation of erythrocytes,
macrophages, and fibroblasts.74,75 Hydrogen cyanide inhibits oxidative enzymes. Carbon monoxide decreases the oxygen-carrying capacity of
hemoglobin by competitively inhibiting oxygen
binding.72,76 This pathophysiologic triad reduces
the cellular response and efficiency of the healing
process. Smoking also increases platelet aggregation, increases blood viscosity, decreases collagen
deposition, and decreases prostacyclin formation,
which all negatively affect wound healing.73
The vasoconstriction associated with smoking is
not a transient phenomenon. Smoking a single cigarette may cause cutaneous vasoconstriction for up
to 90 minutes, and a pack-a-day smoker sustains
tissue hypoxia for most of each day. Tobacco-using
patients are therefore at risk of cutaneous hypoxia
from decreased arterial O2 and decreased tissue
perfusion as well as increased carboxyhemoglobin
levels.
Lathyrogens. As a group, lathyrogens prevent
the formation of aldehyde intermediates in the crosslinking process of collagen, reducing the strength of
the collagen bundles. This dramatic effect on collagen is brought about by beta-aminopropionitrile
(BAPN). BAPN and another lathyrogenic agent,
d-penicillamine, have been used in the pharmacologic control of scar tissue.
Nitric Oxide. Nitric oxide is suspected of playing a role in the early phases of wound healing,
possibly serving as a modulatory/demodulatory sec-
ond messenger for several of the polypeptide growth
factors.77
Oxygen-derived Free Radicals. Univalent
reductions of oxygen generate highly reactive, potentially cytotoxic free radicals.78 When released
into the extracellular matrix, these oxygen-derived
metabolites may cause cellular injury by 1) degrading hyaluronic acid and collagen; 2) destroying cell
membranes; 3) disrupting organelle membranes;
and 4) interfering with important protein enzyme
systems. Oxygen free radical production can be
triggered by radiation, chemical agents, ischemia,
and inflammation. Several studies seem to support
a direct involvement of oxygen radicals in wound
healing.78
Age. Wound healing is a function of age. The
patient’s age affects a number of elements in wound
healing, notably the rate of multiplication of cells
and the rate of production of various substances by
cells.79 Both tensile strength and wound closure rates
decrease with age.80 As the individual gets older
the phases of healing are protracted, so that events
begin later, proceed more slowly, and often do not
reach the same level.81–83
Some authors84 propose that the real factor contributing to delayed healing in the elderly is intolerance to ischemia, rather than any inherent alteration in the normal processes of wound healing as a
consequence of age. Although increasing age is
typically linked with delayed healing, it is difficult to
separate the effects of age alone from those of diseases commonly associated with age.85
Mechanical Stress. Mechanical stresses on the
healing wound affect the quantity, aggregation, and
orientation of collagen fibers.86 Abnormal tension
on the skin can give rise to blanching and subsequent necrosis, rupture of the dermis, and permanent stretching.87 The effect of mechanical stress
on wound healing has been studied on expanded
skin wounds in rabbits.88 The expanded wounds
showed significant increases in breaking strength
and energy absorption compared with the implanted
but non-expanded control wounds. The collagen in
expanded wounds was found to be better organized than in controls, and was oriented parallel to
the force vector. The authors conclude that the
mechanical stress of subcutaneous expansion
9
SRPS Volume 10, Number 7, Part 1
“accelerates wound healing by producing stronger
and more organized scars” at the expense of scar
stretching.88
Nutrition. Malnutrition manifests as delayed tensile strength of wounds in the rat model.89 The
effect is particularly marked early in the healing
process, but eventually levels off and ultimately both
the control and starved animals heal equally.
Serum protein levels <2g% in humans are
associated with a prolonged inflammatory phase
and impaired fibroplasia.90 Of the essential amino
acids, methionine, which is later converted to cysteine, is critical to restoring inflammation and
increasing production of fibroblasts to reverse the
effects of protein depletion.91
Much less is known about the role of carbohydrates and fats in the healing process. Glucose is
required as an energy source by leukocytes during
the inflammatory phase of wound healing, while
fats are necessary for the synthesis of new cells.
Essential fatty acid deficiency does not appear to
have any detrimental effect on wound healing.92
Hydration. A well hydrated wound will epithelialize faster than a dry one,18,93,94 explaining why
occlusive wound dressings and grafts hasten epithelial repair and control the proliferation of granulation tissue.
Environmental Temperature. Wound healing
is accelerated at environmental temperatures of
30°C, whereas tensile strength decreases by 20%
in a cold (12°C) wound environment. Induced
hypothermia below 28°C in animals resulted in
decreased wound tensile strength up to the fifth
postoperative day,95 presumably through reflex vasoconstriction and perhaps blood sludging.
Denervation. Denervation has no effect on
either wound contraction or epithelialization. Denervated skin, however, is less susceptible to local
temperature changes and more prone to ulcerate
than normal skin because of high rates of collagenase activity. Paralyzed persons tend to develop
massive, rapidly destructive ulcers over anesthetic
areas, and these ulcers are up to 5X worse than the
usual pressure sores seen in debilitated patients with
intact nervous systems.96
10
Ischemia. The initial anaerobic conditions in a
wound following injury stimulate cells to adopt
anaerobic production of ATP via glycolysis.97 The
increased metabolism and protein synthesis during
the proliferative phase of healing require large quantities of ATP via oxidative phosphorylation, and these
are provided by glucose and oxygen through a rich
blood supply. Hypoxia potentially slows or halts the
healing process.98
The physiologic response of the vascular endothelium to localized hypoxia in the early phase of
healing is to precipitate vasodilation and stimulate
fibrin deposition, proinflammatory activity, capillary leak, and neovascularization. The endothelial
cell response to sustained hypoxia is apoptosis
induced by tumor necrosis factor. Wound neutrophil activity is also impaired at lower oxygen tensions.99 Collagen synthesis is disrupted in hypoxic
conditions, and fibroblasts may not participate in
the formation of the extracellular matrix.100
Foreign Bodies. Foreign bodies, including nonviable tissue, are a physical obstacle to wound healing and an asylum for bacteria. Like infection, foreign bodies prolong the inflammatory phase and
wounds fail to contract, repopulate the area with
capillaries, or completely epithelialize. Wounds
with necrotic tissue will not heal until all the necrotic
tissue is removed.101
Infection. Infection prolongs the inflammatory
phase of healing, while subinfective bacterial levels
appear to accelerate wound healing and the formation of granulation tissue.102,103 Bacterial counts
>105 or the presence of any beta-hemolytic streptococcus inhibits healing by prolonging the inflammatory phase and interfering with epithelialization,
contraction, and collagen deposition.104 Bacterial
endotoxins decrease tissue PO 2 and stimulate
phagocytosis and the release of collagenase and
reactive oxygen species, further degrading collagen
and contributing to the destruction of previously
normal tissue adjacent to the wound.
In the presence of significant infection, leukocyte chemotaxis and migration, phagocytosis, and
intercellular killing are decreased. Excessive bacterial colonization likewise impairs angiogenesis and
epithelialization. The granulation tissue of infected
wounds is more edematous, somewhat hemorrhagic, and more fragile than that of clean wounds.
SRPS Volume 10, Number 7, Part 1
Epithelialization does not proceed in the presence
of a significant bacterial load because the toxins
and metabolites of bacteria inhibit epidermal
migration and even digest tissue proteins and
polysaccharides in the dermis.102,105,106 Finally, heavy
bacterial contamination promotes collagenolytic
activity through the action of microbial collagenase
and endotoxins capable of cleaving the collagen
molecule, ultimately resulting in decreased wound
strength and contraction.102
Edema. Edema further compromises tissue perfusion and interferes with wound healing. Mast
cells in skeletal muscle produce most of the NO
associated with ischemia-reperfusion injury.107 Mast
cells are inflammatory cells that, when stimulated,
release histamine and numerous cytokines responsible for the intense inflammatory reaction and
edema. In addition, tissue edema due to lowered
plasma oncotic pressures, a leaky endothelium, and
impaired peripheral perfusion may further compromise tissue perfusion by raising interstitial pressures.108 In turn, raised tissue pressure, either
external (compression) or internal (compartment syndrome), induces capillary closure through its effect
on critical closing pressures.
Idiopathic Manipulation. The degree of tissue
necrosis increases with the severity of the trauma.
Rough tissue handling, overzealous cauterization,
abundant blood clots, tight sutures, tissue ischemia,
and subsequent necrosis extend the period of
inflammation and retard healing.
Chemotherapy. Antimetabolic, cytotoxic, and
steroidal agents are all associated with compromised
immunity, increased susceptibility to sepsis, and failure of tissue repair.109–111 Chemotherapeutic agents
generally decrease fibroblast proliferation and
wound contraction,112–114 although thio-TEPA and
chloroquine mustard do not seem to affect wound
healing when administered in therapeutic doses.
Actinomycin D, bleomycin, and BCNU are more
detrimental to wound strength than vincristine,
methotrexate, 5-fluorouracil, or cyclophosphamide. 112 Cyclophosphamide inhibits the early
vasodilatory phase of inflammation, while methotrexate apparently does not act directly upon the
wound but does potentiate infection. When chemotherapy is begun 10–14 days postoperatively,
little effect is noted on wound healing over the long
term despite a demonstrable early decrease in
wound strength.
Radiation Therapy. Acute radiation injury is
manifested by stasis and occlusion of small vessels,
with a consequent decrease in wound tensile
strength and total collagen deposition. Although
decreased blood flow to the wound tissues certainly contributes to poor healing, Miller and
Rudolph115 cite evidence of a direct adverse effect
of ionizing radiation on fibroblast proliferation, with
possible permanent damage to the fibroblasts. Irradiated skin is thus irreversibly injured, and the injury
itself may be progressive.115
Diabetes Mellitus. Diabetes mellitus affects soft
tissue healing via metabolic, vascular, and neuropathic pathways.116 Small vessel occlusive disease
is no longer considered to be a component of diabetes mellitus.117 Rather, it is the larger arteries, not
the arterioles, that are typically affected in diabetic
patients. Factors that affect the microcirculation in
diabetes include stiffened red blood cells and
increased blood viscosity; susceptibility of the tibial
and peroneal arteries to atherosclerosis; high venous
back-pressure in the lower extremities that increases
transudation and edema; affinity of glycosylated
hemoglobin for oxygen contributing to low oxygen
delivery at the capillary; and impaired phagocytosis
and bacterial killing, which along with neuropathy
and ischemia make the patient vulnerable to infection.117
Other Systemic Conditions. Obesity, cardiovascular disease, COPD, cancer, endocrine disorders, small vessel disease, and renal or hepatic failure all delay wound healing. Local hypoperfusion
due to small vessel occlusion secondary to emboli,
vasculitis, and arterial or venous thrombosis, or
locally raised tissue pressures due to extrinsic or
intrinsic factors (eg, hematoma or extravasation) render the wound ischemic and retard healing. The
stress of a critical illness may further impair healing
by placing high demands on tissue oxygen.108
ADJUNCTS TO WOUND HEALING
Adjuncts to wound healing include hydrotherapy,
ultrasound, negative pressure therapy, hyperbaric
11
SRPS Volume 10, Number 7, Part 1
oxygen, electrostimulation, lasers, light-emitting
diode (LED) therapy, growth factors, and bioengineered skin.
Hydrotherapy. Whirlpool treatments are among
the oldest adjunct therapies still in use for the management of chronic wounds. Hydrotherapy is most
effective when given once or twice a day with
concomitant dressing changes. Antibacterial agents
can be added to the whirlpool water to increase
the bactericidal effect on the wound.
A new form of hydrotherapy is replacing the
whirlpool; it is called pulsed lavage. Pulsed lavage
delivers an irrigating solution under pressure (4–
15psi) that stimulates formation of granulation tissue.118
Clean, nondraining wounds with healthy red
granulation tissue should never be subjected to
hydrotherapy. Even minimal water agitation can
mechanically damage the fragile new cells.
Ultrasound. Ultrasound is the result of electrical energy that is converted to sound waves at
frequencies >20,000Hz. Sound waves are transmitted to the tissue through a hydrated medium
sandwiched between the tissue and the transducer.
The depth of penetration of the ultrasound energy
depends on the frequency: the lower the frequency, the deeper the penetration.
The therapeutic effects of ultrasound therapy stem
from its thermal and nonthermal properties. The
thermal component at a setting of 1–1.5W/cm2 has
been used to improve scar outcome. The
nonthermal component at a setting of 0.3–1W/cm2
produces both cavitation (formation of gas bubbles)
and streaming (a steady unidirectional force), which
in the laboratory cause changes in cell membrane
permeability, increase cellular recruitment, collagen
synthesis, tensile strength, angiogenesis, wound contraction, fibrinolysis, and stimulate fibroblast and
macrophage production.119–122 Clinically, the results
of ultrasound therapy on the healing of wounds are
equivocal.123–128
Negative Pressure Therapy (V.A.C.). Vacuumassisted closure consists of using a subatmospheric
pressure dressing to convert an open wound into a
controlled closed wound.129,130 The negative pressure relieves interstitial fluid and edema to improve
tissue oxygenation; removes inflammatory media-
12
tors that suppress the normal progression of healing;130,131 speeds up formation of granulation tissue;
and reduces bacterial counts in the wound. A V.A.C.
dressing gives the surgeon time to transform a hostile wound into a manageable one.
Hyperbaric Oxygen (HBO). Dividing cells in a
wound require a minimum oxygen tension of
30mmHg (normal range 30–50mmHg). Tissues in
wounds that are not healing show oxygen values of
5–20mmHg. When those wounds are placed in
hyperbaric chambers at pressures of 2.4ATA, the
tissue oxygen tension rises to 800–1100mmHg.119
Besides providing more oxygen to the wound site,
HBO also increases expression of NO, which is
crucial for wound healing.132 Many reports attest to
the benefit of HBO therapy in amputations,133
osteoradionecrosis,134,135 surgical flaps,136 and skin
grafts,136–138 but the results are not impressive in
necrotizing soft-tissue infections.
Hyperbaric oxygen administration increases tissue oxygenation considerably as long as the wound
vessels are not obliterated, but cannot alter wound
ischemia in the absence of satisfactory perfusion.
In an ischemic rabbit ear model, HBO in combination with PDGF or TGF-β1 had a synergistic effect
that totally reversed the healing impairment caused
by ischemia.139 In severely compromised wounds,
Mathes, Feng, and Hunt140 recommend surgical
transplantation of a blood supply to bring O2 into
the ischemic tissues and enhance the healing process.
Electrostimulation. Electrostimulation is
believed to accelerate the wound healing process
by imitating the natural electrical current that occurs
in skin when it is injured.141–144 Electrical current
applied to wounded tissue increases the migration
of neutrophils and macrophages,145–147 and promotes
fibroblasts.148–150 Electrostimulation results in a 109%
increase in collagen149 and 40% increase in tensile
strength151 and may also improve blood flow in a
wound.152,153
Four types of electrostimulation are commonly
used: direct current, low-frequency pulsed current, high-voltage pulsed current, and pulsed electromagnetic fields.119
Lasers. Low-energy laser management of open
wounds has been used for over 35 years in Europe
SRPS Volume 10, Number 7, Part 1
and Russia, where it is called “biostimulation.”154
Weak biostimulation excites physiologic processes
and results in increased cellular activity in wounded
skin.155,156 The mechanism is believed to be the
stimulation of ascorbic acid uptake by cells, stimulation of photoreceptors in the mitochondria, changes
in cellular ATP, and cell membrane stabilization.157–
159
The common types of low-energy lasers used in
wound management are the helium-neon laser and
the gallium-arsenide (or infrared) lasers.
Lasers accelerate healing of ischemic, hypoxic,
and infected wounds, especially when combined
with hyperbaric oxygen treatments.160 Low-energy
lasers promote epithelialization for wound closure161
and better tissue healing.162–169 Laser biostimulation
has different effects at different wavelengths, and
optimal treatment requires several applications at
various wavelengths.
LED. The treatment area for a laser is limited;
that is, large areas must be treated in a grid-like
pattern. In contrast, light-emitting diodes (LED) produce multiple wavelengths (680, 730, and 880nm
simultaneously159 or 670, 720, and 880nm170 in large,
flat arrays to treat large wounds. NASA developed
LED based on their research on wound healing in a
weightless environment. Work done on space
shuttle missions, on the international space station,
and aboard submarines shows significant improvement in wound healing with LED therapy alone or
in combination with hyperbaric oxygen treatment.
Growth Factors. McGrath2 defines growth factors as follows: “A polypeptide growth factor is an
agent promoting cell proliferation. . . . These proteins also induce the migration of cells, and thus are
not only mitogens but are also chemoattractants
that recruit leukocytes and fibroblasts to the injured
area.” Of particular importance to wound healing
are the fibroblast growth factors (Table 2).4 Their
effect on the repair process is illustrated in Figure 6.
Platelets contain growth factors that stimulate
angiogenesis, fibroplasia, and collagen production.
These are called platelet-derived wound healing
factors (PDWHF).171 A beta-chain recombinant
c-sis homodimer of platelet-derived growth factor
(rPDGF-β) appears to have immunologic properties
similar to PDGF—ie, it stimulates fibroblast mitogenesis and chemotaxis of PMNs, MONOs, and fibroblasts.172 Both PDGF and rPDGF-β accelerate
wound healing by augmenting the inflammatory
response and the accumulation of granulation tissue.
Table 2
Growth Factor Signals at the Wound Site
(Reprinted with permission from Martin P: Wound healing—aiming for perfect skin regeneration. Science 276:75, 4 Apr 1997.)
13
SRPS Volume 10, Number 7, Part 1
effects of cytokines on abnormal scars are being
investigated.185–187
Transforming growth factor beta (TGF-β) has been
linked clinically and experimentally to dermal proliferative disorders. Polo and colleagues189 found
an abnormal dose response by fibroblasts of proliferative scars to TGF-β2 stimulation. This response
was not demonstrated by nonburn hypertrophic
scars.
The commercially available growth factor products and their uses are summarized in Table 3.
Bioengineered Skin. Skin equivalents provide
a living supply of growth factors and cytokines and a
collagen matrix for a wound to build upon. The
underlying principles and specific benefits of these
products are discussed elsewhere in this overview.
The bioengineered skin replacements currently on
the market are shown in Table 4.
Fig 6. Peptide growth factors released by the cells recruited
into the injured area. (Reprinted with permission from McGrath
MH: Peptide growth factors and wound healing. Clin Plast Surg
17(3):421, 1990.)
Brown and associates173 studied epidermal growth
factor (EGF) added to silver sulfadiazine in the healing of wounds. The cream mixture was applied to
skin-graft donor sites of 12 patients. Complete healing was noted 1.5 days sooner in the experimental
wounds than in the control wounds, which received
silver sulfadiazine alone. In a separate study on
chronic wounds, EGF applied topically b.i.d. resulted
in complete healing in 8/9 wounds at a mean 34
days.
In vitro, EGF is a growth-promoting protein for
skin fibroblasts and other cell types. In vivo, EGF
stimulates epithelial proliferation in the skin, lung,
cornea, trachea, and gastrointestinal tract. Epidermal growth factor affects keratinocyte proliferation
mainly by increasing their rate of migration, which
in turn increases the number of dividing cells,
growth rate, culture lifetime, and the ability to begin
new colonies.174 Along with transforming growth
factor alpha (TGF-α), other peptide growth factors,175–184 and cytokines,185–187 EGF is “part of a
complex program to orchestrate growth and differentiation of epidermal keratinocytes.”174,188 The
14
FETAL WOUND HEALING
Tissue repair in the mammalian fetus is fundamentally different from normal postnatal healing.
“In adult humans, injured tissue is repaired by collagen deposition, collagen remodeling, and eventual scar formation. [In contrast], fetal wound healing seems to be more of a regenerative process
with minimal or no scar formation.”190
Siebert et al191 examined healing fetal wounds
histologically and biochemically and found that they
contained a small amount of collagen identical to
that found in the exudate from wounds in adults, ie,
Type III collagen but no Type I. The fetal wound
matrix was also rich in hyaluronic acid, which has
been associated experimentally with decreased scarring postnatally. The authors propose a mechanism
of hyaluronic acid-collagen-protein complex acting
in fetal wound healing to check scar formation, and
concluded that healing in fetuses involved a much
more efficient process of matrix reorganization than
that which takes place after birth. True regeneration apparently does not play a role in fetal healing,
based on the few appendageal elements seen.
Rowsell192 suggests that the collagen present in
fetal wounds is “structural” rather than “scar tissue”
collagen. The amounts of collagen deposited in fetal
and in adult wounds are not only markedly different, but the deposited collagen is also handled differently. The fetal pattern of wound healing “is
SRPS Volume 10, Number 7, Part 1
Table 3
Commercially Available Growth Factors, Indications and Benefits
Table 4
Bioengineered Skin Replacements
characterized, at least in the early fetus, by the
deposition of glycosaminoglycans at the wound site
into which rapidly proliferating mesenchymal cells
of all types migrate, differentiate, and mature.”193
The transition from fetal to adult patterns of wound
healing for different tissues probably occurs at different times during gestation.
In their review of scarless wound healing in the
mammalian fetus, Mast and coworkers190 state that
“a striking difference between postnatal and fetal
repair is the absence of acute inflammation in fetal
wounds,” and offer several hypotheses to explain
this phenomenon. Epithelialization occurs at a much
faster rate in fetal wounds, but adult-like angiogen-
esis is absent. More important, the fetal wound
matrix is markedly different from the adult’s in that
it lacks collagen and instead contains predominantly
hyaluronic acid. The fetal wound contains a persistent abundance of HA while collagen deposition is
rapid, nonexcessive, and highly organized, so that
the normal dermal structure is restored and scarring
does not occur. The authors speculate about the
applications of scarless fetal healing, namely for
intrauterine repair and in the treatment of pathologic, postnatal processes.
Whitby and Ferguson193 studied the distribution
of growth factors in healing fetal wounds in an
attempt to identify the mechanism controlling the
15
SRPS Volume 10, Number 7, Part 1
healing process in fetuses. They found plateletderived growth factor (PDGF) in fetal, neonatal,
and adult wounds, but transforming growth factor
beta and basic fibroblast growth factor (bFGF) were
not detected in the fetal wounds. They conclude
that it may be possible to manipulate the adult
wound to produce more fetal-like, scarless wound
healing by therapeutically altering the levels of
growth substances and their inhibitors. This hope is
shared by other groups194–199 though it has not yet
materialized in the clinical setting. Other growth
factors are under study also.200
Tenascin (cytotactin) is a large, extracellular matrix
glycoprotein synthesized by fibroblasts that is
present during embryogenesis but only sparsely distributed in the connective tissue papillae of adults.
The protein is re-expressed, however, in healing
wounds, particularly close to the basement membranes at the wound edges beneath the proliferating and migrating epithelium, and later on during
healing in the regenerating connective tissue area.
This expression subsided later on during healing.201
Compared with adult wounds, tenascin is present
earlier in fetal wounds, and may be responsible for
initiating cell migration and the rapid epithelialization of fetal wounds.202 Some investigators201,202
believe that tenascin could be a modulator of cell
growth and movement and that it may influence
the deposition and organization of other extracellular matrix glycoproteins during tissue repair.
WOUND CARE
Cleaning and Irrigation
The general surgical principles of cleanliness and
gentleness in managing wounds remain the mainstay of accepted medical practice. Next to debridement, cleaning the wound is the most important
thing one can do to prepare the wound. It is not
enough to simply soak the affected part; irrigation
with at least 7psi of pressure is needed to flush out
any bacteria in a wound.203 High-pressure irrigation, however, may injure adjacent healthy tissue
and cause lateral spread of the irrigating fluid, with
resultant postoperative edema, therefore high-pressure irrigation should be reserved for highly contaminated wounds.
Hollander looked at wound infection rates and
cosmetic appearance of 1923 facial lacerations 1
16
week after repair.204 The infection rate was similar
in 1090 lacerations that were irrigated (0.9%) vs
833 that were not irrigated (1.4%), but there was a
trend toward better early cosmetic appearance in
the nonirrigated wounds.
Wounds can be effectively cleansed with ordinary tap water.205 Potent antibacterial agents like
hydrogen peroxide, povidone-iodine, alcohol, etc.
are unnecessary and will destroy healthy tissue. If
they are used on a wound, they must be thoroughly
rinsed out with sterile saline before the wound is
sutured or bandaged. Most uncomplicated wounds
can be irrigated with 50–100mL/cm of wound
length, whereas contaminated wounds and wounds
at high risk of becoming infected (marine wounds,
farm injuries, and gunshot wounds) require 1–2L of
irrigation.
Debridement
Adequate debridement is perhaps the most
important step to produce a wound that will heal
rapidly and without infection. Necrotic tissue is a
safe haven for bacteria and the physical presence
of the dead cells prevents the wound from contracting and healing.
Scrubbing with a saline-soaked sponge is a very
effective way of removing bacteria, proteinaceous
coagulum and debris.206 Scrubbing can also significantly damage healthy tissue and widen the area of
injury. Scrubbing is best reserved for highly contaminated wounds with embedded particles—the
so-called “road rash.”
Nonselective debridement is also called
mechanical debridement and may include any one
or a combination of dry-to-dry, wet-to-dry, and/or
wet-to-wet dressing changes; Dakin’s solution or
hydrogen peroxide; and hydrotherapy or high-powered wound irrigation. Non-selective debridement
is used for wounds with large amounts of necrotic
tissue and debris. Once granulation tissue begins
to develop, a more selective form of debridement
should be used.
Selective debridement can be sharp, enzymatic,
autolytic, or biologic. Surgical debridement is the
most effective, aggressive, and rapid means of
removing large quantities of devitalized tissue.
Clearly demarcated areas of living and dead tissues
need to be appreciated or else too much viable
tissue can be removed.207
SRPS Volume 10, Number 7, Part 1
Enzymatic debridement takes advantage of naturally occurring enzymes that will selectively digest
devitalized tissue. Enzymatic debridement has the
advantage of working continuously while the patient
is at home or in the hospital. This form of debridement is slower and less aggressive than surgical
debridement. Depending on the thickness of the
eschar or fibrinous material to be debrided, crosshatching of the surface might speed the process by
increasing the available surface area. The enzymes
are typically applied daily and covered with gauze.
They can be used for weeks and may need up to 1
month of treatment for success. Silver sulfadiazine
(Silvadene) should not be used concurrently because
it will deactivate the enzyme. Some agents digest
necrotic tissue from the bottom up (eg, collagenase) while others work from the top down (eg,
papain–urea preparations) (Table 5).208
Autolytic debridement allows the body’s own
enzymes and moisture to break down necrotic tissue. It acts in 7–10 days under semiocclusive and
occlusive dressings, but not under gauze dressings.209
Transparent films, hydrocolloids, and calcium alginates may all be used to enhance autolytic debride-
ment. Hydrogels hasten the autolytic process by
quickly rehydrating necrotic tissue. Autolytic
debridement is usually ineffective in malnourished
patients.
Biologic debridement with maggots was first
introduced in the US in 1931 and was routinely
used until the mid-1940s. With the advent of antibacterials maggot therapy became rare until the
early 1990s, when it once again became popular.
Up to 1000 sterile maggots of the green bottle fly,
Lucilia (Phaenicia) sericata, are placed in the wound
and left for 1–3 days. Maggot debridement can be
used for any kind of purulent, sloughy wound on
the skin, independent of the underlying diseases or
the location on the body, and for ambulatory as
well as for hospitalized patients. In addition to stimulating host healing through debridement and resultant cytokine release, the maggots secrete calcium
salts and bactericidal peptides (defensins)210 that provide an antimicrobial benefit. One of the major
advantages of this type of debridement is that the
maggots separate the necrotic tissue from the living
tissue, making surgical debridement easier. Offensive odors and pain associated with the wound
Table 5
Enzymatic Debridement Agents
17
SRPS Volume 10, Number 7, Part 1
decrease significantly,211,212 and a complete debridement is achieved in most cases.
WOUND CLOSURE
INTRODUCTION
Ancient Hindu medicine described the use of
insect mandibles to approximate skin wounds.213
From these modest beginnings, increasingly sophisticated wound closure materials and techniques
have evolved.
Healing by primary intention is achieved by
direct approximation of the wound margins and is
preferable in most instances. However, when
infection or excessive tension precludes primary
closure, spontaneous contraction and epithelialization of open wounds (secondary intention) or
delayed surgical closure (tertiary intention) may
be necessary.214,215
tion by maintaining normothermia, and addressing
malnutrition when present.
Scars are generally less conspicuous if they can
be made to follow a skin line.218 The surgical incisions are planned so that the final scar lies parallel
or adjacent to the relaxed skin tension lines
(RSTL).219–223 The RSTL in the face are the lines of
facial expression.223 In young, unlined persons, the
RSTL can be visualized by pinching the skin in various directions. In older people the RSTL coincide
with the nadir of wrinkles.
Elective incisions for the removal of skin lesions
should be planned as a long ellipse approximately
four times longer than wide (Fig 7). If the ellipse is
too short, the skin will bunch at the ends in a dogear.163
PRINCIPLES
Crikelair216 listed the Halstedian fundamentals of
surgical wound closure which apply to the management of any skin wound.
• Place incisions to follow tension lines and natural folds in the skin.
• Handle tissues gently and debride only as much
as necessary to ensure an adequately clean bed.
•
•
•
•
•
Ensure complete hemostasis.
Eliminate tension at the skin edges.
Use fine sutures and remove them early.
Evert wound edges.
If possible, choose patients whose age is closer
to 90 than to 9 years.
• Allow time for scars to mature before repeat
intervention.
PREOPERATIVE EVALUATION
Hunt and Hopf217 indicate the importance of
simple, inexpensive, and readily available interventions in the perioperative setting. Their paper
focuses on correcting for hyperglycemia and steroid use before surgery, preventing vasoconstric-
18
Fig 7. Elliptical excision. A, If the ellipse is too short, dog ears will
form at the ends. B, Correct method. (Reprinted with permission
from Grabb WC: Basic Techniques of Plastic Surgery. In: Grabb
WC and Smith JW (eds), Plastic Surgery, 3rd Ed. Boston, Little
Brown, 1979.)
When the orientation of the RSTL cannot be
determined, the lesion can be excised as a circle
provided the margins are undermined in all directions. The natural skin tension will pull the wound
into an elliptical configuration and one may then
proceed with suturing.218
Semicircular lacerations, if sutured linearly, tend
to yield a trapdoor deformity. Gahhos and
SRPS Volume 10, Number 7, Part 1
Simmons224 recommend immediate Z-plasty for the
repair of curved lacerations. Borges225 disagrees,
arguing that (1) most lacerations go beyond the skin
and therefore it is difficult to decide what may be
viable tissue; (2) patients may not like a zigzag scar
if they have not had an opportunity to compare it
with the scar produced by linear closure; and (3)
the risk of infection or hematoma after a traumatic
laceration is greater than after elective scar revision.
WOUND PREPARATION
Local anesthesia in the face is induced with a
dilute anesthetic solution injected at key points over
the nerve to the wounded area using a 25-gauge or
smaller needle.226 The syringe should be small and
the pressure on the plunger no more than needed
for a slow but steady flow.
Traumatic wounds must be rid of all devitalized
tissue and foreign material. Only minimal debridement is recommended in the head and neck
because of the ample blood supply of the area and
the mutilating consequences of overly aggressive
debridement. After sharp debridement the wound
should be thoroughly cleansed with normal saline
or with povidone iodine for antisepsis.
If primary closure is contemplated, the wound
edges are trimmed to make them perpendicular to
the bed. The exception is in hair-bearing areas,
where they should parallel the hair shafts. Every
effort should be made to preserve key anatomic
landmarks—the vermilion border, eyelid, eyebrow,
nostril, and auricular helix—by precisely aligning
the wound edges during closure.
SURGICAL TECHNIQUES
Meticulous surgical technique is required to
obtain an inconspicuous scar. Critical elements
include the obliteration of dead space, layered tissue closure, and eversion of skin margins.
Deep dermal sutures align the skin edges and
help decrease tension on the skin closure. Everting
skin sutures are placed by encompassing a larger
amount of deep dermis than epidermis in the closure (Fig 8). They are tied under the minimal tension necessary to oppose the skin margins.
Nonabsorbable synthetic monofilament sutures
(nylon, Prolene, Novafil) are minimally reactive and
Fig 8. Technique of layered wound closure everting the skin
edges. (Modified from Spicer TE: Techniques of facial lesion
excision and closure. J Dermatol Surg Oncol 8:551, 1982.)
thus preferred for skin closure when cosmesis is
essential. Absorbable synthetic braided sutures
(Vicryl, Dexon) are ideal for deep dermal closure,
acting as transient but necessary skin splints.
Absorbable natural sutures (catgut, chromic catgut)
induce inflammation as they are degraded by
phagocytosis. They are useful where suture removal
is difficult and cosmesis is not critical (eg, in the oral
cavity, nasal cavity, and non-facial wounds in children).227–233
The simple interrupted suture is the most common skin closure method. Horizontal mattress sutures
facilitate tissue eversion with the use of 50% fewer
sutures, whereas vertical mattress sutures are useful
in wounds under significant tension. Running
sutures speed the closure of uncomplicated, linear
wounds. Unlike interrupted sutures, they do not
allow the differential adjustment of suture tension
that is required in complex wounds. Subcuticular
running sutures yield cosmetically pleasing results
in wounds under mild tension.234–238
Tissue bonding with cyanoacrylate adhesives is
becoming an increasingly popular method of wound
closure in Canada and Europe. Mizrahi239 reported
the use of cyanoacrylate glue in more than 1500
simple pediatric lacerations, with a 2.4% complication rate. Applebaum240 cites the advantages of rapid
19
SRPS Volume 10, Number 7, Part 1
and painless application at an average materials cost
of $2.86 per patient. These products are not currently in mainstream use in the United States.
A skin-stretching device has been developed
recently by Hirschowitz.241 Marketed in the U.S.
as the Sure-Closure device, it uses the skin property of mechanical creep242 to achieve primary
closure of large wounds that would otherwise
require grafts or flaps. Promising results have been
demonstrated in the closure of fasciotomies,
amputation stumps, and other wounds of the trunk
and lower extremity.
For difficult wound closure in the acute setting,
Abramson and colleagues243 describe a simple technique of intraoperative skin stretching with 18-gauge
spinal needles placed parallel to the wound margins
aided by a rib approximator.
Markovchick244 lists his recommendations for
suture repair of soft-tissue injuries in an emergency
department, including preferred anesthetic, suture
material, surgical technique, wound dressing, and
timing of suture removal (Table 6).
POSTOPERATIVE CARE
Immediately after completing the closure, antibiotic ointment is applied to the suture line without
further occlusive covering. Most surgeons recommend that the wound be kept dry for the first 2
days, after which gentle washing is encouraged.
Borges,245 however, questions the wisdom of keeping a wound dry, and instead recommends immediate application of a light dressing to prevent scab
formation and to maintain a moist wound environment. In support of this practice Noe and Keller246
report no suture disruption, wound dehiscence, or
infection in 100 patients who washed their wounds
with soap and water twice a day beginning the
morning after surgery.
In the head and neck surgical sutures are
removed in 3–5 days, while elsewhere they are
left in place for 7–10 days. To remove it, the
suture is cut close to the skin edge and its free
end is pulled across the wound, not away from it.
Crikelair216 notes that the two most common
causes of unsightly suture marks are delayed
removal beyond 10 days and excessive tension
20
of the closure. The size of the individual “bites”,
type of needle, and suture material are not significant to the esthetic outcome.
The eventual width of a scar is proportional to
the force required for closure. Wray247 suggests
prolonged support of the wound edges with tape to
effectively minimize scar width. Nonwoven
microporous tape is superior in terms of breaking
strength, extensibility, adhesive capacity, porosity,
and resistance to infection.248
For a wound to heal as a good scar without
hypertrophy, adhesion, or contracture, the processes of scar formation and remodeling must follow a precisely chartered, finely tuned course.
Parsons249 makes the following points regarding
scar prognosis:
• A scar usually looks its worst between 2 weeks
and 2 months after injury. Scar revision should
await scar maturation, which can take from 4 to
24 months depending on the type of injury as
well as on the patient’s age and genetic background. The only exception to this rule is when
there is loss of function—eg, scars crossing concave surfaces or the flexor aspects of joints, which
tend to contract into tethering bands that prevent full extension.
• A scar becomes noticeable if it interrupts the
homogeneous flow of tissue planes through color,
contour, or texture differences—eg, hyperpigmented, depressed, or shiny scars.
• The final appearance of a scar depends more on
the type of injury than on the method of suture.
Bruising and infection, traumatic tattooing,
improper orientation of a laceration, tension,
and beveling of edges on closure predict a poor
outcome.
• Differences among suture materials are of negligible importance to the result, but other technical factors of suture placement and removal do
affect the final scar.
• Immobilization is as important in soft-tissue healing as it is in bone fractures. Tension across the
wound causes minute wound disruptions and
subsequent excessive scarring. Adhesive strips
across the suture line should be kept in place for
1 or 2 weeks after the sutures are removed.
SRPS Volume 10, Number 7, Part 1
Table 6
Suture Repair of Soft-Tissue Injuries
(Reprinted with permission from Markovchick V: Suture materials and mechanical after care. Emerg Med Clin North Am 10(4):673, 1992.)
21
SRPS Volume 10, Number 7, Part 1
WOUND DRESSINGS
There are more than 2000 wound dressing materials available commercially. See the Appendix
for an overview of their respective properties, indications, advantages, and disadvantages.
The red-yellow-black classification of wounds has
removed the mystery in choosing a dressing. The
RYB system is used for wound healing by secondary
intention and is based on the balance of healthy
granulation tissue and necrotic tissue (Table 7).
When treating a wound with multiple colors, the
worst problem should be treated first: black before
yellow before red.
Semipermeable Occlusive Dressings
There is evidence that debridement, angiogenesis, dermal repair, and epithelialization are
accelerated under occlusive dressings. The mechanisms involved include thermal insulation, changes
in wound pH, PO2 and PCO2, and maintenance of
growth factors in the moist environment. 250
Because occlusive dressings can cause skin maceration from excessive fluid accumulation, many
popular modern dressings are semipermeable,
allowing escape of moisture vapor and passage of
gases but preventing entry of bacteria and liquid
water.250 Carver and Leigh250 review the various
types of commercially available occlusive dressings,
Table 7
Wound Management Protocol: The Red-Yellow-Black Classification
22
SRPS Volume 10, Number 7, Part 1
including alginates, adhesive-coated films, hydrocolloids, hydrogels, foams, and absorptive powders
and pastes.
Katz et al251 compared the effects of 6 commercially available semiocclusive dressings on the healing of contaminated surface wounds. All the materials tested were equally effective in increasing
the rate of reepithelialization; all, however, produced microenvironments that were conducive
to the growth of bacteria. Although occlusive dressings may provide a physical barrier to exogenous
microorganisms, by themselves they are unable to
prevent infection once pathogens are introduced,
and may actually promote infection by encouraging bacterial proliferation, particularly with prolonged occlusion.
Alginates are particularly well suited for use in
wounds with heavy exudates. Upon contact with
the wound exudate, the alginate is converted to
a sodium salt, which results in a hydrophilic gel
and an occlusive environment that promotes
wound healing. The dressing must be changed
when the gel-like substance begins to weep exudate.252
Creams are opaque, soft solids or thick liquids
intended for external application. Medications are
dissolved or suspended in the emulsion base, a
water–oil substance. Creams are usually applied to
moist, weeping lesions and have a slight drying
effect. Creams can be formulated to aid in drug
penetration into or through the skin. Ointments
are semisolid preparations that melt at body temperature and are used for their emollient properties. Their primary role in wound healing is to aid
in rehydrating the skin and for topical application of
drugs.
Foam dressings consist of hydrophobic polyurethane sheets with a nonabsorbent, adhesive
occlusive cover. Foam dressings are very absorbent and nonadherent to the wound. Because
they absorb environmental water, reepithelialization does not occur as readily as under moisture-promoting dressings.
Film dressings are transparent polyurethane membranes with water-resistant adhesives. They are
highly elastic and conform easily to body contours.
Film dressings are semipermeable to moisture and
oxygen and impermeable to bacteria. The trapped
moisture promotes autolytic debridement, but can
also macerate the wound in the event of heavy
exudate. Because the membrane is transparent,
film dressings are best for visual monitoring of
wounds. They do not hold up well in friction areas,
and the adhesive can tear the skin in elderly
patients.253
Gauze dressings are highly permeable to air and
allow rapid moisture evaporation. They can stick to
newly formed granulation tissue and damage it
when dressing is removed, and dressing changes
can be painful. In addition, both woven and nonwoven gauze will leave behind some lint and fibers
which can harbor bacteria.
Hydrocolloid dressings are completely impermeable and therefore should not be used for dressing
wounds with anaerobic infections. These dressings
adhere well, are comfortable for the patient, and
are effective in absorbing minimal to moderate
amounts of exudate. Hydrocolloid dressings are
well suited for wounds over high-friction areas.
Hydrogel dressings are simply starch and water
polymers that are manufactured as gels, sheets, or
impregnated gauze. They rehydrate a wound, and
because of their high water content, they do not
absorb large amounts of wound exudate.
Vacuum-assisted Closure (V.A.C.) Dressing
V.A.C. dressings provide a negative-pressure
environment around the wound that helps remove
interstitial fluid and edema and improve tissue oxygenation. They also remove inflammatory mediators that suppress the normal progression of wound
healing.130,131 Granulation tissue forms more rapidly and bacterial counts decrease to <105 organisms per gram of tissue.129 V.A.C. dressings are
convenient to use and associated with few complications. V.A.C. dressings are employed in a variety
of situations such as soft-tissue loss, exposed bone
and hardware, osteomyelitis, weeping wounds,
infected wounds, and as a skin graft bolster.
Silver-impregnated Dressings
Silver-impregnated dressings offer an excellent
way to kill bacteria without antibiotics while still
providing a moist environment for wound healing.
Some of the brand names and manufacturers are
Acticoat (Smith & Nephew), Arglaes (Medline
Industries), AcryDerm Silver (Acrymed Portland),
and Silveron (Silveron). The silver in these prod-
23
SRPS Volume 10, Number 7, Part 1
ucts must be in the Ag+ nonmetallic, ionic form to
inhibit cell wall synthesis, ribosome activity, membrane transport, and transcription in bacteria. Silverimpregnated dressings provide broad-spectrum
antimicrobial coverage and are effective against
methicillin-resistant S. aureus and vancomycinresistant enterococci as well as against yeast and
fungi.254–256
Oasis (Cook Surgical) is a unique wound dressing
made from porcine small intestinal submucosa. Oasis
is simple to use and appears to act as a scaffold for
collagen to stimulate wound healing in chronic and
possibly in acute wounds.257 Oasis is relatively
inexpensive, easy to handle, safe, and appears to
have a sound scientific basis for its claim that it
promotes healing.258
Apligraf
For several years, Apligraf has been associated
with improved healing over conventional therapy
in skin ulcers from venous insufficiency or diabetic
neuropathy. Apligraf is cultured human skin delivered “fresh” on a culture medium to be placed on
a patient’s ulcer. Apligraf is bilayered living skin—
epidermis and dermis—that contains no Langerhans cells, melanocytes, macrophages, lymphocytes,
hair, or blood vessels. Cytokines have been identified in it, including interleukin, platelet-derived
growth factor, tumor necrosis factor, vascular
endothelial growth factor, and fibroblast growth factor. It is derived from human foreskin that has
undergone extensive viral and genetic processing.259,260
Treatment with Apligraf is expensive, but when
all factors are taken into consideration (the actual
cost of the bandage plus all health care resources
such as office visits, home visits, laboratory tests,
treatment failures and complications, and subsequent hospitalizations), Apligraf therapy is less costly
than traditional therapies for chronic ulcers.261
Dermagraft
Dermagraft is a human fibroblast-derived dermal
substitute that consists of neonatal dermal fibroblasts
cultured in vitro on bioabsorbable mesh to produce
a living, metabolically active tissue containing the
normal dermal matrix proteins and cytokines.262 To
date there are no trials comparing the efficacy of
24
Dermagraft vs. Apligraf, although multiple studies
attest to a higher percentage of healed diabetic
foot ulcers treated with Dermagraft compared with
controls.262–266
HYPERTROPHIC SCARS
AND KELOIDS
INTRODUCTION
“A preferred scar is one that has matured rapidly
without contracture or increase in width, and
without forming more collagen than is necessary for
its strength.”
van den Helder and Hage (1994)267
While most modern societies perceive prominent scars as disfiguring, some primitive societies
continue to use scarification for ornamental purposes.268 The existence of surface scarring was probably recognized centuries before Jean-Louis Alibert
described the cheloide.269 However, the wide variety of current theories and proposed treatments for
these abnormal scars demonstrates how inadequate
our understanding remains.
Gross Morphology
Hypertrophic scars are characteristically elevated
above the skin surface but limited to the initial
boundaries of the injury. The severity of the initial
tissue injury determines the extent of scar. Hypertrophic scars may occur at any age or site and tend
to regress spontaneously. They are more common
than keloids and are generally more responsive to
treatment.270–273 Hypertrophic scars may regress with
time and occur earlier after injury (usually within 4
weeks).
Keloids are distinguished clinically from hypertrophic scars by their extension beyond the original
wound and lack of regression. They may develop
from either superficial or deep injuries, are better
correlated with young age and dark skin color, and
are frequently resistant to treatment.270–273 Most
keloids form within 1 year of wounding, although
some may begin to grow years after the initial
injury.271 Symptoms associated with keloid forma-
SRPS Volume 10, Number 7, Part 1
tion include pain, pruritus, hyperpigmentation, disfigurement, and decreased self-esteem (especially
in teenagers). Persistent pruritus is associated with
keloid formation.274 Areas of the head and neck
that are spared include the eyelids and the mucous
membranes.274
Rudolph275 described a third type of abnormal
scar, the widespread scar, which apparently results
not from excessive collagen deposition but rather
from a mishap occurring during the third phase of
healing as a consequence of continued tension and
mobility of the wound. The typical widespread
scar is flat, wide, and often depressed.
ETIOLOGY AND PATHOGENESIS
The underlying mechanism of abnormal scars is
an excessive accumulation of collagen from increased
collagen synthesis or decreased collagen degradation.276,277 A number of genetic and environmental
factors have been implicated in the pathogenesis of
hypertrophic scars and keloids (Fig 9).
Fig 9. Factors implicated in the pathogenesis of hypertrophic
scarring. (Reprinted with permission from Thomas DW et al: The
pathogenesis of hypertrophic/keloid scarring. Int J Oral Maxillofac
Surg 23:232, 1994.)
The most common triggering mechanism for
keloid formation is earlobe piercing, although
localized skin trauma, vaccination, hormonal excess,
increased skin tension, genetic factors, and other
minor factors have also been implicated.278 Virtually all abnormal scars are associated with trauma,
including surgery, lacerations, tattoos, burns, injections, bites, vaccinations, and occasionally blunt
impact.271 Skin tension is frequently implicated,
especially in hypertrophic scar formation. Areas of
high skin tension, such as the anterior chest, shoulders, and upper back are commonly involved.279,280
Brody and colleagues281 point out that hypertrophic
scars may result from compressive forces across the
scar rather than excessive tension, as hypertrophic
scar contractures occur only on the flexor surfaces
of joints. Other local etiologic factors include wound
infection or anoxia, prolonged inflammatory
response, and a wound orientation different from
the relaxed skin tension lines.
Tissue hypoxia has been implicated in keloidal
scar formation. 282 The mechanism by which
hypoxia may lead to keloidal scar formation is
unclear. Vascular endothelial growth factor (VEGF)
is released from fibroblasts in response to hypoxia.
Gira et al283 found that VEGF production was
abundant in keloids and the source of the VEGF
was the overlying epidermis. In contrast,
Steinbrech et al284 found no difference in levels
of VEGF between keloidal fibroblasts and normal
dermal fibroblasts.
There is a theory that keloidal scars are caused
by an immune reaction to sebum.285 Proponents
suggest random damage to pilosebaceous structures
in the skin.286 This theory is supported by the following observations: keloids are more common in
adolescence; they rarely occur on the palms and
soles; spontaneous keloids occur in skin areas with
sebaceous activity; and one scar may be keloidal
whereas an adjacent scar may be normal.
Keloids can be considered a mesenchymal neoplasm. Keloid fibroblast have been shown to contain the oncogene gli-1 and express the protein
Gli-1,287 and in this regard are similar to basal cell
carcinomas. This oncogene is not expressed in
fibroblasts from normal tissue and non-hypertrophic
scars (no reports in the literature whether it is
expressed in fibroblasts of hypertrophic scars).
A detailed review of keloids, their etiology, pathogenesis, and treatment by Shaffer et al288 is highly
recommended. A brief discussion of the differences between keloids and hypertrophic scars is
presented.
EPIDEMIOLOGY
Keloids are far more common in blacks than in
other races, whereas other abnormal scars do not
exhibit an ethnic predilection. Even though they
25
SRPS Volume 10, Number 7, Part 1
can occur at any age, keloids are prevalent in patients
between 10 and 30 years of age,289 while young
children 290 and older adults 291 are rarely
affected.294 There are many reports of keloids
being more frequent in women, but this may just
be a reflection of which sex seeks correction.292
A study of rural Africans reveals a similar incidence of keloids in men and women.293 Although
keloids can occur in persons of all races, darkly
pigmented skin is affected 15X more often than
lighter skin.295,296
Keloids show racial and familial heritability, indicating a genetic component. A predisposition to
keloid formation is inherited as an autosomal dominant297 or autosomal recessive trait.298 Keloids tend
to have accelerated growth during puberty or pregnancy and to resolve after menopause.299,300
HISTOLOGY
Microscopic analysis reveals large collagen
bundles in keloidal scars but not in hypertrophic
scars. 301,302 Collagen bundles are “crisp” in
hypertrophic scars and more “glazed” in keloidal
scars.303 Keloidal scars may have few macrophages but abundant eosinophils, mast cells, plasma
cells, and lymphocytes.301 Keloidal scars are associated with a mucopolysaccharide ground substance and hypertrophic scars have only scant
amounts.301
Hypertrophic scars have nodules containing
cells and collagen within the mid-to-deep part of
the scar. 304 Within these nodules are smooth
muscle actin-staining myofibroblasts which are
absent from normal dermis, normal scars, and
88% of keloids. On electron microscopy, Ehrlich
et al304 found an amorphous substance around
keloidal fibroblasts that separate them from the
collagen bundles. This substance was not seen in
hypertrophic scars.
BIOCHEMICAL AND METABOLIC ACTIVITY
The increased metabolic activity of hypertrophic scars and keloids is reflected in elevated
glycolytic enzyme activity, fibronectin deposition,
and collagen MRNA expression.305–307 Unlike normal wounds, fibroplasia in these abnormal scars
continues well beyond the third post-injury week
without resolution.271 The scars remain imma-
26
ture, with an abnormally high content of Type III
collagen and a disorganized pattern of collagen
deposition.308 The scars are initially hypoxic but
later exhibit increased blood flow that is three to
four times greater than that of normal scars.309
Although hypertrophic scars and keloids are histologically indistinguishable by light microscopy,279
Ehrlich et al304 have recently demonstrated a number of electron microscopic and immunochemical differences. Keloids contain thick collagen
fibers with increased epidermal hyaluron content,310 whereas hypertrophic scars exhibit nodular structures with fine collagen fibers and
increased levels of alpha-SM actin216,220,221,223,311
(Table 8).
Ueda et al312 found that keloidal scars have
higher levels of adenosine triphosphate (ATP) and
fibroblasts than hypertrophic scars. Nakaoka et al313
found a higher density of fibroblasts in both keloidal scars and hypertrophic scars, but keloidal scars
had a higher expression of proliferating cell nuclear
antigen, which may help explain the tendency of
keloidal scars to grow beyond the boundary of the
original wound.
Immunologic alterations have been demonstrated
in abnormal scars, including irregular immunoglobulin and complement levels,314,315 increased mast
cells and TGF-β,316,317 and decreased TNF and
interleukin-1.318,319
Antinuclear antibodies against fibroblasts and
epithelial and endothelial cells have been found in
patients with keloidal scars but not in those with
hypertrophic scars.320
Lower rates of apoptosis have been observed in
keloidal fibroblasts.321 It has been suggested that
keloidal fibroblasts resist physiological cell death,
continuing to proliferate and produce collagen.322
Keloidal fibroblasts have increased levels of PAI1 and low levels of urokinase.323 This may lead to
reduced collagen removal and contribute to scar
formation.288
TREATMENT
Prevention is the best therapy for keloids. Preventive measures include avoiding nonessential
cosmetic surgery, closing wounds with minimal tension following skin creases, and using cuticular,
monofilament, synthetic permanent sutures in an
effort to decrease tissue reaction.274 One should
SRPS Volume 10, Number 7, Part 1
Table 8
Biochemical Alterations in Abnormal Scars
(Adapted from Aston SJ, Beasley RW, Thorne CHM, eds, Grabb and Smith’s Plastic Surgery, ed5. Philadelphia, Lippincott-Raven,
1997, Ch 1.)
also avoid Z-plasties or any wound-lengthening techniques and any incisions that cross joints.
No universally effective treatment for keloids
exists. A “shotgun approach” to treatment is most
often used, and specific modalities are chosen on a
patient-to-patient basis.278 For example, although
injected triamcinolone is considered to be efficacious as a first-line therapy, silicone gel sheeting
may be more useful in children and others who
cannot tolerate the pain of other therapies.324
Lindsey and Davis325 reported a 15% overall recurrence rate in 202 patients with head and neck
keloids treated with excision, intralesional steroids,
silicone sheeting, and radiation therapy. All patients
had more than 2-years of follow-up.
Steroids — intralesional injection, topical ointment,
or as a surgical adjuvant
Pressure therapy
Retinoic acid (topical)
Verapamil (intralesional injection)
5-fluorouracil (intralesional injection)
Penicillamine
Colchicine
Thiopeta
Hyaluronidase
Vitamin E (oral)
Silicone sheet or gel
Interferon — IFN-α-2b or IFN-γ
The following is a list of current treatment options
for keloids:278
Excision and closure by direct approximation, local
flap, homograft, or keloid skin suturing
Cryosurgery
Laser excision — argon, CO2, or Nd:YAG laser
Radiation therapy — as primary treatment or surgical adjuvant
Excision Alone. Excision alone has not been
successful in eliminating keloids. Recurrence rates
range from 45% to 93%.296,326 Apfelberg et al327
proposed using the keloid epidermis as an autograft
after keloid excision to avoid donor site morbidity,
decrease the amount of tension on the closure, and
to lessen the cosmetic deformity. Weimar and
Ceilley 328 used the autograft technique with
27
SRPS Volume 10, Number 7, Part 1
adjunctive pressure therapy and steroid injections.
Adams and Gloster329 recommend excision and
suprakeloid flap closure (Fig 10) with postoperative
radiation therapy for the successful treatment of an
earlobe keloid.
Fig 11. Core excision of a dumbbell keloid of the ear having both
a posterior and anterior component. (Reprinted with permission
from Porter JP: Treatment of the keloid: What is new? Otolaryngol
Clin North Am 35:207, 2002.)
Fig 10. Keloid of the earlobe: dissection from the epidermis and
closure with suprakeloid flap. The excision is followed by
radiotherapy to the site to prevent recurrence. (Reprinted with
permission from Adams BB, Gloster HM: Surgical pearl: excision
with suprekeloid flap and radiation therapy for keloids. J Am Acad
Dermatol. 47:307, 2002.)
Surgical Excision and Steroids. Treatment of
an earlobe keloid consists of a single intralesional
injection of triamcinalone acetonide, 40mg/mL,
through a 27-gauge needle. It should be very
difficult to inject the medication; if it injects freely,
then the needle is incorrectly positioned. Approximately 0.3mL of steroid is injected into the lesion.
If the response is significant, the injection is repeated after 1 month. If there is no response at 1
month, the keloid is excised by the core technique278 (Fig 11). Approximately 5mg of triamcinalone acetonide, 10 mg/mL, is deposited in the
wound at the time of excision. The wound is closed
anteriorly and is allowed to granulate posteriorly.
After reepithelialization has occurred, the patient
is instructed to begin use of silicone gel twice
daily. Monthly steroid injections of the 40mg/mL
concentration are performed for 2–3 months to
prevent recurrence.
Core excision of a dumbbell keloid on the earlobe with adjuvant steroids shows excellent cure
rates. The anterior wound is closed primarily and
the posterior wound is allowed to granulate.
Salasche330 reports successful treatment of 6 patients
28
without recurrence at the 1-year follow-up period.
Adjuvant therapy has become the standard of care
to effect improved outcomes.
Laser Excision. Lasers are believed to wound in
such a way so as to minimize scar contraction. Both
carbon dioxide and argon lasers showed early promise in keloid excision, but long-term studies revealed
recurrence rates of up to 92% when used as a
single treatment modality. 294,296,331–333 The most
promising form of laser therapy seems to be the
585nm flashlamp-pumped pulsed-dye laser (PDL),
which has been effective in reducing pruritus,
erythema, and the height of keloids, with improvement in 57% to 83% of cases.331–335 The best results
are obtained when laser excision is combined with
adjunctive therapy.
Steroids. Intralesional steroids are used often
for the initial treatment of keloids, but more commonly they are the adjuvant treatment of choice
perioperatively. Steroids suppress the inflammatory phase of wound healing, decrease collagen
production by the fibroblast, and control fibroblast proliferation. Triamcinolone acetonide,
40mg/mL, is the usual agent, and is administered
preoperatively, intraoperatively, and/or postoperatively. No single regimen has proved to be
most effective.
SRPS Volume 10, Number 7, Part 1
Table 9
Reports of X-ray Therapy for Keloids
(Reprinted with permission from Norris JEC: Superficial X-ray therapy in keloid management: a retrospective study of 24 cases and literature
review. Plast Reconstr Surg 95:1051, 1995.)
Adverse reactions to the use of intralesional steroids may include local depigmentation or
hypopigmentation, epidermal atrophy, telangiectasia, and skin necrosis. Systemic side effects and
Cushing’s syndrome are rare and associated with
improper dosages. Ketchum and colleagues336
injected up to 120mg triamcinolone intralesionally
at the time of excision, and noted 88% regression
to varying degrees and disappearance of pruritus
within 3–5 days. Complications included atrophy,
depigmentation, and recurrence. Currently most
practitioners do not administer such high doses;
rather, monthly doses of ~12mg are recommended.337
Radiation Therapy. Radiation therapy has been
used for treating keloids since 1906.296 Used alone,
radiation therapy is associated with a wide range of
cure rates (15%–94%).326
Radiotherapy is best used in conjunction with
surgical excision. When the lesions are first excised
and subsequently radiated, the response rates
increase to 33%–100%.326 More recent studies show
even better response rates (64%–98%).326 In large
keloids resistant to treatment, radiotherapy offers a
reduction in recurrence rate, from 50%–80% with
surgery alone, to ~25% with combined surgery
and early postoperative radiotherapy (Table 9).338,339
Success seems to depend on the number of rads
delivered to the surgical site and start of RT immediately postoperatively. Preoperative irradiation
does not offer any advantage. The usual dosage is
15–20Gy administered over 5 or 6 treatment sessions. Possible complications include scar hyperpigmentation and, rarely, malignant degeneration.340
Controversy abounds regarding the safety of
delivering radiation to a benign tumor,341 fueled by
anecdotal reports of malignant tumors developing
after RT of a keloid. Although the recommended
dose for the treatment of keloids is low, long-term
follow-up is needed to put this issue to rest.
Pressure Therapy. Pressure therapy is effective in the treatment of hypertrophic scars and
keloids, especially after burn injury.342 This therapeutic strategy is used in combination with other
treatment modalities (eg, silicone gels or sheets).
The applied pressure should be 24–30mmHg to
avoid excessive compression of peripheral blood
vessels. Maximum benefit is achieved from wear-
29
SRPS Volume 10, Number 7, Part 1
ing the pressure appliance for 18–24h/d for at least
4–6 months.296,343,344
Pressure is thought to decrease tissue metabolism and increase collagenase activity within the
wound.272 Pressure techniques include various compression wraps and custom garments for large areas,
or the use of large clip-on earrings after excision of
earlobe keloids. 345 Pressure therapy requires
patience and perseverance, as continuous application of pressure is required for several months to
obtain a satisfactory result.
Several authors report good response rates of
90%–100% in patients treated with keloid excision
followed by pressure therapy,296,343,344 especially
when the keloid was located on the earlobe.
Intralesional verapamil combined with 6 months of
pressure therapy after keloid excision resulted in a
55% cure rate in one series.346
Interferon. Interferons interfere with the ability
of fibroblasts to synthesize collagen. Specifically,
IFN-α-2b normalizes the collagen and glycosaminoglycan of the keloid.347 Complications of IFN-α2b injection include flu-like symptoms of headache,
fever, and myalgias. In a retrospective study, Berman
and Flores347 found lower recurrence rates with
postexcisional IFN-α-2b (18.7%) than with either
excision alone (51.1%) or postexcisional triamcinalone injections (58.4%). Conejo-Mir et al348
report 0% recurrence at 3 years with the combination of CO2 laser excision and IFN-α-2b injections
for keloids of the earlobe.
Interferon-γ is believed to work similarly to IFN-α2b. There have been several anecdotal reports regarding the benefits of IFN-γ in treating the keloid.
Pittet et al349 reported improvement of hypertrophic
scars in 7 patients who were given human recombinant gamma-interferon in twice-weekly intralesional
injections for 4 weeks. Granstein350 and Larrabee351
have also reported modest success with gammainterferon in a small number of patients.
A small pilot study by Broker et al352 followed
the course of patients with two keloids, one of
which was treated with IFN-γ injections and the
other with placebo injections after excision. Only
7 patients were enrolled in the study and 3
dropped out by the 1-year follow-up examination.
Both experimental and control groups had uniformly poor results, with an approximate 75%
recurrence.
30
Other researchers have used antitransforming
growth factor-beta (anti-TGF-β) to decrease scarring in experimental animals. 317 Tredget 353
describes antagonizing the proliferative effects of
TGF-β2 and histamine with interferon-α-2b.
Imiquimod is an immune response modifier that
stimulates innate and cell-mediated immune pathways, enhancing the body’s natural ability to heal.354
Imiquimod also induces the local synthesis and
release of cytokines, including IFN[alpha],
IFN[gamma], tumor necrosis factor-[alpha], and
interleukins-1, -6, -8, and -12 when topically
applied.355 A number of recent case reports and
clinical studies document success with imiquimod
under conditions where interferons are also successful. Nightly application of topical imiquimod
5% cream for 8 weeks after surgical excision of 13
keloids from 12 patients resulted in no recurrence
of keloidal growth at 24 weeks.356
Silicone Gel Sheeting. The mechanism of action
of silicone gel sheeting is not known. Histologic
examination reveals no evidence of silicone leakage into the tissues. Hydrocolloid dressings are
occlusive and facilitate scar hydration, and are considered to be safe in the treatment of wounds in the
initial stages of healing.357
Depending on the series, between 80% and 100%
of patients show significant improvement of their
hypertrophic scars with silicone gel.358–360 In patients
with keloids, however, silicone gel is successful only
35% of the time.360 Silicone gel sheeting may reduce
recurrence rates after excision of keloids. It is a benign
intervention that does not cause any problems and
may be useful as an adjunctive measure. In human
trials, topical silicone gel was used to treat 22 keloids
in 18 patients, with a significant response rate of
86%.361 Possible drawbacks to silicone gel include
patient noncompliance (especially children) and
occasional rashes, skin breakdown, or difficulty
obtaining adherence to the scar.362
The review by Shaffer et al288 summarizes and
compares all keloid treatments in the literature.
SURGICAL TREATMENT
Keloids that are resistant to corticosteroid injection, pressure therapy, or other topical therapy
should be considered for surgical excision. Surgery
alone is associated with recurrence rates of 50%–
SRPS Volume 10, Number 7, Part 1
80% and is therefore indicated only in compliant
patients who are willing to undergo adjuvant therapy
postoperatively to try to avoid a recurrence.363
Hypertrophic scars, although more responsive to
appropriate surgery, also frequently require adjuvant treatment.
Guidelines for the surgical management of
abnormal scars are as follows:
Z-plasty
A Z-plasty entails creation of triangular transposition flaps which are used to lengthen a contracted
scar or to reorient a scar parallel to the RSTLs (Fig
12). Although a single large Z-plasty often gives
more length, multiple small Z-plasties may better
camouflage the scar.
• combination therapy—eg, surgery and corticosteroids—is more effective in preventing recurrence than any single modality
• for small scars, surgical excision and corticosteroids are appropriate therapy
• for moderately large scars, pressure therapy should
be added to the surgery-steroid combination
• for very large, treatment-resistant scars, the best
results are reported with a combination of surgery and postoperative radiotherapy
• pressure and irradiation are useful surgical adju-
vants but are ineffective in the treatment of
established lesions
• skin grafts should be harvested from areas where
pressure can be easily applied
The goals of excisional scar revision are to redirect the scar, divide it into smaller segments, and
make it level with the adjacent skin. The location
and size of the scar will also influence the choice of
revision procedure.364
Fusiform Excision
Fusiform excision is the most commonly used
technique of scar revision because of its simplicity
and because it does not add to scar length. Ideally
an ellipse at least four times as long as it is wide
should be removed to prevent dog-ears. Fusiform
excision is indicated for short, linear, minimally
wide but unsatisfactory scars that approximate the
RSTLs. The technique is much less effective in
addressing depressed scars or wide hypertrophic
scars resulting from primary wound closure.365
Bowen and Charnock 366 recently described a
double-blade scalpel for excising long, linear scars,
and reported excellent results in 27 widespread
abdominal scars.
Fig 12. Z-plasty angles and their theoretical gain in length. (After
Grabb WC: Basic Techniques of Plastic Surgery. In: Grabb WC,
Smith JW (eds), Plastic Surgery, 3rd Ed. Boston, Little Brown, 1979.)
The three limbs of the Z must be of equal length.
Increasing the angles between the limbs will gain
length at the expense of increased tension. The
usual Z-plasty angle is 60° and the resulting scar will
31
SRPS Volume 10, Number 7, Part 1
be 75% longer than the original minus 25%–45%
lost to skin elasticity.218,367,368 Z-plasty scar revision
is indicated in the following circumstances:369
• antitension-line (ATL) scars of the eyelids, lips,
nasolabial folds, and nonfacial areas
• scars on the forehead, temples, nose, cheeks,
and chin running at less than 35° of inclination
to the RSTLs
• severe trapdoor and depressed scars
• small linear scars not amenable to fusiform excision
• most areas of multiple scarring
W-plasty
Unlike Z-plasties, a W-plasty breaks up the
straight-line configuration of a scar without adding
length to its axis (Fig 13). Since it requires excision
of additional tissue, it should not be used in scars
under significant tension. W-plasty scar revision is
indicated for the following conditions:220,370
• ATL scars of the forehead, eyebrows, temples,
cheeks, nose, and chin
• bowstring scars
• small but broad, depressed scars
Y-V-plasty
Fig 13. W-plasty. A, W-plasty for repair of a straight scar.
Triangles become smaller at the end of the scar, and the length
of the limbs of the flap is tapered to avoid puckering. B, On
a curved scar, the angles of the inner aspect of the curve should
be more acute than the angles of the outer aspect of the curve.
(After Borges AF: W-plasty. Ann Plast Surg 3:153, 1979;
reprinted with permission from McCarthy JG: Introduction to
Plastic Surgery. In: McCarthy JG (ed), Plastic Surgery. Philadelphia, WB Saunders, 1990. Vol 1, Ch 1, pp 1-68.)
A series of Y incisions can be made on the same
plane across a scar to break up the scar cord and
lengthen it.371 The tongue at the top of the Y stem
can be advanced to form a V without raising the
dermis (Fig 14). This ensures a good blood supply.
Running Y-V plasties are indicated in the management of some contracted burns scars and may be
used in conjunction with W-plasties to break up a
linear scar.
Serial Excision
Staged excision is appropriate for wide scars
that cannot be excised completely without tension. Although largely supplanted by tissue
expansion, serial excision remains simpler and
more cost-effective.234
32
Fig 14. The running Y-V-plasty. (Reprinted with permission from
Olbrisch RR: Running Y-V plasty. Ann Plast Surg 26:52, 1991.)
SRPS Volume 10, Number 7, Part 1
Tissue Expansion
Full-thickness unscarred skin can be recruited
from areas adjacent to large hypertrophic scars and
burn scar contractures by placement and gradual
inflation of expanders. In a second stage, the scar is
excised and the expanded skin is used to resurface
the tissue deficit.372 Tonnard et al373 described a
technique for scar-length reduction by circumferential adjacent tissue recruitment using two semicircular expanders.
Skin Stretching
The Sure-Closure device is discussed in the
Wound Closure section. The device has been proposed to excise and primarily close large scars on
the trunk and extremities.241
Miscellaneous
Dermabrasion. Dermabrasion removes the epidermis and partial-thickness dermis and smoothes
surface irregularities. It is most effective for mildly
elevated or depressed scars, particularly acne scars.
Dermabrasion is often used as an adjunct to scar
excision.374,375
Scalpel Sculpturing. Snow et al376 reported using
a #15 scalpel blade to microshave and feather the
skin edges as an alternative to dermabrasion. Other
authors have used razor blades to contour small,
mildly elevated scars.377
Cryosurgery. The first prospective study of
cryosurgery for abnormal scars was recently reported
by Zouboulis et al.378 Good-to-excellent responses
were seen in 57 of 93 White patients treated with
nitrous oxide once a month for at least 3 months.
Significant pain occurred in 32% of patients and
lesional pigmentary changes were seen in 11%.
Laser. Lasers have been applied to the management of abnormal scars because of their ability to
remove lesions precisely with minimal injury to
normal adjacent tissue. The Nd:YAG, CO2, and
argon lasers have been used with modest success.379,380 Dierickx et al381 reported 80% improvement in 26 patients with erythematous or pigmented
scars after treatment with the flashlamp-pumped
pulsed dye laser. Alster and Nanni382 report symp-
tomatic improvement of hypertrophic burn scars
after treatment with the 585nm pulsed dye laser,
namely improved scar pliability and texture and
decreased erythema.
EXOTIC WOUNDS
This section will address some of the more exotic
wounds, including
Extravasation injuries
Radiation burns
High-pressure injuries
Chemical burns
Ballistics and high-velocity missile wounds
Aquatic animal wounds
Bites — snakes, spiders, centipedes
Stings — scorpions and caterpillars
EXTRAVASATION INJURIES
Leakage of solution from a vein into the surrounding tissue spaces during intravenous administration may lead to severe local tissue injury. Adult
patients undergoing chemotherapy have a 4.7%
risk of extravasation.383 In children the risk is 11%
to 58%.384 Usually extravasation is recognized early,
remains localized, and heals spontaneously. The
injury can be classified as necrotic, irritant, or vesicant. The most common agents involved are
osmotically active chemicals (eg, total parenteral
nutrition), cationic solutions (eg, potassium ion [K+],
calcium ion [Ca2+]), and cytotoxic drugs.385
Certain groups of patients are prone to extravasation injury: Babies in special care units are at
greater risk because of their immature skin and
their frequent need for antibiotics or intravenous
electrolyte and nutritional support. Elderly patients
may be unable to report the pain from extravasation injury and the general fragility of their skin and
veins make them more susceptible to injury.386
Cancer patients often have fragile veins that are
difficult to cannulate. Patients who are unable to
communicate or have a decreased level of consciousness may have extravasation injuries that go
unnoticed.
33
SRPS Volume 10, Number 7, Part 1
The sequelae of extravasation are often more
serious than the original injury and are often
underestimated. Common sites of injury are the
dorsum of the hand and the antecubital fossa, where
there is little soft-tissue coverage.385 Extravasation
may result in large wounds that require debridement and coverage with a split skin graft or local
flap, and when next to a major artery in the forearm or leg, extravasation may lead to amputation.
Severe damage to the underlying nerves and tendons can also happen. Chemotherapeutic agents
may produce an insidious injury because they spread
to the surrounding tissue and produce indolent
ulcers that resemble radiation necrosis.385
The extent of damage after extravasation injury
depends on the toxicity of the drug, the site of
extravasation, the amount that has leaked out, and
the general nutrition of the patient. The clinical
presentation varies. There may be a loss of blood
return at the cannula site, which may be accompanied by pain (a burning sensation). Persistent pain
suggests a more severe injury.387 Erythema may be
present, accompanied by swelling of the surrounding area and local blistering, suggesting at least a
partial-thickness injury, which may also be associated with mottling and darkening of the skin. Early,
firm induration and pain are good indicators of eventual ulceration, which may lead to eschar beneath
which is the ulcer cavity.
A wide array of treatments has been proposed,
ranging from no intervention to early aggressive
excision.388–390 If the extravasated drug is an antibiotic or hypertonic solution, application of ice to the
area, elevation, and monitoring the patient for 48
hours are usually sufficient.391 Scuderi and Onesti392
recommend local injection of copious amounts of
saline and topical application of corticosteroids if
only a few hours have elapsed since injury.
Extravasated high osmolarity contrast medium
(such as is commonly used for contrast CT scans) is
treated with 4–6 small incisions around the area
of extravasation. A blunt-ended liposuction cannula with side holes is inserted in the incisions and
used to aspirate extravasated material and subcutaneous fat. Saline is then injected through the
same cannula, up to 200mL. After extensive irrigation, the saline is aspirated using the liposuction
device.393
Khan and Holmes394 list five mechanisms of
extravasation necrosis:
34
1) direct cellular toxicity (chemotherapeutic agents,
pentathol)
2) osmotically active substances with an osmolality
greater than that of serum (parenteral nutrition,
contrast dye)
3) ischemic necrosis from vasopressors and cationic
solutions (epinephrine, dopamine)
4) mechanical compression
5) bacterial colonization
The authors devised a kit and protocol for the
rapid treatment of extravasations caused by cytotoxic drugs.394 The kit contains hydrocortisone
cream, injectable hyaluronidase and lidocaine,
sodium chloride infusion, and a number of syringes
and needles. The aim is to flush out as much of the
cytotoxic agent as possible.
When preventive measures and drug therapy
are insufficient to avert tissue necrosis, or if the
injury is extensive or more than a few hours old,
early surgery is indicated. Gault386 reviewed a series
of 96 patients with extravasation injuries seen at
two London hospitals during a 6-year period. Of
the 44 patients treated by either saline flushout
(37), liposuction (1), or both (6), 86% healed without soft-tissue loss. Examination of the flushout fluid
confirmed the presence of the extravasated material. Early treatment was associated with a good
outcome. Patients who were referred late suffered
skin necrosis and significant scarring around tendons, nerves, and joints, and many required extensive reconstruction.
Most authors now recommend early detection
and excision of all affected tissue following
Adriamycin extravasation.395–398 The excision may
be guided by fluorescence microscopy; 396,397
delayed closure is indicated.
RADIATION INJURY
The morphologic and functional changes that
occur in noncancerous tissue as a direct result of
ionizing radiation can range from mild to extremely
debilitating or life-threatening. Ionizing radiation
causes damage to tissue by means of energy transference. Free radicals are formed and cause intracellular and molecular damage. The primary targets
of ionizing radiation are cellular and nuclear membranes and DNA. The susceptibility of an individual
SRPS Volume 10, Number 7, Part 1
cell to radiation damage is directly proportional to
its mitotic rate. The most sensitive cells are those
which divide rapidly, such as cells of the skin, bone
marrow, and gastrointestinal tract. In addition to
sensitivity of the exposed cell, morbidity from
radiation depends on the dose received, time over
which the dose is received, volume of tissue irradiated, and type of radiation.399 Cellular changes
resulting from low-dose radiation are probably due
to an apoptotic mechanism, whereas changes
related to high-dose radiation are probably due to
direct cellular necrosis.
The direct effects of radiation can be immediate, acute (days to weeks), or delayed (months to
years). Acute effects result from necrosis of the rapidly proliferating cell lines. A transient, faint erythema
may appear during the first week of treatment due
to dilation of capillaries and may be associated with
an increase in vascular permeability. Radiation
inhibits mitotic activity in the germinal cells of the
epidermis, hair follicles, and sebaceous glands. Epilation and dryness of the skin occur. By the third or
fourth week of radiation, typical erythema is localized to the radiation field and the skin is noticeably
red, edematous, warm, and tender. Larger vessels
may be obstructed by fibrin thrombi, edema is
prominent, and there may be small foci of hemorrhage.400 Cellular exudate is rare. If the total radiation dose to the skin does not exceed 30Gy, the
erythema phase is followed during the fourth or
fifth week by a dry desquamation phase characterized by pruritus, scaling, and an increase in melanin pigmentation in the basal layer. Within 2 months
the inflammatory exudate and edema have subsided, leaving an area of brown pigmentation.
If the total radiation dose to the skin is >40Gy,
the erythema phase is followed by a moist desquamation phase. This stage usually begins in the fourth
week and is often accompanied by considerable
discomfort. Bullous formation occurs above the basal
layer and sometimes just below the epidermis. Eventually the roofs of the bullae are shed and the entire
epidermis may be lost in portions of the irradiated
area. Edema and fibrinous exudate persist. In the
absence of infection, reepithelization of the
denuded skin usually begins within 10 days. Ulcers
may appear 2 weeks or more after radiation exposure. These ulcers are a result of direct necrosis of
the epidermis; they usually heal but tend to
recur.399,401
Approximately 1 year after radiation treatment
the epidermis is thin, dry, and semitranslucent, with
vessels easily seen. Hair follicles and sebaceous
glands are usually absent. Some sweat glands may
also have been destroyed. In time, increasing fibrosis of the skin is present. Much of the collagen and
subcutaneous adipose tissue are replaced by atypical fibroblasts and dense fibrous tissue that may
cause induration of the skin and may limit movement. In radiation injury of soft tissue, fibrinous
exudate accumulates under the epidermis. Characteristic features of delayed radiation lesions are
eccentric myointimal proliferation of the small
arteries and arterioles as well as telangiectasia. These
changes may progress to thrombosis or complete
obstruction. Delayed ulcers are more common than
acute ulcers and result from ischemic changes in
small arteries and arterioles; they heal slowly and
may persist for several years. Irradiated skin in the
chronic stage is thin, hypovascularized, extremely
painful, and easily injured by any slight trauma or
infection.399,401
Skin reactions to radiation should be treated early
to prevent complications later. Keeping the skin
moist and pliable to prevent fissures and cracks and
free of infection is extremely important. Mendelsohn et al402 has compiled a list of products to treat
radiation-induced skin changes (Table 10). If an
ulcer develops, the normal wound care protocols
should be initiated. In severe cases, wide
debridement and a skin graft or flap coverage may
be necessary.
Treatment with hyperbaric oxygen accelerates
healing in some patients,403,404 but its effectiveness
in soft-tissue necrosis from radiation injury is
unproven. Experimental therapies include topical
TGF-β1, 405 granulocyte-macrophage colonystimulating factor (GM-CSF),406 orgotein (a Cu/Zn
chelate with superoxide dismutase),407 topical vitamin C, 408,409 topical corticosteroids,410 glucorticoids,411 NSAIDs,412 aloe vera gel,413,414 heliumneon laser treatments,415 and oral pentoxifylline
treatment.416
HIGH-PRESSURE INJECTION INJURIES
High-pressure injection devices such as are used
for painting, cleaning, degreasing, etc. can produce
pressures of 600–12,000psi.417,418 The substance
enters the skin through a seemingly insignificant
35
SRPS Volume 10, Number 7, Part 1
Table 10
Skin Care Products Used for Different Radiation Skin Reactions
(Adapted from Mendelsohn FA, Divino CM, Reis ED, Kerstein MD: Wound care after radiation therapy. Adv Skin Wound Care, 15:216, 2002.)
wound and rapidly spreads through the tissues along
fascial planes. In the hand, the injected material
can course volar to the tendon sheath and extend
into the forearm. The tendon sheath is rarely
breached. The degree of injury varies with the
injection pressure and type of injected material.
With high injection pressures and large amounts of
caustic substances, tissue damage can be so extensive that salvage may not be possible. Amputation
rates after high-pressure injection injuries range up
to 48% in the literature.419
Water, low volume vaccines, and air generally
cause no serious damage.420,421 In these cases medical treatment with wide spectrum antibiotics and
tetanus prophylaxis are usually all that is needed.422
Other times the pressure itself is responsible for the
initial damage; a compartment syndrome may be
induced immediately by the amount of material
injected and later by the inflammation elicited.423
Digital injection injuries do worse than palmar
injuries because of the limited space available for
expansion.423,424
An immediate progressive toxic effect has been
shown to take place in cases of paint and paint
thinners,425 and a foreign body reaction occurs if
36
the material is not removed, leading to fibrosis and
draining sinuses.424
The nature of the injected material is probably
the most important factor in the subsequent injury.
Injected paint wounds have a worse outcome than
those injected with oil or grease. Spirit-based paints
cause damage by disintegration of cell membranes,
whereas oil-based paints cause an intense inflammatory response. Latex paints in a water base are
the least noxious.419
Not surprisingly, delayed and conservative treatment of high pressure injection injuries is associated with very poor results and frequent amputation.424,426,427 The proper management of these
lesions is primarily surgical, with immediate removal
of the foreign material, debridement, cleansing of
necrotic areas, and insertion of a drain. X-ray evaluation should precede the surgical treatment, both
to detect fractures and to guide the decompression. Angiograms are also useful to show any areas
that are not being perfused. Medical treatment
includes tetanus and antimicrobial prophylaxis and
antibiotic administration. A postoperative physical
rehabilitation program will help reduce the degree
of functional impairment.426
SRPS Volume 10, Number 7, Part 1
CHEMICAL BURNS
The proper treatment of chemical burns is tailored to the wounding agent, as follows.
Black Liquor
Black liquor is a warm alkaline solution (pH 11–
13) that is used to convert wood chips to pulp.428 It
consists of a mixture of sodium bicarbonate (10%),
sodium hydroxide (60%), sodium sulfide (4%), sodium thiosulfate (5%), and sodium sulfate (4%) at a
temperature of 85–95°C. Surgical treatment begins
with irrigation with tap water. Silver sulfadiazine
cream and sodium chloride solution occlusive dressings are applied twice daily. Debridement and skin
grafting procedures may be necessary.428
Treatment initially involves water irrigation or
use of phosphate buffer or 5% thiosulfate soaks,
which convert hexavalent chromic ion into a less
toxic trivalent form. Topical use of 10% calcium
ethylenediamine tetraacetic acid (EDTA) ointment;
5–10% sodium citrate; lactate- or tartrate-soaked
dressings; or cream containing ascorbic acid, sodium
pyrosulfate, ammonium chloride, tartaric acid, and
glucose is recommended to prevent further absorption. Dimercaprol, ascorbic acid, or sodium calcium edetate are often used as systemic treatment.432,433
If the burn is <2% TBSA and is superficial, calcium EDTA dressings may be used.432,433 For burns
>2% TBSA, immediate wide excision reduces systemic chromium absorption, and should be followed
by split-skin grafts. Peritoneal dialysis in the first 24
hours prevents parenchymal chromium uptake.
Cement
Cement burns are either alkaline or heat related.
Wet cement is roughly 64% calcium oxide and
21% silicon oxide and has a pH of ~12.5. Abrasions by the coarse cement allow the alkali to enter
the skin and cause increased tissue destruction. The
most frequently affected areas are the knees, calves,
and feet. Because the initial contact is typically
painless, the injury progresses from prolonged contact with the skin.429,430 In time there is reddish
discoloration of the contact areas, followed by a
gradual change to a deep purple-blue color and this
may go on to painful burns, blistering, and ulceration.429,431 Treatment consists of removing the agent
with a cloth followed by washing the affected area
with soap and copious amounts of running water.431
Chromic Acid
Chromic acid is an industrial chemical used for
electroplating in alloy and dye production. Chromic acid burns produce coagulative necrosis and
may lead to systemic toxicities, including gastrointestinal hemorrhage, vomiting, diarrhea, renal or
hepatic failure, CNS disorders, anemia, and
coagulopathies. An exchange transfusion may be
required to remove hexavalent chromium bound
to hemoglobin from the circulation. Circulating
chromium may also be removed by peritoneal
dialysis or by hemodialysis the day after the burn
occurs.432,433
Formic Acid
Formic acid or formate is used industrially as a
descaling agent, as a rubber processor, and as a
textile tanning substance. The main concern in
cases of formic acid burn is systemic acidosis, which
impairs the elimination of formic acid because of
increased reabsorption in the proximal tubule.434
Patients often present with hypotension, intravascular hemolysis (because of cytotoxic formate
effects), hematuria, hemoglobinuria, kidney failure,
CNS depression, and evidence of other organ damage.434
Treatment is similar to that of other acid burns.
All clothing is removed and the patient is thoroughly
washed with water. Internally, the formate is
removed or neutralized with intravenous hydration
and aggressive bicarbonate therapy. Folic acid can
be administered to accelerate formate breakdown.
Dialysis may be necessary.
Hydrofluoric Acid (HF)
HF is used to frost, etch, and polish glass and
ceramics; to remove sand from metal castings; to
clean stone and marble; and to treat textiles. HF is
also prevalent in the manufacture of fertilizers, pesticides, solvents, dyes, plastics, refrigerants, highoctane fluids, rust removers, aluminum brighteners, and heavy-duty cleaners.435,436 Although an
acid, HF causes injury similar to an alkali because it
37
SRPS Volume 10, Number 7, Part 1
reaches deeply into tissue. Because of its ability to
penetrate lipid membranes, HF breaches cell membranes and binds calcium and magnesium ions within
the cell. The initial corrosive burn causes little damage compared with the secondary damage produced by the fluoride ions. The F ions produce
extensive liquefaction of soft tissues and decalcification and corrosion of bone. Most exposures
involve dilute HF on small spots. Exposure of concentrated HF to even small areas (~2%) of the body
often has a fatal outcome.435,436
The clinical presentation is of blanched tissue
with surrounding erythema and immediate severe
pain. Edema and blistering occur within 1–2 hours,
then gray areas followed by necrosis and deep
ulceration within 6–24 hours and possible tenosynovitis and osteolysis. Even burns from dilute HF,
if left untreated, will progress to similar destruction.436 In addition to the obvious burn, systemic
effects of hypocalcemia and hyponatremia must also
be addressed. Cardiac arrhythmia often results from
hypocalcemia, and free fluoride ions may cause
respiratory arrest and ventricular arrhythmia.436
Treatment consists of copious irrigation for about
20 minutes to clean the wound of any unreacted
chemicals and to dilute the chemical that is in contact with the skin. Washing is extremely important
in HF burns because the toxic properties derive
from complex ions that are not present at concentrations of <10%. Some authors advocate the use
of neutralizing agents such as sodium bicarbonate
and phosphate buffer.437 After washing, the free
fluoride ions must be converted to an insoluble
fluoride salt by means of benzalkonium chloride,
either 0.2% (Hyamine 1622) or 0.13% (Zephiran).
Use of these compounds is controversial because
of the discomfort they cause, the potential toxicity
of Hyamine, and the possible ineffectiveness of
Hyamine in deeper tissues.437
Minor burns may be treated with topical 2.5%
calcium gluconate jelly. If calcium carbonate gel is
used, large amounts may be required for treatment
and it may stain the skin. Some authors recommend a subcutaneous injection of 10% calcium
gluconate on the periphery of the burn, but generally this treatment is reserved for patients who have
a central, hard, gray area with surrounding erythema
and those with severe, throbbing pain.437 Infiltration therapy is invasive and may introduce infection and hypercalcemia. In patients with severe
38
hand burns, consider an arterial infusion of calcium
solution via the brachial, ulnar, or radial arteries.
Monitoring of serum calcium and magnesium levels is extremely important.437
The role of surgery is to debride blisters and to
excise any necrotic tissue from the burned area so
that treatment with topical agents or infiltration may
be effective. Excision of the involved tissue is often
attempted to reduce systemic toxicity and to aid in
wound treatment.437
Phenol
Phenol has antiseptic properties and is used in
chemical face peels, nerve injections, and as a topical anesthetic for skin and mucous membranes.438
Acute poisoning may occur from phenol absorption. The patient experiences initial bradycardia,
followed by tachycardia and a decrease in blood
pressure. Systemic toxicity is proportional to the
plasma concentration of free phenol. Phenol
depresses the CNS and may lead to respiratory arrest;
it may also produce peripheral nerve demyelinization and RBC lysis, central lobular necrosis of the
liver, and renal failure through direct damage to
the glomeruli.438 Skin damage of acute phenol poisoning includes denaturation and necrosis followed
by gangrene. Typically there is a partial-thickness
chemical burn accompanied by severe pain, swelling, and redness. Phenol may have some local
anesthetic properties, which allow extensive damage to occur before the patient feels pain.438
Treatment consists of decontamination with a
50% concentration of PEG 300 or 400 and extensive lavage with soapy water. A solvent cleaner
may also be used to remove phenol from the skin.
Irrigation with water, glycerin, or Zephiran has also
been recommended. The burn wounds are covered with a silver sulfadiazine dressing.438
White Phosphorus
White phosphorus is used in the manufacture of
various insecticides, fertilizers, and incendiary
weapons. Phosphorus burns may be caused by
either liquid or solid white phosphorus. When white
phosphorus contacts the skin, a painful, necrotic,
yellow chemical burn with a garlic-like odor results.
The phosphorus is extremely lipid-soluble and
readily penetrates the dermal layers. As skin pen-
SRPS Volume 10, Number 7, Part 1
etration progresses, white phosphorus continues to
be oxidized until it is removed by debridement or
consumed by oxidation.439
White phosphorus is difficult to remove and often
becomes embedded in the skin. Immediate treatment consists of prompt removal of all clothing in
contact with the agent. The skin is then washed
with cool water to end oxidation of the white phosphorus. Greasy dressings should be avoided because
they contribute to tissue permeability. The phosphorus is then neutralized with a dilute solution of
copper sulfate (1%–5%) briefly applied to the wound
(because of the danger of copper toxicity). Bicarbonate may be used to neutralize the pH of the
wound.439
BULLET WOUNDS
Santucci and Chang440 reviewed the tissue effects
of different bullet types, as follows:
Jacketed bullets travel faster than 2000ft/sec
and are used primarily in assault rifles. They are
more likely to wound than to kill. Hollow-point
bullets are designed so that the tip flattens and
expands on impact, to 2–3X the original diameter.
They cause more tissue damage and a larger permanent wound cavity. These bullets are prohibited
by the Geneva Convention for military use but are
sold legally to U.S. civilians. Exploding bullets are
designed to detonate on impact, but do not explode
reliably. Surgeons must be careful when handling
these bullets, which should always be grasped with
forceps. PTFE (cop killer) bullets have a steel or
tungsten core coated with PTFE and are intended
to penetrate Kevlar vests. Similarly, armor piercing rounds have a hardened steel or tungsten core
designed to penetrate light military armor of trucks
and other vehicles. Black talon bullets have a
reverse-tapered hollow point designed to open into
petal-like blades that cut tissue as it spins into the
wound. These bullets should always be grasped
with forceps or hemostats because the razor-sharp
blades will easily cut the surgeon’s fingers. Frangible bullets, eg, the Glaser Safety Slugs, use a
lightweight cup of jacketed lead filled with small
lead shots. When the bullet hits its target, the cup
collapses and empties its shot contents into tissue,
causing massive destruction at a relatively superficial level. A large caliber round at close range
causes severe, widespread tissue damage.
Shotshells are meant to turn handguns and small
rifles into minishotguns. Shotgun injuries are devastating at close range. Air bursting ammunition
will be fired from US Army M-16 rifles in the near
future. When fired, high explosive, air bursting
ammunition will detonate at a prescribed distance
to send shrapnel to multiple targets. The projected
increase in wounding power is 4-fold over standard
rifle rounds.
The authors440 dispelled some misconceptions
about high velocity projectiles, primarily that ballistic wounds require massive debridement. Their
extensive review of the literature led them to the
following conclusions:
1) It is not true that high velocity weapons always
cause more tissue damage than low velocity
weapons. In fact, the fastest bullets are just as
likely to keep traveling past the victim after leaving the body and impart little wounding energy
onto the target.
2) It is not a good idea to debride the bullet path
up to 30X the diameter of the bullet; this may
actually harm the patient. Overdebridement is
to be avoided.
3) The current recommendation is to debride
obviously detached and nonviable tissue, then
reexamine the wound after 2 days for additional
debridement if necessary.
WOUNDS BY AQUATIC ANIMALS
The treatment of wounds inflicted by some marine
vertebrates, from stingrays to sea snakes, is summarized in Table 11.
Marine wounds easily become infected, and as
such most wounds should be left to heal secondarily. Special culture media are required for isolation of certain marine organisms. Infected wounds
should also be cultured for routine aerobes and
anaerobes. Management of marine acquired infections should include therapy against Vibrio spp. Any
patient with a marine acquired wound who develops rapidly progressive cellulitis or myositis should
be suspected of having Vibrio parahemolyticus or
Vibrio vulnificus infection.441
Soft-tissue infections are common after alligator
and crocodile bites, and broad-spectrum antibiotics should be administered prophylactically. A variety of gram-negative aerobes including Aeromonas
39
SRPS Volume 10, Number 7, Part 1
Table 11
Emergency Treatment of Wounds Caused by Marine Organisms
(Reprinted with permission from McGoldrick J, Marx JA: Marine envenomations. Part 1: Vertebrates. J Emerg Med 9:497, 1991.)
hydrophila, Acinetobacter, Citrobacter, Enterobacter, Yersinia, Proteus, and Pseudomonas; anaerobes such as Bacteroides, Clostridium, Fusobacterium, and Peptococcus; and fungi such as Candida,
Aspergillus, and Torulopsis have been cultured from
the mouths of alligators.442 The same principles of
diagnosis and treatment apply for alligators bites as
for shark attacks, including the administration of
tetanus toxoid vaccine.
Wounds from stinging animals should be soaked
in hot water as soon as possible to inactivate any
heat-labile components of the venom and perhaps
to help reverse local toxin-induced vasospasm and
tissue ischemia.441,443,444 This should be continued
for 30–90 minutes or until the pain is relieved. If
pain is not controlled with the hot water soak, a
regional nerve block or local infiltration with
bupivacaine can be performed.441 Delayed primary wound closure may be performed later.
BITES
Snakes
Venomous snakes are responsible for 8000 of
the 45,000 snake bites reported in the U.S. annually,445 yet fewer than 15 cases per year are fatal.446
In other parts of the world, however, approximately
30,000 fatal snake bites are sustained annually.447
These figures underscore the importance of prompt
and appropriate treatment of snake bites.
40
A regional poison-control center (which in the
U.S. may be reached through the national hotline,
800-222-1222) should be contacted for assistance
in treating patients who have been bitten by a snake.
These centers are staffed by persons who have been
trained in all types of poisoning and maintain a list
of consulting physicians throughout the country who
are experienced in the management and treatment
of bites from venomous snakes.
Pit Vipers
The vast majority of venomous snake bites in
North America are by pit vipers (Crotalidae). Pit
vipers are distinguished by a heat-sensing pit located
between the eye and the nostril, and are most common in the southern U.S. This family of snakes
includes the cottonmouth, copperhead, and rattlesnakes. Pit viper venom contains at least 26 enzymes
and 69 enzymatic peptides capable of producing
extensive local tissue necrosis.448 Systemic envenomation increases capillary permeability, which may
induce coagulopathy, shock, and acute renal failure.449
Proper patient assessment should include identification of the species of snake, its size, the presence or absence of discrete fang marks, and any
evidence of local or systemic toxicity. The eastern
and western diamondback rattlesnakes account for
most fatalities. Deaths typically occur in children,
in the elderly, and in people who are either not
SRPS Volume 10, Number 7, Part 1
given antivenom or receive too little of it or too
late.446
The current treatment for snake bite is summarized by Seiler et al448 as follows (Table 12):
• Incision and suction. This technique is only
effective if perfomed within 45 minutes of the
bite, and thus is of limited value in the emergency department. A linear incision should be
made through skin only, across the fang marks
and slightly beyond.450 Suction is applied with a
Sawyer venom extractor.
• Loose tourniquet. A loosely applied tourniquet will
reduce venom dissemination from the affected
limb by 50%. The tourniquet should be applied 1
hour after the snake bite only if a significant delay
in hospital transport time is anticipated. Tourniquets that are too tight will exacerbate tissue loss
from the injured extremity.448
• Antibiotics and tetanus prophylaxis. Both measures are appropriate. Rattlesnake fangs may harbor gram negative organisms, and clostridial
infections have been reported.451,452
• Surgical debridement. Wound debridement is
indicated for the removal of all necrotic tissue.
Because most of the injected venom remains in
the subcutaneous tissue for a few hours, some
authors recommend aggressive early local excision to remove the contaminated tissues.452,453
Others advocate a more conservative approach.454,455
Severe
envenomations by rattlesnakes may be associated with increased compartment pressure.
The clinical diagnosis requires objective evidence of elevated compartment pressure to
>30mmHg. The bite site should be elevated
and the patient given an additional 4–6 vials of
FabAV in 1h.446 The extra antivenom should
effectively neutralize the venom components
and reduce compartment pressure. Fasciotomies
are controversial and may actually prolong the
recovery.
• Compartment pressure release.
• Antivenom. Indications for the use of antivenom
have not been strictly defined. Most authors
reserve antivenom administration for confirmed
cases of envenomation by a medium to large
snake, particularly a rattlesnake; for patients with
signs and symptoms of systemic envenomation;
and for children under age 12.454,456–458
After rattlesnake bites, signs of worsening local
injury (pain, swelling, and ecchymosis), coagulopathy, or systemic effects (hypotension and altered
mental status) dictate administration of antivenom. FabAV is a lyophilized antivenom. Each
dose must be reconstituted and then diluted to a
volume of 250mL in a crystalloid fluid before being
administered. The initial dose is given by slow
infusion for the first 10min, and the infusion of
the rest of the dose is completed over the course
of 1h. The dose of antivenomn is correlated with
the clinical severity of envenomation. In most
reported cases, 8–12 vials are sufficient to establish initial control.459 Skin testing is unreliable in
predicting the development of immediate (anaphylaxis) or delayed (serum sickness) hypersensitivity reactions to antivenom. Because the complications of antivenom administration can be lifethreatening, it should be used selectively and
judiciously. 460,461
Other types of therapy for crotalid bites include
hyperbaric oxygen, cryotherapy, corticosteroids, and
electroshock. None of these has proved efficacy.448
Coral Snakes
Only one other snake indigenous to North
America poses any serious threat to man, and
that is the coral snake. Unlike pit vipers, coral
snakes possess a potent neurotoxic venom consisting chiefly of acetylcholinesterase. Coral-snake
envenomations produce little or no pain but may
result in tremors, marked salivation, and changes
in mental status, including drowsiness and
euphoria. The neurologic manifestations are usually cranial-nerve palsies such as ptosis, dysarthria, dysphagia, dyspnea, and respiratory paralysis.
The onset of neurotoxic effects may be delayed
up to 12h.446 Once manifestations appear, it may
not be possible to prevent further effects or reverse
the changes that have already occurred. Although
local tissue destruction is minimal, envenomation
may cause respiratory paralysis and immediate death
(Table 12). Subacute deaths are usually due to
aspiration pneumonia.462
41
SRPS Volume 10, Number 7, Part 1
Spiders
Although all spiders are venomous, only a handful of spiders are dangerous to man from among the
more than 100,000 species worldwide. Two North
American species, the black widow and the brown
recluse, are capable of penetrating the skin and
injecting sufficient venom to inflict serious injury.
Black Widow
The black widow spider (Latrodectus mactans)
is widely distributed throughout the continental
United States. Although both sexes carry venom,
only the female spider is large enough to cause
significant envenomation in man.463 The venom is
a potent neurotoxin that causes an irreversible blockade of nerve conduction. The initial sharp pain at
the envenomation site is often accompanied by
two small red marks—the fang punctures. Within
20 to 30 minutes of the bite, neurologic signs and
symptoms begin to manifest, including first localized and then generalized muscle cramps, abdominal pain, restlessness, perspiration, and occasionally
convulsions or shock. If the patient is not treated,
milder symptoms may linger for days or weeks.464
Pennell et al465 recommend the following therapeutic regimen (Table 12):
• Calcium gluconate. A 10mL dose of a 10% solu-
tion of calcium gluconate is administered intravenously over 15–20 minutes. If this is effective
in controlling pain, the diagnosis of black widow
envenomation is confirmed.
• Muscle relaxants. One ampule of methocarbamol (Robaxin) or 5–10mg of diazepam
(Valium) may be given.
• Black widow antivenin. A single 2.5mL vial of
Lyovac is administered intravenously in severely
envenomated patients.
At greatest risk of an adverse outcome from black
widow bites are young children, the elderly, and
people who have underlying medical problems.
These patients should be monitored closely and
treated aggressively.466
Brown Recluse
The brown recluse spider (Loxosceles reclusa) is
common throughout the southern United States.
42
Although nondescript in appearance, the spider may
be distinguished by its long slender legs, fiddle-like
markings on its dorsal thorax, and shiny brown
exoskeleton.467 The bite usually goes unnoticed at
first. Within several hours, however, increasing pain
is accompanied by erythema and blistering at the
puncture site, which frequently has a pale halo.
Over the next few days, a central ulceration may
spread to adjacent skin, resulting in extensive tissue
destruction and occasional limb loss.
Systemic envenomation is uncommon but may
cause hemolytic anemia, thrombocytopenia, and
disseminated intravascular coagulation. Five of the
six reported deaths from brown recluse bites have
been in children.468,469
Treatment remains controversial. Dapsone, an
anti-leprosy drug, has been advocated for the prevention of tissue necrosis. Oral administration of
dapsone (100–200mg q.d. x 10–25d) inhibits neutrophil migration. Patients must be selected carefully and monitored closely, since dapsone may
induce a dose-dependent hemolytic anemia or
agranulocytosis.467,470 Surgical excision may result
in significant scarring and soft-tissue defects and
does not appear to inhibit the spread of venom.
Conservative surgical debridement limited to
infected or obviously necrotic tissues is appropriate
(Table 12).
Centipedes
Like spiders, centipedes are venomous, and any
centipede with large-enough fangs to penetrate
human skin has the ability to envenomate humans.
Centipede envenomation usually results in burning
pain, local swelling, lymphangitis, and lymphadenopathy. Symptoms may persist for weeks and then
disappear, only to recur. Systemic reactions in the
United States are rare. Treatment is symptomatic,
and infiltration of the bitten area with lidocaine or
other anesthetic agent promptly relieves pain. Tetanus prophylaxis should be provided.471
STINGS
Scorpions
In 2002 there were 15,687 calls to U.S. poison
control centers related to scorpion stings. Of these,
485 (3%) required medical attention, 2 resulted in
SRPS Volume 10, Number 7, Part 1
Table 12
Symptoms and Treatment of Patients after Snake and Spider Bites
death, and 8 had major complications.472 Worldwide there are an estimated 5000 deaths from scorpion stings every year.
Scorpions have a stinger at the end of their tail
through which they introduce venom that immobilizes their prey. The size of a scorpion does not
correlate with its aggressiveness or the potency of
its venom. Scorpions can control the amount of
venom released per sting depending on the victim’s
size, and can sting repeatedly and rapidly when
faced with large prey. In the United States and
Mexico, the small Centruroides scorpions account
for the majority of severe human envenomations.473
Scorpion venom varies among species, but
generally is a mixture of single-chain polypeptides
containing neurotoxins that block ion channels,
particularly sodium and potassium. A pronounced
acetylcholine and catecholamine release triggers
secondary effects. The most notable aspect of a
scorpion sting is significant pain at the puncture site
with little redness and edema. Typical adults experience local pain and some paresthesias extending
along the affected limb that can last for several hours,
but have minimal systemic effects. Systemic
envenomation is the cause of most deaths in children and the elderly. Initially there is a transient
excess cholinergic tone at the neuromuscular junction resulting in salivation, lacrimation, urinary
incontinence, defecation, gastroenteritis, and emesis (SLUDGE syndrome). The subsequent norepinephrine release causes tachycardia, hypertension,
hyperpyrexia, myocardial depression, and pulmonary edema that can be fatal. The pain, paresthesias,
and tachycardia can persist for 2 weeks.473
Caterpillars
Caterpillars are the larval stages of moths and
butterflies. There are approximately 50 species of
caterpillar in the United States that can cause
envenomation, with symptoms that range from a
painful sting to dermatitis and conjunctivitis. The
puss caterpillar, Megalopyge opercularis, is one of
the more toxic species, sometimes resulting in epidemics of envenomation. It is common in the southeastern United States and its body has toxincontaining spines. A person who brushes against
this caterpillar experiences an intense burning sensation at the contact site, followed shortly by redness, swelling, and proximally radiating pain.
Vesicles usually appear, and pain and pruritus can
last for days.474 The swelling can be impressive
and involve an entire limb. Some patients go into
shock or have seizures.475
Treatment consists of local wound care and cleansing, immobilization and elevation of the affected
extremity and tetanus prophylaxis. Any embedded
broken-off spines are removed with adhesive tape.
Diphenhydramine may be necessary for the relief
of pruritus. Early application of ice may provide
pain relief, but morphine or meperidine may be
necessary in more severe cases.475
43
SRPS Volume 10, Number 7, Part 1
BIBLIOGRAPHY
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
44
Madden JW, Arem AJ: Wound Healing: Biologic and
Clinical Features. In: Sabiston DC Jr (ed), Davis-Christopher Textbook of Surgery, 12th Ed. Philadelphia, Saunders,
1981, Ch 14.
McGrath MH: Peptide growth factors and wound healing.
Clin Plast Surg 17(3):421, 1990.
Moulin V: Growth factors in skin wound healing. Eur J Cell
Biol 68:1, 1995.
Martin P: Wound healing—Aiming for perfect skin regeneration. Science 276:75, 1997.
Howes EL, Sooy JW, Harvey SC: Healing of wounds as
determined by their tensile strength. JAMA 92:42, 1929.
Hunt TK et al (eds): Soft and Hard Tissue Repair:
Biological and Clinical Aspects, 1st Ed. New York, Praeger,
1984, p 5.
Bryant WM: Wound healing. CIBA Found Symp 29(3),
1977.
Grillo HC: Origin of fibroblasts in wound healing: An
autoradiographic study of inhibition of cellular proliferation by local x-irradiation. Ann Surg 157:453, 1963.
Stewart RJ et al: The wound fibroblast and macrophage.
Their origin studied in a human after bone marrow
transplantation. Br J Surg 68:129, 1981.
Delaunay A, Bazin S: Mucopolysaccharides, collagen,
and nonfibrillar proteins in the field of inflammation. Int
Rev Connect Tissue Res 2:301, 1964.
Chapman JA, Kellgren JH, Steven FS: Assembly of collagen
fibrils. Fed Proc 25:1811, 1966.
Madden JW, Peacock EE: Studies on the biology of
collagen during wound healing. III. Dynamic metabolism
of scar collagen and remodeling of dermal wounds. Ann
Surg 174:511, 1971.
Bailey AJ et al: Polymorphism in the experimental granulation tissue. Biochem Biophys Res Comm 66:1160, 1975.
Peacock EE: Collagenolysis: The other side of the
equation. World J Surg 4:297, 1980.
Peacock EE: Symposium on biological control of scar
tissue. Plast Reconstr Surg 41:8, 1968.
Barbul A: Immune aspects of wound repair. Clin Plast Surg
17(3):433, 1990.
Wahl SM: Host immune factors regulating fibrosis. CIBA
Found Symp 14:175, 1985.
Thakral KK, Goodson WH, Hunt TK: Stimulation of
wound blood vessel growth by wound macrophages. J
Surg Res 26:430, 1979.
Clark RA et al: Role of macrophages in wound healing.
Surg Forum 27:16, 1976.
Thompson WD et al: Fibrinolysis and angiogenesis in
wound healing. J Pathol 165:311, 1991.
Karasek MA: Mechanisms of angiogenesis in normal and
diseased skin. Int J Dermatol 30:831, 1991.
Simpson DM, Ross R: Effects of heterologous antineutrophil
serum in guinea pigs: Hematologic and ultrastructural
observations. Am J Pathol 55:49, 1971.
Peterson JM et al: Significance of T lymphocytes in wound
healing. Surgery 102:300, 1987.
Rudolph R, Cheresh D: Cell adhesion mechanisms and
their potential impact on wound healing and tumor
control. Clin Plast Surg 17(3):457, 1990.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
Ryan TJ: Exchange and the mechanical properties of the
skin: Oncotic and hydrostatic forces control by blood
supply and lymphatic drainage. Wound Rep Reg 3:258,
1995.
Prockop DJ et al: The biosynthesis of collagen and its
disorders. N Engl J Med 301:13, 1979.
Bailey AJ et al: Characterization of the collagen of human
hypertrophic and normal scars. Biochem Biophys Acta
405:412, 1975.
Harper E, Gross J: Collagenase, procollagenase, and
activator relationships in tadpole tissue cultures. Biochem
Biophys Res Comm 48:1147, 1972.
Peacock EE Jr: Wound Repair, 3rd Ed. Philadelphia,
Saunders, 1984.
Gabbiani G, Ryan GB, Majno G: Presence of modified
fibroblasts in granulation tissue, and possible role in
wound contraction. Experientia 27:549, 1970.
Gabbiani G et al: Granulation tissue as a contractile organ:
A study of structure and function. J Exp Med 135:719,
1972.
Montandon D et al: The contractile fibroblast: Its
relevance in plastic surgery. Plast Reconstr Surg 52:286,
1973.
Ryan GB et al: Myofibroblasts in human granulation
tissue. Hum Pathol 5:55, 1974.
Montandon D, D’Andiran G, Gabbiani G: The mechanism of wound contraction and epithelialization. Clinical
and experimental studies. Clin Plast Surg 4:325, 1977.
Rudolph R et al: The life-cycle of the myofibroblast. Surg
Gynecol Obstet 145:389, 1977.
Rudolph R: Location of the force of wound contraction.
Surg Gynecol Obstet 148:547, 1979.
McGrath MH, Hundahl SA: The spatial and temporal
quantification of myofibroblasts. Plast Reconstr Surg
69:975, 1982.
McGrath MH: The effect of prostaglandin inhibitors on
wound contraction and the myofibroblast. Plast Reconstr
Surg 69:74, 1982.
Gabbiani G, Majno G: Dupuytren’s contracture: Fibroblast contraction? Am J Pathol 66:131, 1972.
Pirani CL, Levenson SM: Effect of vitamin C deficiency on
healed wounds. Proc Soc Exp Biol Med 82:95, 1953.
Levenson SM et al: The healing of rat skin wounds. Ann
Surg 161:293, 1965.
Hunt TK, Pai MP: The effect of variant ambient oxygen
tensions on wound metabolism and collagen synthesis.
Surg Gynecol Obstet 135:561, 1972.
Stephens FO, Hunt TK: Effect of changes in inspired
oxygen and carbon dioxide tensions on wound tensile
strength. Ann Surg 173:515, 1971.
Silver IA: Oxygen tension and epithelialization. In:
Maibach HI, Rovee DT (eds), Epidermal Wound Healing.
Chicago, Year Book, 1972, p 291.
Hunt TK: Disorders of wound healing. World J Surg 4:271,
1980.
Bains JW, Crawford DT, Ketchum AS: Effect of chronic
anemia on wound tensile strength: Correlation with
blood volume, total red cell volume, and proteins. Ann
Surg 164:243, 1966.
SRPS Volume 10, Number 7, Part 1
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
Heughan C, Grislis G, Hunt TK: The effect of anemia on
wound healing. Ann Surg 179:163, 1974.
Jonsson K et al: Tissue oxygenation, anemia, and perfusion in relation to wound healing in surgical patients. Ann
Surg 214:605, 1991.
Stephens FO, Dunphy JE, Hunt TK: Effect of delayed
administration of corticosteroids on wound contraction.
Ann Surg 173:214, 1971.
Ehrlich P, Tarver H, Hunt TK: The effects of vitamin A and
glucocorticoids upon repair and collagen synthesis. Ann
Surg 177:22, 1973.
Hunt TK et al: Effect of vitamin A on reversing the inhibitory
effect of cortisone on healing of open wounds in animals
and man. Ann Surg 170:633, 1969.
Hunt TK: Vitamin A and wound healing. J Am Acad
Dermatol 15(4 Pt 2):817, 1986.
Ashcroft GS, Greenwell-Wild T, Horon MA, et al: Topical
estrogen accelerates cutaneous wound healing in aged
humans associated with an altered inflammatory response.
Am J Pathol 155:1137, 1999.
Ruberg RL: Role of nutrition in wound healing. Surg Clin
North Am 64:705, 1984.
Baker JL: The effectiveness of alpha-tocopherol (vitamin
E) in reducing the incidence of spherical contracture
around breast implants. Plast Reconstr Surg 68:696,
1981.
Ludin EN: Vitamin E and capsular contracture (Letter).
Reply by JL Baker. Plast Reconstr Surg 69:1029, 1982.
Ehrlich P, Tarver H, Hunt TK: Inhibitory effect of vitamin
E on collagen synthesis and wound repair. Ann Surg
175:235, 1972.
Taren DL et al: Increasing the breaking strength of wounds
exposed to preoperative irradiation using vitamin E supplementation. Int J Nutr Res 57:133, 1987.
Liszewski RF: The effect of zinc on wound healing: a
collective review. J Am Osteopath Assoc 81:104, 1981.
Lee PWR et al: Zinc in wound healing. Surg Gynecol
Obstet 143:549, 1976.
Mora RJF: Malnutrition: organic and functional consequences. World J Surg 23:530, 1999.
Tengrup I, Ahonen J, Zederfeldt B: Granulation tissue
formation in zinc-treated rats. Acta Chir Scand 146:1,
1980.
Byrne DJ et al: Effect of fibrin glues on the mechanical
properties of healing wounds. Br J Surg 78:841, 1991.
Kulick MI, Smith SA, Hadler K: Oral ibuprofen: Evaluation
of its effect on peritendinous adhesions and the breaking
strength of a tenorrhaphy. J Hand Surg 11A:110, 1986.
Kulick MI: In vivo-in vitro investigation of the effect of
nonsteroidal anti-inflammatory agents on collagen synthesis. Presented at the 71st Annual Clinical Congress of the
American College of Surgeons, Chicago, 1987.
Dingfelder JR: Prostaglandins: A review. N Engl J Med
307:747, 1982.
Mosely LH, Finseth F: Cigarette smoking: impairment of
digital blood flow and wound healing in the hand. Hand
9:97, 1977.
Goldminz D, Bennett RG: Cigarette smoking and flap and
full-thickness graft necrosis. Arch Dermatol 127:1012,
1991.
Jensen JA, Goodson WH, Hunt TK: Cigarette smoking
decreases tissue oxygen. Arch Surg 126:1131, 1991.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
Jones JK, Triplett RG: The relationship of cigarette smoking
to impaired intraoral wound healing. J Oral Maxillofac
Surg 50:237, 1992.
Siana JE, Rex S, Gottrup F: The effect of cigarette smoking
on wound healing. Scand J Plast Reconstr Surg 23:207,
1989.
Silverstein P: Smoking and wound healing. Am J Med
93:22S, 1992.
Smith JB, Fenske NA: Cutaneous manifestations and
consequences of smoking. J Am Acad Dermatol 34:717,
1996.
Forrest CR, Pang CY, Lindsay WK: Dose and time effects
of nicotine treatment on the capillary blood flow and
viability of random pattern skin flaps in the rat. Br J Plast
Surg 40:295, 1987.
Kayser MR: Surgical flaps. Select Read Plast Surg 9(1),
1999.
Goodman LS, Gilman A: The Pharmacologic Basis of
Therapeutics, 3rd Ed. New York, Macmillan, 1965, pp
581-584, 916-918.
Stewart AG, Phan LH, Grigoriadis G: Physiological and
pathophysiological roles of nitric oxide. Microsurgery
15:693, 1994.
White MJ, Heckler FR: Oxygen free radicals and wound
healing. Clin Plast Surg 17(3):473, 1990.
Chvapil M, Koopmann CF Jr: Age and other factors
regulating wound healing. Otolaryngol Clin North Am
15:259, 1982.
Levenson SM, Birkhill FR, Waterman DF: The healing of
soft tissue wounds; the effects of nutrition, anemia and age.
Surgery 28:905, 1950.
Eaglstein WH: Wound healing and aging. Dermatol Clin
4(3):481, 1986.
Gerstein AD et al: Wound healing and aging. Dermatol
Clin 11(4):749, 1993.
Lau HC et al: Wound care in the elderly patient. Surg Clin
North Am 74(2):441, 1994.
Quirinia A, Viidik A: The influence of age on the healing
of normal and ischemic incisional skin wounds. Mech
Ageing Dev 58:221, 1991.
Thomas DR: Age-related changes in wound healing. Drugs
Aging 18:607, 2001.
Forrester JC et al: Wolff’s law in relation to the healing skin
wound. J Trauma 10:770, 1970.
Gibson T, Kenedi RM: Biomechanical properties of skin.
Surg Clin North Am 47:279, 1967.
Timmenga EJF et al: The effect of mechanical stress on
healing skin wounds: An experimental study in rabbits
using tissue expansion. Br J Plast Surg 44:514, 1991.
Temple WJ et al: Effect of nutrition and suture material on
long-term wound healing. Ann Surg 182:93, 1975.
Powanda MC, Moyer ED: Plasma proteins and wound
healing. Surg Gynecol Obstet 153:749, 1981.
Williamson MB, Fromm HJ: Effect of cystine and methionine on healing experimental wounds. Proc Soc Exp Biol
Med 80:623, 1952.
Pollack SV: Wound healing: A review. III. Nutritional
factors affecting wound healing. J Dermatol Surg Oncol
5:615, 1979.
James JH, Watson ACH: The use of opsite, a vapour
permeable dressing, on skin graft donor sites. Br J Plast Surg
28:107, 1975.
45
SRPS Volume 10, Number 7, Part 1
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
46
Dinner MI, Peters CR, Sherer J: Use of a semipermeable
polyurethane membrane as a dressing for split skin graft
donor sites. Plast Reconstr Surg 64:112, 1979.
Hunt TK, Zederfeldt B: Nutritional and Environmental
Aspects in Wound Healing. In: Dunphy JE, Van Winkle
W Jr (eds), Repair and Regeneration. The Scientific Basis
for Surgical Practice. New York, McGraw-Hill, 1969, p
217.
Basson MD, Burney RF: Defective wound healing in
patients with paraplegia and quadriplegia. Surg Gynecol
Obstet 155:9, 1980.
Crowther M, Brown NJ, Bishop ET, et al: Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumours. J Leukoc Biol
70:478, 2001.
Kivisaari J, Vihersaari T, Renval S, et al: Energy metabolism
of experimental wounds at various oxygen environments.
Ann Surg 181:823, 1975.
Allen DB, Maguire JJ, Mahdavian M, et al: Wound hypoxia
and acidosis limit neutrophil bacterial killing mechanisms. Arch Surg 132:991, 1997.
Steinbrech DS, Longaker MT, Mehrara BJ, et al: Fibroblast
response to hypoxia: the relationship between angiogenesis and matrix regulation. J Surg Res 84:127, 1999.
Steed DL: Debridement. Am J Surg 187:71S, 2004.
Robson MC, Stenberg BD, Heggers JP: Wound healing
alterations caused by infection. Clin Plast Surg 17(3):485,
1990.
Laato M et al: Inflammatory reaction and blood flow in
experimental wounds inoculated with Staphylococcus
aureus. Eur Surg Res 20:33, 1988.
Robson MC: Wound infection. A failure of wound
healing caused by an imbalance of bacteria. Surg Clin
North Am 77:637, 1997.
Lawrence JC: Bacteriology and Wound Healing. In: Fox
JA, Fischer J (eds), Cadexomer Iodine. Stuttgart, Schattauer
Verlag, 1983, pp 19-31.
Lawrence JC: The aetiology of scars. Burns 13:S3, 1987.
Messina A, Knight KR, Dowsing BJ, et al: Localization of
inducible nitric oxide synthase to mast cells during ischemia/reperfusion injury of skeletal muscle. Lab Invest
80:423, 2000.
Williams DT, Harding KL: Healing responses to skin and
muscle in critical illness. Crit Care Med 31:S547, 2003.
Dalgleish AG, O’Byrne KJ: Chronic immune activation
and inflammation in the pathogenesis of AIDS and cancer.
Adv Cancer Res 84:231, 2002.
Salm R, Wullich B, Kiefer G, et al: Effects of three-drug
antineoplastic protocol on wound healing in rats: a
biomechanical and histologic study on gastrointestinal
anastomoses and laparotomy wounds. J Surg Oncol
(Suppl) 47:5, 1991.
Bujko K, Suit HD, Springfield DS, et al: Wound healing
after preoperative radiation for sarcoma of soft tissues. Surg
Gynecol Obstet 176:124, 1993.
Cohen SC et al: Effects of antineoplastic agents on wound
healing in mice. Surgery 78:238, 1975.
Graves G, Cunningham P, Raaf J: Effect of chemotherapy
on healing of surgical wounds. Clin Bull 10:144, 1980.
Falcone RE, Nappi JF: Chemotherapy and wound healing. Surg Clin North Am 64:779, 1984.
Miller SH, Rudolph R: Healing in the irradiated wound.
Clin Plast Surg 17(3):503, 1990.
116. Reiber GE, Lipsky BA, Gibbons GW: The burden of
diabetic foot ulcers. Am J Surg 76:5S, 1998.
117. Morain WD, Colen LB: Wound healing in diabetes
mellitus. Clin Plast Surg 17(3):493, 1990.
118. Haynes LJ, Brown MH, Handley BC, et al: Comparison of
Pulsavac and sterile whirlpool regarding the promotion of
tissue granulation. Phys Ther 74:S4, 1994.
119. Hess CL, Howard MA, Attinger CE: A review of mechanical
adjuncts in wound healing: hydrotherapy, ultrasound,
negative pressure therapy, hyperbaric oxygen, and
electrostimulation. Ann Plast Surg 51:210, 2003.
120. Davis SC, Ovington LG: Electrical stimulation and ultrasound in wound healing. Dermatol Clin 11:775, 1993.
121. Webster DF, Harvey W, Dyson M, Pond JB: The role of
ultrasound-induced cavitation in the “in vitro” stimulation
of collagen synthesis in human fibroblasts. Ultrasonics
18:33, 1980.
122. Wiles PG, Boothby M, Griffith M, et al: Pulsed ultrasound
therapy and skin blood flow. Lancet 330:572, 1987.
123. Dyson M, Franks C, Sucking J: Stimulation of healing of
varicose ulcers by ultrasound. Ultrasonics 14:232, 1976.
124. Callam MJ, Harper DR, Dale JJ: A controlled trial of weekly
ultrasound therapy in chronic leg ulceration. Lancet
330:204, 1987.
125. Lundeberg T, Nordstrom F, Brodda-Jansen G, et al: Pulsed
ultrasound does not improve healing of venous ulcers.
Scand J Rehabil Med 22:195, 1990.
126. Selkowitz DM, Cameron MH, Mainzer A, Wolfe R: Efficacy of pulsed low-intensity ultrasound in wound healing: a single-case design. Ostomy Wound Manage 48:40,
2002.
127. McDiarmid T, Burns PN, Lewith GT, Machin D: Ultrasound in the treatment of pressure sores. Physiotherapy
71:66, 1985.
128. Nussbaum EL, Biemann I, Mustard B: Comparison of
ultrasound/ultraviolet-C and laser for treatment of pressure ulcers in patients with spinal cord injury. Physical
Therapy 74:812, 1994.
129. Morykwas MJ, Argenta LC, Shelton-Brown EI, McGuirt W:
Vacuum-assisted closure: a new method for wound
control and treatment: animal studies and basic foundation. Ann Plast Surg 38:553, 1997.
130. Argenta LC, Morykwas MJ: Vacuum-assisted closure: a
new method for wound control and treatment: clinical
experience. Ann Plast Surg 38:563, 1997.
131. Bucalo B, Eaglstein WH, Falanga V: Inhibition of cell
proliferation by chronic wound fluid. Wound Rep Regen
1:181, 1993.
132. Boykin JV Jr: The nitric oxide connection: hyperbaric
oxygen therapy, becaplermin, and diabetic ulcer management. Adv Skin Wound Care 13:19, 2000.
133. Nichter LS, Morwood DT, Williams GS, et al: Expanding
the limits of composite grafting: a case report of successful
nose replantation assisted by hyperbaric oxygen therapy.
Plast Reconstr Surg 87:337, 1991.
134. Hart GB, Mainous EG: The treatment of radiation necrosis
with hyperbaric oxygen (OHP). Cancer 37:2580, 1976.
135. Mounsey RA, Brown DH, O’Dwyer TP, et al: Role of
hyperbaric oxygen therapy in the management of mandibular osteoradionecrosis. Laryngoscope 103:605, 1993.
136. Bowersox JC, Strauss MB, Hart GB: Clinical experience
with hyperbaric oxygen therapy in the salvage of ischemic
skin flaps and grafts. J Hyperb Med 1:141, 1986.
SRPS Volume 10, Number 7, Part 1
137. Perrins DJD: Influence of hyperbaric oxygen on the
survival of split skin grafts. Lancet 1:868, 1967.
138. Bill TJ, Hoard MA, Gampper TJ: Applications of hyperbaric oxygen in otolaryngology head and neck surgery:
facial cutaneous flaps. Otolaryngol Clin North Am 34:753,
2001.
139. Zhao LL, Davidson JD, Wee SC, et al: Effect of hyperbaric
oxygen and growth factors on rabbit ear ischemic ulcers.
Arch Surg 129:1043, 1994.
140. Mathes SJ, Feng L-J, Hunt TK: Coverage of the infected
wound. Ann Surg 198:420, 1983.
141. Barker AT: Measurement of direct current in biological
fluids. Med Biol Eng Comput 19:507, 1981.
142. Barket AT, Jaffe LF, Vanable JW: The glabrous epidermis
of cavies contains a powerful battery. Am J Physiol
242:R358, 1982.
143. Cunliffe-Barnes T: Healing rate of human skin determined
by measurement of electric potential of experimental
abrasions: study of treatment with petrolatum and with
petrolatum containing yeast and liver extracts. Am J Surg
69:82, 1945.
144. Foulds IS, Barker AT: Human skin battery potentials and
their possible role in wound healing. Br J Dermatol
109:515, 1983.
145. Eberhardt A, Szczypiorski P, Korytowski G: Effects of
transcutaneous electrostimulation on the cell composition of skin exudates. Acta Physiol Pol 37:1986.
146. Fukushima K, Senda N, Iuri H, et al: Studies of galvanotaxis
of leukocytes. Med J Osaka Univ 4:195, 1953.
147. Orida N, Feldman JD: Directional protrusive pseudopodial activity and motility in macrophages induced by
extracellular electric fields. Cell Motil 2:243, 1982.
148. Cruz NI, Bayron FE, Suarez AJ: Accelerated healing of fullthickness burns by the use of high-voltage pulsed galvanic
stimulation in the pig. Ann Plast Surg 23:49, 1989.
149. Alvarez OM, Mertz PM, Smerbeck RV, Eaglstein WH: The
healing of superficial skin wounds is stimulated by external
electrical current. J Invest Dermatol 81:144, 1983.
150. Bourguignon GJ, Bourguignon LY: Electric stimulation of
protein and DNA synthesis in human fibroblasts. FASEB J
1:398, 1987.
151. Smith J, Romansky N, Vomero J, Davis RH: The effect of
electrical stimulation on wound healing in diabetic mice.
J Am Podiatr Assoc 74:71, 1984.
152. Hecker B, Carron H, Schwartz DP: Pulsed galvanic
stimulation: effects of current frequency and polarity on
blood flow in healthy subjects. Arch Phys Med Rehabil
66:369, 1985.
153. Kaada B: Vasodilation induced by transcutaneous nerve
stimulation in peripheral ischemia (Raynaud’s phenomenon and diabetic polyneuropathy). Eur Heart J 3:303,
1982.
154. Karu T: Photobiology of low-power laser effects. Health
Phys 56:691, 1989.
155. Beauvoit B, Kitai T, Chance B: Contribution of the
mitochondrial compartment to the optical properties of
the rat liver: a theoretical and practical approach. Biophys
J 67:2501, 1994.
156. Beauvoit B, Evans SM, Jenkins TW, et al: Correlation
between the light scattering and the mitochondrial content of normal tissues and transplantable rodent tumors.
Anal Biochem 20:226, 1995.
157. Greco M, Guida G, Perlino E, et al: Increase in RNA and
protein synthesis by mitochondria irradiated with heliumneon laser. Biochem Biophys Res Commun 163(3):1428,
1989.
158. Karu T, Pyatibrat L, Kalendo G: Irradiation with He–Ne
laser increases ATP level in cells cultivated in vitro. J
Photochem Photobiol B 27:219, 1995.
159. Whelan HT, Houle JM, Donohoe DL, et al: Medical
applications of space light-emitting diode technology—
space station and beyond. Space Tech Appl Int Forum
458:3, 1999.
160. Conlan MJ, Rapley JW, Cobb CM: Biostimulation of
wound healing by low-energy laser irradiation. J Clin
Periodont 23:492, 1996.
161. McCaughan JS Jr, Bethel BH, Johnston T, Janssen W: Effect
of low-dose argon irradiation on rate of wound closure.
Lasers Surg Med 5:607, 1985.
162. Lyons RF, Abergel RP, White RA, et al: Biostimulation of
wound healing in vivo by a helium-neon laser. Ann Plast
Surg 18:47, 1987.
163. Kana JS, Hutschenreiter G, Haina D, Waidelich W: Effect
of low-power density laser radiation on healing of open
skin wounds in rats. Arch Surg 116:293, 1981.
164. Mester E, Jaszsagi-Nagy E: The effects of laser radiation on
wound healing and collagen synthesis. Studia Biophys
Band 35:227, 1973.
165. Mester E, Mester AF, Mester A: The biochemical effects of
laser application. Lasers Surg Med 5:31, 1985.
166. Karu T: Laser biostimulation: a photobiological phenomenon. J Photochem Photobiol B 3:638, 1989.
167. Abergel RP, Lyons RF, Castel JC, et al: Biostimulation of
wound healing by lasers: experimental approaches in
animal models and in fibroblast cultures. J Dermatol Surg
Oncol 13:127, 1987.
168. Hunter J, Leonard L, Wilson R, et al: Effects of low energy
laser on wound healing in a porcine model. Lasers Surg
Med 3:285, 1984.
169. Braverman B, McCarthy RJ, Ivankovich AD, et al: Effect of
helium–neon and infrared laser irradiation on wound
healing in rabbits. Lasers Surg Med 9:50, 1989.
170. Whelan HT, Buchmann EV, Whelan NT, et al: NASA lightemitting diode medical applications from deep space to
deep sea. Space Tech Appl Intl Forum 552:35, 2001.
171. Knighton DR et al: Classification and treatment of chronic
nonhealing wounds. Successful treatment with autologous platelet-derived wound healing factors (PDWHF).
Ann Surg 204:322, 1986.
172. Pierce GF et al: In vivo incisional wound healing augmented by platelet-derived growth factor and recombinant c-sis gene homodimeric proteins. J Exp Med 167:974,
1988.
173. Brown GL et al: Enhancement of wound healing by
topical treatment with epidermal growth factor. N Engl J
Med 321:76, 1989.
174. Yates RA et al: Epidermal growth factor and related growth
factors. Int J Dermatol 30:687, 1991.
175. Bennett NT, Schultz GS: Growth factors and wound
healing: Part II. Role in normal and chronic wound
healing. Am J Surg 166:74, 1993.
176. Falanga V: Growth factors and wound healing. J Dermatol
Surg Oncol 19:711, 1993.
177. Falanga V: Growth factors and wound healing. Dermatol
Clin 11(4):667, 1993.
47
SRPS Volume 10, Number 7, Part 1
178. Steenfos HH: Growth factors and wound healing. Scand
J Plast Reconstr Hand Surg 28:95, 1994.
179. Boulton L, Fattu A: Topical agents and wound healing.
Clin Dermatol 12(1):95, 1994.
180. Lawrence WT, Diegelmann RF: Growth factors in wound
healing. Clin Dermatol 12(1):157, 1994.
181. Peschel C, Huber C, Aulitzky WE: Clinical applications of
cytokines. Presse Med 23:1083, 1994.
182. Wang HJ, Wan HL, Yang TS, et al: Acceleration of skin graft
healing by growth factors. Burns 22:10, 1996.
183. Hom DB: Growth factors in wound healing. Otolaryngol
Clin North Am 28(5):933, 1995.
184. Rennekampff HO, Kiessig V, Loomis W, Hansbrough JF:
Growth peptide release from biologic dressings: a comparison. J Burn Care Rehabil 17:522, 1996.
185. Igarashi A, Nashiro K, Kikuchi K, et al: Connective tissue
growth factor gene expression in tissue sections from
localized scleroderma, keloid, and other fibrotic skin
disorders. J Invest Dermatol 106:729, 1996.
186. Ricketts CH, Martin L, Faria DT, et al: Cytokine mRNA
changes during the treatment of hypertrophic scars with
silicone and nonsilicone gel dressings. Dermatol Surg
22:955, 1996.
187. Zhou L-J, Ono I, Kaneko F: Role of transforming growth
factor-â1 in fibroblasts derived from normal and hypertrophic scarred skin. Arch Dermatol Res 289:646, 1997.
188. Robson MC, Mustoe TA, Hunt TK: The future of recombinant growth factors in wound healing. Am J Surg
176(Suppl 2A):80S, 1998.
189. Polo M, Smith PD, Kim YJ, et al: Effect of TGF-â2 on
proliferative scar fibroblast kinetics. Ann Plast Surg 43:185,
1999.
190. Mast BA et al: Scarless wound healing in the mammalian
fetus. Surg Gynecol Obstet 174:441, 1992.
191. Siebert JW et al: Fetal wound healing: A biochemical
study of scarless healing. Plast Reconstr Surg 85:495, 1990.
192. Rowsell AR: Discussion of “Fetal wound healing: A
biochemical study of scarless healing” by JW Siebert et al.
Plast Reconstr Surg 85:503, 1990.
193. Whitby DJ, Ferguson MW: Immunohistochemical localization of growth factors in fetal wound healing. Dev Biol
147:207, 1991.
194. Lorenz HP, Adzick NS: Scarless skin wound repair in the
fetus. West J Med 159:350, 1993.
195. Bleacher JC et al: Fetal tissue repair and wound healing.
Dermatol Clin 11(4):677, 1993.
196. Sullivan KM, Lorenz HP, Meuli M, et al: A model of scarless
human fetal wound repair is deficient in transforming
growth factor beta. J Pediatr Surg 30:198, 1995.
197. Ellis IR, Schor SL: Differential effects of TGF-â1 on
hyaluronan synthesis by fetal and adult skin fibroblasts:
implications for cell migration and wound healing. Exp
Cell Res 228:326, 1996.
198. Cass DL, Meuli M, Adzick NS: Scar wars: implications of
fetal wound healing for the pediatric burn patient. Pediatr
Surg Int 12:484, 1997.
199. Liechty KW, Crombleholme TM, Cass DL, et al: Diminished interleukin-8 (IL-8) production in the fetal wound
healing response. J Surg Res 77:80, 1998.
200. Stelnicki EJ, Longaker MT, Holmes D, et al: Bone morphogenetic protein-2 induces scar formation and skin maturation in the second trimester fetus. Plast Reconstr Surg
101:12, 1998.
48
201. Luomanen M, Virtanen I: Distribution of tenascin in
healing incision, excision and laser wounds. J Oral Pathol
Med 22:41, 1993.
202. Whitby DJ et al: Rapid epithelialisation of fetal wounds is
associated with the early deposition of tenascin. J Cell Sci
99:583, 1991.
203. Stevenson TR, Thacker JG, Rodeheaver GT, et al: Cleansing the traumatic wound with high pressure syringe irrigation. JACEP 5:17, 1976.
204. Hollander JE, Richman PB, Werblud M, et al: Irrigation in
facial and scalp lacerations: does it alter outcome? Ann
Emerg Med 31:73, 1998.
205. Valente JH, Forti RJ, Freundlich LF, et al: Wound irrigation
in children: saline solution or tap water? Ann Emerg Med
41:609, 2003.
206. Rodeheaver GT, Smith SL, Thacker JG, et al: Mechanical
cleansing of contaminated wounds with a surfactant. Am
J Surg 129:241, 1975.
207. Steed DL: Debridement. Am J Surg 187(5A):71S, 2004.
208. Ayello EA, Cuddigan JE: Debridement: controlling the
necrotic/cellular burden. Adv Skin Wound Care 17:66,
2004.
209. Mertz PM: Dressing effects on wound healing. Nurs RSA
7:12, 1992.
210. Dimarcq JL, Zachary D, Hoffmann JA, et al: Insect immunity: expression of the two major inducible antibacterial
peptides, defensin and diptericin, in Phormia terranovae.
EMBO J 9:2507, 1990.
211. Bonn D: Maggot therapy: an alternative for wound
infection. Lancet 356(9236):1174, 30 Sep 2000.
212. Mumcuoglu KY: Clinical applications for maggots in
wound care. Am J Clin Dermatol 2:219, 2001.
213. Edlich RF, Thacker JG, Silloway KA, et al: Scientific basis
of skin staple closure. In: Habal MB (ed), Advances in
Plastic and Reconstructive Surgery. Chicago, Year Book,
1986, p 233-271.
214. Zitelli JA: Secondary intention healing—an alternative to
surgical repair. Clin Dermatol 2:92, 1984.
215. Fernandez A, Finley JM: Wound healing: helping a
natural process. Postgrad Med 74:311, 1983.
216. Crikelair GF: Surgical approach to facial scarring. JAMA
172:140, 1960.
217. Hunt TK, Hopf HW: Wound healing and wound infection. What surgeons and anesthesiologists can do. Surg
Clin North Am 77(3):587, 1997.
218. Grabb WC: Basic Techniques of Plastic Surgery. In:
Grabb WC, Smith JW (eds), Plastic Surgery, 3rd Ed. Boston,
Little Brown, 1979.
219. Borges AF: Scar analysis and objectives of revision procedures. Clin Plast Surg 4:223, 1977.
220. Borges AF: Principles of scar camouflage. Fac Plast Surg
1:181, 1984.
221. Borges AF, Larrabee WF Jr: Controversies in wound
management. Am J Cosmetic Surg 3:5, 1986.
222. Borges AF: Principlization of Scar Revision. In: Millard DR
(ed), Principlization of Plastic Surgery. Boston, Little
Brown, 1986, p 344-5.
223. Borges AF: Relaxed skin tension lines (RSTL) versus other
skin lines. Plast Reconstr Surg 73:144, 1984.
224. Gahhos FN, Simmons RI: Immediate Z-plasty for semicircular wounds. Plast Reconstr Surg 80:416, 1987.
225. Borges AF: Z-plasty for the acute laceration (letter). Plast
Reconstr Surg 82:193, 1988.
SRPS Volume 10, Number 7, Part 1
226. Orentreich D, Orentreich N: Acne scar revision update.
Dermatol Clin 5:359, 1987.
227. Guyuron B, Vaughan C: A comparison of absorbable and
nonabsorbable suture materials for skin repair. Plast
Reconstr Surg 89:234, 1992.
228. Webster RC, Davidson TM, Smith RC: Wound closure
with absorbable sutures. Laryngoscope 86:1280, 1976.
229. Campbell EJ, Bailey JV: Mechanical properties of suture
materials in vivo and after in vivo implantation in horses.
Vet Surg 21:355, 1 992.
230. Rodeheaver GT, Powell TA, Thacker JG, et al: Mechanical
performance of monofilament synthetic absorbable sutures. Am J Surg 154:544, 1987.
231. Bourne RB, Bitar H, Andreae PR: In vivo comparison of four
absorbable sutures: Vicryl, Dexon Plus, Maxon, and PDS.
Can J Surg 31:43, 1988.
232. Bernstein G: Polybutester suture. J Dermatol Surg Oncol
14:615, 1988.
233. Hermann JB, Kelly RJ, Higgins GA: Polyglycolic acid
sutures. Arch Surg 100:486, 1970.
234. McCarthy JG: Introduction to Plastic Surgery. In: McCarthy
JG (ed), Plastic Surgery. Philadelphia, WB Saunders, 1990.
Vol 1, Ch 1, p 48-54.
235. Lindholt JS, Moller-Christensen T, Steele RE: The cosmetic
outcome of the scar formation after cesarean section:
percutaneous or intracutaneous suture? Acta Obstet
Gynecol Scand 73:832, 1994.
236. Wong NL: Review of continuous sutures in dermatologic
surgery. J Dermatol Surg Oncol 19:923, 1993.
237. Kolbusz RV, Bielinski KB: Running vertical mattress suture.
J Dermatol Surg Oncol 18:500, 1992.
238. Bennett RG: The Fundamentals of Cutaneous Surgery.
St Louis, Mosby, 1990, pp 463-471.
239. Mizrahi S, Bickel A, Ben-Layish E: Use of tissue adhesive
in the repair of lacerations in children. J Pediatr Surg
23:312, 1988.
240. Applebaum JS, Zalut T, Applebaum D: The use of tissue
adhesion for traumatic laceration repair in the emergency
department. Ann Emerg Med 22:1190, 1993.
241. Hirschowitz B, Lindenbaum E, Har-Shai Y: A skin-stretching device for the harnessing of the viscoelastic properties
of skin. Plast Reconstr Surg 92:260, 1993.
242. Lam AC, Nguyen QH, Tahery DP, et al: Decrease in skinclosing tension intraoperatively with suture tension adjustment reel, balloon expansion, and undermining. J
Dermatol Surg Oncol 20:368, 1994.
243. Abramson DL, Gibstein LA, Pribaz JJ: An inexpensive
method of intraoperative skin stretching for closure of large
cutaneous wounds. Ann Plast Surg 38:540, 1997.
244. Markovchick V: Suture materials and mechanical after
care. Emerg Med Clin North Am 10:673, 1992.
245. Borges AF: Can stitches get wet? (letter). Plast Reconstr Surg
82:204, 1988.
246. Noe JM, Keller M: Can stitches get wet? Plast Reconstr Surg
81:82, 1988.
247. Wray RC: Force required for wound closure and scar
appearance. Plast Reconstr Surg 72:380, 1983.
248. Rodeheaver GT et al: Evaluation of surgical tapes for
wound closure. J Surg Res 39:251, 1985.
249. Parsons RW: Scar prognosis. Clin Plast Surg 4:181, 1977.
250. Carver N, Leigh IM: Synthetic dressings. Int J Dermatol
31:10, 1992.
251. Katz S, McGinley K, Leyden JJ: Semipermeable occlusive
dressings. Effects on growth of pathogenic bacteria and
reepithelialization of superficial wounds. Arch Dermatol
122:58, 1986.
252. Piacquadio D, Nelson DB: Alginates. A “new” dressing
alternative. J Dermatol Surg Oncol 18:992, 1992.
253. Lionelli GT, Lawrence WT: Wound dressings. Surg Clin
North Am 83:617, 2003.
254. Tredget EE, Shankowsky HA, Groeneveld A, Burrell R: A
matched-pair, randomized study evaluating the efficacy
and safety of Acticoat silver-coated dressing for the treatment of burn wounds. J Burn Care Rehabil 9:531, 1998.
255. Yin HQ, Langford R, Burrell RE: Comparative evaluation
of the antimicrobial activity of ACTICOAT antimicrobial
barrier dressing. J Burn Care Rehabil 20:195, 1999.
256. Innes ME, Umraw N, Fish JS, et al: The use of silver coated
dressings on donor site wounds: a prospective, controlled
matched pair study. Burns 27:621, 2001.
257. Prevel CD, Eppley BL, Summerlin DJ, et al: Small intestinal
submucosa: utilization as a wound dressing in fullthickness rodent wounds. Ann Plast Surg 35:381, 1995.
258. Mostow EN, Haraway GD, Dalsing M, et al: Effectiveness
of an extracellular matrix graft (OASIS Wound Matrix) in
the treatment of chronic leg ulcers: a randomized clinical
trial. J Vasc Surg 41:837, 2005.
259. Trent JF, Kirsner RS: Tissue engineered skin: Apligraf, a bilayered living skin equivalent. Int J Clin Pract 52:408,
1998.
260. Kirsner RS: The use of Apligraf in acute wounds. J Dermatol
25:805, 1998.
261. Schonfeld WH, Villa KF, Fastenau JM, et al: An economic
assessment of Apligraf (Graftskin) for the treatment of hardto-heal venous leg ulcers. Wound Repair Regen 8:251,
2000.
262. Edmonds M, Foster AV, McColgan M: “Dermagraft”: a
new treatment for diabetic foot ulcers. Diabet Med
14:1010, 1997.
263. Edmonds M, Bates M, Doxford M, et al: New treatments
in ulcer healing and wound infection. Diab/Metab Res Rev
16(Suppl):S51, 2000.
264. Gentzkow GD, Iwasaki SD, Hershon KS, et al: Use of
Dermagraft, a cultured human dermis, to treat diabetic
foot ulcers. Diabetes Care 19:350, 1996.
265. Eaglstein WH: Dermagraft treatment of diabetic ulcers. J
Dermatol 25:803, 1998.
266. Marston WA, Hanft J, Norwood P, Pollak R: The efficacy
and safety of Dermagraft in improving the healing of
chronic diabetic foot ulcers: results of a prospective
randomized trial. Diabetes Care 26:1701, 2003.
267. Helder CJM, Hage JJ: Sense and nonsense of scar creams
and gels. Aesthetic Plast Surg 18:307, 1994.
268. Handel N: Surgical alteration of appearance among
primitive societies in New Guinea. Plast Reconstr Surg
95:181, 1995.
269. Goldwyn RM: Keloid. Plast Reconstr Surg 68:640, 1981.
270. Orentreich D, Orentreich N: Acne scar revision update.
Dermatol Clin 5:359, 1987.
271. Murray JC: Scars and keloids. Dermatol Clin 11:697,
1993.
272. Thomas DW, Hopkinson I, Harding KG, Shepherd JP: The
pathogenesis of hypertrophic/keloid scarring. Int J Oral
Maxillofac Surg 23:232, 1994.
49
SRPS Volume 10, Number 7, Part 1
273. Ketchum LD, Cohen IK, Masters FW: Hypertrophic scars
and keloids. A collective review. Plast Reconstr Surg
53:140, 1974.
274. Poochareon VN, Berman B: New therapies for the
management of keloids. J Craniofac Surg 14:654, 2003.
275. Rudolph R: Wide spread scars, hypertrophic scars, and
keloids. Clin Plast Surg 14:253, 1987.
276. Cohen IK, Diegelmann RF: The biology of keloid and
hypertrophic scar and influence of corticosteroids. Clin
Plast Surg 4:297, 1977.
277. Cohen IK, Keiser HR, Sjoerdsma A: Collagen synthesis in
human keloid and hypertrophic scar. Surg Forum 22:488,
1971.
278. Porter JP: Treatment of the keloid: what is new? Otolaryngol
Clin North Am 35:207, 2002.
279. Grabb WC: Keloids and hypertrophic scars. U Mich Med
J 33:38, Jan-Feb 1967.
280. Rockwell WB, Cohen IK, Ehrlich HP: Keloids and hypertrophic scars: A comprehensive review. Plast Reconstr Surg
84:827, 1989.
281. Brody GS, Peng STJ, Landel RF: The etiology of hypertrophic scar contracture: another view. Plast Reconstr Surg
67:673, 1981.
282. Kischer CW, Thies AC, Chvapil M: Perivascular
myofibroblasts and microvascular occlusion in hypertrophic scars and keloids. Hum Pathol 13:819, 1982.
283. Gira AK, Brown LF, Washington CV, et al: Keloids demonstrate high-level epidermal expression of vascular endothelial growth factor. J Am Acad Dermatol 50:850,
2004.
284. Steinbrech DS, Mehrara BJK, Chau D, et al: Hypoxia
upregulates VEGF production in keloid fibroblasts. Ann
Plast Surg 42:514, 1999.
285. Yagi K, Dafalla AA, Osman AA: Does an immune reaction
to sebum in wounds cause keloid scars? Beneficial effect
of desensitisation. Br J Plast Surg 32:223, 1979.
286. Fong EP, Chye LT, Tan WL: Keloids: time to dispel the
myths? Plast Reconstr Surg 104:1199, 1999.
287. Kim A, DiCarlo J, Cohen C, et al: Are keloids really “gliloids”? High-level expression of gli-1 oncogene in keloids.
J Am Acad Dermatol 45:707, 2001.
288. Shaffer JJ, Taylor SC, Cook-Bolden F: Keloidal scars: a
review with a critical look at therapeutic options. J Am
Acad Dermatol 46(2SupplUnderst):S63, 2002.
289. Ketchum LD, Cohen IK, Masters FW: Hypertrophic scars
and keloids. A collective review. Plast Reconstr Surg
53:140, 1974.
290. Moustafa MFH, Abdel-Fattah AFMA: Keloids of the earlobe in Egypt. Their rarity in childhood and their treatment. Br J Plast Surg 29:59, 1976.
291. Koonin AJ: Aetiology of keloids. Review of the literature
and a new hypothesis. S Afr Med J 38:913, 1964.
292. Cohen IK, McCoy BJ: The biology and control of surface
overhealing. World J Surg 4:289, 1980.
293. Oluwasanmi JO: Keloids in the African. Clin Plast Surg
1:179, 1974.
294. Berman B, Bieley HC: Keloids. J Am Acad Dermatol
33:117, 1995.
295. Murray JC: Scars and keloids. Dermatol Clin 11:697,
1993.
296. Niessen FB, Spauwen PH, Schalkwiijk J, et al: On the
nature of hypertrophic scars and keloids: a review. Plast
Reconstr Surg 104:1435, 1999.
50
297. Omo-Dare P: Genetic studies on keloid. J Natl Med Assoc
67:428, 1975.
298. Bloom D: Heredity of keloids: review of the literature and
report of a family with multiple keloids in 5 generations.
NY State J Med 56:511, 1956.
299. Moustafa MFH, Abdel-Fattah AFMA: Presumptive evidence of the effect of pregnancy estrogens on keloid
growth. Case report. Plast Reconstr Surg 56:450, 1975.
300. Ford LC et al: Increased androgen binding in keloids. A
preliminary communication. J Dermatol Surg Oncol
9:545, 1983.
301. Blackburn WR, Cosman B: Histologic basis of keloid and
hypertrophic scar differentiation. Arch Pathol 82:67,
1966.
302. Boyadjiev C, Popchristova E, Mazgalova J: Histomorphic
changes in keloids treated with kenacort. J Trauma 38:299,
1995.
303. Kischer CW: Comparative ultrastructure of hypertrophic
scars and keloids. Scan Electron Microsc (Part 1):423,
1984.
304. Ehrlich HP, Desmouliere A, Diegelmann RF, et al: Morphological and immunochemical differences between
keloid and hypertrophic scar. Am J Pathol 145:105,
1994.
305. Kischer CX, Hendrix MJ: Fibronectin in hypertrophic
scars and keloids. Cell Tissue Res 231:29, 1983.
306. Shetlar MR, Dobrovsky M, Linares H: The hypertrophic
scar: glycoprotein and collagen components of burn
scars. Proc Soc Exp Biol Med 138:298, 1971.
307. Lee KS, Song JY, Suh MH: Collagen MRNA expression
detected by in situ hybridization in keloid tissue. J Dermatol
Sci 2:316, 1991.
308. Clore JN, Cohen IK, Diegelmann RF: Distribution of Type
III collagen in keloid biopsies and fibroblasts in culture.
Biochem Biophys Acta 586:384, 1979.
309. Ehrlich HP, Kelley SF: Hypertrophic scar: an interruption
in the remodeling of repair—a laser Doppler flow study.
Plast Reconstr Surg 90:993, 1992.
310. Bertheim U, Hellstrom S: The distribution of hyaluron in
human skin and mature, hypertrophic and keloid scars.
Br J Plast Surg 47:483, 1994.
311. Moy LS: Management of acute wounds. Dermatol Clin
11:759, 1993.
312. Ueda K, Furuya E, Yasuda Y, et al: Keloids have continuous
high metabolic activity. Plast Reconstr Surg 104:694,
1999.
313. Nakaoka H, Miyauchi S, Miki Y: Proliferating activity of
dermal fibroblasts in keloids and hypertrophic scars. Acta
Dermatol Venereol 75:102, 1995.
314. Cohen IK et al: Immunoglobulin, complement, and
histocompatibility antigen studies in keloid patients. Plast
Reconstr Surg 63:689, 1979.
315. Kischer CW et al: Immunoglobulins in hypertrophic scars
and keloids. Plast Reconstr Surg 71:821, 1983.
316. Topol BM, Lewis VL, Benveniste K: The use of antihistamines to retard the growth of fibroblasts derived from
human skin, scar, and keloid. Plast Reconstr Surg 68:228,
1981.
317. Shah H, Foreman DM, Ferguson MWJ: Control of scarring
in adult wounds by neutralizing antibody to TGF-beta.
Lancet 339:213, 1992.
318. Castagnoli C, Stella M, Berthod C, et al: TNF production
and hypertrophic scarring. Cell Immunol 147:51, 1993.
SRPS Volume 10, Number 7, Part 1
319. McCauley RL, Chopra V, Li YY, et al: Altered cytokine
production in black patients with keloids. J Clin lmmunol
12:300, 1992.
320. Janssen de Limpens AM, Cormane RH: Keloidal scars and
hypertrophic scars—immunological aspects. Aesthetic
Plast Surg 6:149, 1982.
321. Ladin DA, Hou Z, Patel D, et al: P53 and apoptosis
alterations in keloids and keloid fibroblasts. Wound Repair
Regen 6:28, 1998.
322. Sayah DN, Soo C, Shaw WW, et al: Downregulation of
apoptosis-related genes in keloid tissues. J Surg Res 87:209,
1999.
323. Tuan TL, Zhu JY, Sun B, et al: Elevated levels of plasminogen activator inhibitor-1 may account for the altered
fibrinolysis by keloid fibroblasts. J Invest Dermatol
106:1007, 1996.
324. Mustoe TA, Cooter RD, Gold MH, et al: International
clinical recommendations on scar management. Plast
Reconstr Surg 110:560, 2002.
325. Lindsey WH, Davis PT: Facial keloids. A 15-year experience. Arch Otolaryngol Head Neck Surg 123:397, 1997.
326. Lawrence WT: In search of the optimal treatment of
keloids: report of a series and a review of the literature. Ann
Plast Surg 27:164, 1991.
327. Apfelberg DB, Maser MR, Lash H: The use of epidermis
over a keloid as an autograft after resection of the keloid.
J Derm Surg 2:409, 1976.
328. Weimar VM, Ceilley RI: Treatment of keloids on earlobes.
J Dermatol Surg Oncol 5:522, 1979.
329. Adams BB, Gloster HM: Excision with suprakeloidal flap
and radiation therapy for keloids. J Am Acad Dermatol
47:307, 2002.
330. Salasche SJ, Grabski WJ: Keloids of the earlobes: a surgical
technique. J Dermatol Surg Oncol 9:552, 1983.
331. Norris JE: The effect of carbon dioxide laser surgery on the
recurrence of keloids. Plast Reconstr Surg 87:44, 1991.
332. Henderson DL, Cromwell TA, Mes LG: Argon and carbon
dioxide laser treatment of hypertrophic and keloid scars.
Lasers Surg Med 3:271, 1984.
333. Apfelberg DB, Maser MR, White DN, et al: Failure of
carbon dioxide laser excision of keloids. Lasers Surg Med
9:382, 1989.
334. Alster TS: Improvement of erythematous and hypertrophic scars by the 585-nm flashlamp pulsed dye laser.
Ann Plast Surg 32:186, 1994.
335. Alster TS, Williams CM: Treatment of keloid sternotomy
scars with 585-nm flashlamp-pumped pulsed-dye laser.
Lancet 345:1198, 1995.
336. Ketchum LD, Smith J, Robinson DW, et al: The treatment
of hypertrophic scar, keloid, and scar contracture by
triamcinolone acetonide. Plast Reconstr Surg 38:209,
1966.
337. Sclafani AP, Gordon L, Chadha M, et al: Prevention of
earlobe keloid recurrence with postoperative corticosteroid injections versus radiation therapy. A randomized,
prospective study and review of the literature. Dermatol
Surg 22:569, 1996.
338. Norris JEC: Superficial x-ray therapy in keloid management: a retrospective study of 24 cases and literature
review. Plast Reconstr Surg 95:1051, 1995.
339. Escarmant P, Zimmermann S, Amar A, et al: The treatment
of 783 keloid scars by iridium 192 interstitial irradiation after
surgical excision. Int J Rad Oncol Biol Phys 26:245, 1993.
340. Horton CE, Crawford J, Oakey RS: Malignant change in
keloids. Plast Reconstr Surg 12:86, 1953.
341. Botwood N, Lewanski C, Lowdell C: The risks of treating
keloids with radiotherapy. Br J Radiol 72:1222, 1999.
342. Carr-Collins JA: Pressure techniques for the prevention
of hypertrophic scar. Burn Rehabil Reconstr 19:733,
1992.
343. Berman B, Bieley HC: Adjunct therapies to surgical
management of keloids. Dermatol Surg 2:126, 1996.
344. Sherris DA, Larrabee WF, Murakami CS: Management of
scar contractures, hypertrophic scars, and keloids.
Otolaryngol Clin North Am 28:1057, 1995.
345. Brent B. The role of pressure therapy in management of
earlobe keloids: preliminary report of a controlled study.
Ann Plast Surg 1:579, 1978.
346. Lawrence WT: Treatment of earlobe keloids with surgery
plus adjuvant intralesional verapamil and pressure earrings. Ann Plast Surg 37:167, 1996.
347. Berman B, Flores F: Recurrence rates of excised keloids
treated with postoperative triamcinolone acetonide injections or interferon alfa-2b injections. J Am Acad Dermatol
37:755, 1997.
348. Conejo-Mir JS, Corbie R, Linares M: Carbon dioxide laser
ablation association with interferon-alfa-2b injections
reduces the recurrence of keloids. J Am Acad Dermatol
39:1039, 1998.
349. Pittet B, Rubbia-Brandt L, Desmouliere A, et al: Effect of
gamma-interferon on the clinical and biologic evolution
of hypertrophic scars and Dupuytren’s disease: An open
pilot study. Plast Reconstr Surg 93:1224, 1994.
350. Granstein RD, RookA, Flotte TJ: A controlled trial of
intralesional recombinant interferon gamma in the treatment of keloidal scarring. Arch Dermatol 126:1295,
1990.
351. Larrabee WF, East CA, Jaffe HS. Intralesional interferon
gamma treatment for keloids and hypertrophic scars. Arch
Otolaryngol Head Neck Surg 116:1159, 1990.
352. Broker BJ, Rosen D, Amsberry J, et al: Keloid excision
and recurrence prophylaxis via intradermal interferongamma injections: a pilot study. Laryngoscope
106:1497, 1996.
353. Tredget EE, Shankowsky HA, Pannu R, et al: Transforming
growth factor-â in thermally injured patients with hypertrophic scars: effects of interferon á-2b. Plast Reconstr Surg
102:1317, 1998.
354. Sauder D: New immune therapies for skin disease:
imiquimod and related compounds. J Cutan Med Surg
5:2, 2001.
355. Miller RL, Gerster JF, Owens ML, et al: Imiquimod applied
topically: a novel immune response modifier and new
class of drug. Int J Immunopharmacol 21:1, 1999.
356. Kaufman J, Berman B: Topical application of imiquimod
5% cream to excision sites is safe and effective in reducing
keloid recurrences. J Am Acad Dermatol 47:S209, 2002.
357. Clugston PA, Vistnes MD, Perry LC, et al: Evaluation of
silicone-gel sheeting on early wound healing of linear
incisions. Ann Plast Surg 34:12, 1995.
358. Ahn ST, Monafo WW, Mustoe TA: Topical silicone gel:
A new treatment for hypertrophic scars. Surgery 106:781,
1989.
359. Sawada Y, Sone K: Treatment of scars and keloids with a
cream containing silicone oil. Br J Plast Surg 43:683,
1990.
51
SRPS Volume 10, Number 7, Part 1
360. Dockery GL, Nilson RZ: Treatment of hypertrophic and
keloid scars with Silastic gel sheeting. J Foot Ankle Surg
33:110, 1994.
361. Mercer NSG: Silicone gel in the treatment of keloid scars.
Br J Plast Surg 42:83, 1989.
362. Gibbons M, Zuker R, Brown M, et al: Experience with
Silastic gel sheeting in pediatric scarrring. J Burn Care
Rehabil 15:69, 1994.
363. Cosman B, Crikelair GF, Ju DMC, et al: The surgical
treatment of keloids. Plast Reconstr Surg 27:335, 1961.
364. Borges AF: Scar analysis and objectives of revision procedures. Clin Plast Surg 4:223, 1977.
365. Borges AF: Principlization of Scar Revision. In: Millard DR
(ed), Principlization of Plastic Surgery. Boston, Little
Brown, 1986, pp 344, 345.
366. Bowen ML, Charnock FML: The Bowen double-bladed
scalpel for the reconstruction of scars. Obstet Gynecol
83:476, 1994.
367. Tardy ME Jr, Denneny J: Surgical alternatives in scar
camouflage. Fac Plast Surg 1:209, 1984.
368. Borges AF, Alexander JE: Relaxed skin tension lines, Zplasty on scars and fusiform excision of lesions. Br J Plast
Surg 15:242, 1962.
369. Rohrich RJ, Zbar RIS: A simplified algorithm for the use of
Z-plasty. Plast Reconstr Surg 103:1513, 1999.
370. Borges AF: W-plasty. Ann Plast Surg 3:153, 1979.
371. Olbrisch RR: Running Y-V plasty. Ann Plast Surg 26:52,
1991.
372. Hagerty RC, Zubowitz VN: Tissue expansion in the
treatment of hypertrophic scars and scar contractures.
South Med J 79:432, 1986.
373. Tonnard PL, Monstrey SJ, Van Landuyt KH, et al: Scarlength reduction by ring-shaped expansion. Ann Plast Surg
33:647, 1994.
374. Orentreich D, Orentreich N: Acne scar revision update.
Dermatol Clin 5:359, 1987.
375. Tardy ME Jr, Denneny J: Surgical alternatives in scar
camouflage. Fac Plast Surg 1:209, 1984.
376. Snow SN, Stiff MA, Lambert DR: Scalpel sculpturing
techniques for graft revision and dermatologic surgery. J
Dermatol Surg Oncol 20:120, 1994.
377. Grabski WJ, Salasche SJ, Mulvaney MJ: Razor-blade
surgery. J Dermatol Surg Oncol 16:1121, 1990.
378. Zouboulis CC, Blume U, Buttner P, Orfanos CE: Outcomes of cryosurgery in keloids and hypertrophic scars.
A prospective consecutive trial of cases series. Arch Dermatol
129:1146, 1993.
379. Henderson DL, Cromwell TA, Mes LG: Argon and carbon
dioxide laser treatment of hypertrophic and keloid scars.
Laser Surg Med 3:271, 1984.
380. Sherman R, Rosenfeld H: Experience with the Nd:YAG
laser in the treatment of keloid scars. Ann Plast Surg
20:231, 1988.
381. Dierickx C, Goldman MP, Fitzpatrick RE. Laser treatment
of erythematous/hypertrophic and pigmented scars in 26
patients. Plast Reconstr Surg 95:84, 1995.
382. Alster TS, Nanni CA: Pulsed dye laser treatment of
hypertrophic burn scars. Plast Reconstr Surg 102:2190,
1998.
383. Wang J, Cortes E, Sinks LF, et al: Therapeutic effect and
toxicity of adriamycin in patients with neoplastic disease.
Cancer 28:837, 1971.
52
384. Yosowitz P, Ekland DA, Shaw RC, et al: Peripheral
intravenous infiltration necrosis. Am J Surg 182:553,
1975.
385. Upton J, Mulliken JB, Murray JE: Major intravenous
extravasation injuries. Am J Surg 137:497, 1979.
386. Gault D: Extravasation injuries. Br J Plast Surg 46:91, 1993.
387. Heckler F: Current thoughts on extravasation injuries. Clin
Plast Surg 16:557, 1989.
388. Larson DL: What is the appropriate management of tissue
extravasation by antitumor agents? Plast Reconstr Surg
75:397, 1985.
389. Banerjee A, Brotherston TM, Lamberty BGH, Campbell
RC. Cancer chemotherapy agent induced perivenous
extravasation injuries. Postgrad Med J 63:5, 1987.
390. Loth TS, Eversmann WW: Treatment methods for extravasation of chemotherapeutic agents: a comparative study.
J Hand Surg 11A:388, 1986.
391. Lawson SR: Invited discussion of “Reducing the morbidity
from extravasation injuries,” by MS Khan and JD Holmes.
Ann Plast Surg 48:632, 2002.
392. Scuderi N, Onesti MG: Antitumor agents: extravasatiion,
management, and surgical treatment. Ann Plast Surg
32:39, 1994.
393. Vandeweyer E, Heymans O, Deraemaecker R: Extravasation injuries and emergency suction as treatment. Plast
Reconstr Surg 105:109, 2000.
394. Khan MS, Holmes JD: Reducing the morbidity from
extravasation injuries. Ann Plast Surg 48:628, 2002.
395. Linder RM, Upton J, Osteen R: Management of extensive
doxorubicin hydrochloride extravasation injuries. J Hand
Surg 8:32, 1983.
396. Dahlstrom KK, Chenoufi HL, Daugaard S: Fluorescence
microscopic demonstration and demarcation of doxorubicin extravasation. Experimental and clinical studies.
Cancer 65(8):1722, 15 Apr 1990.
397. Andersson AP, Dahlstrom KK: Clinical results after doxorubicin extravasation treated with excision guided by
fluorescence microscopy. Eur J Cancer 29A:1712, 1993.
398. Heitmann C, Durmus C, Ingianni G: Surgical management
after doxorubicin and epirubicin extravasation. J Hand
Surg 23B:666, 1998.
399. Koenig TR, Wolff D, Mettler FA, Wagner LK: Skin injuries
from fluoroscopically guided procedures: Part 1.
Characterstics of radiation injury. Am J Roentgenol 177:3,
2001.
400. Fajardo LF: Is the pathology of radiation injury different
in small vs large blood vessels? Cardiovasc Radiat Med
1(1):108, Jan-Mar 1999.
401. McLean AS: Early adverse effects of radiation. Br Med Bull
29:69, 1973.
402. Mendelsohn FA, Divino CM, Reis ED, Kerstein MD: Wound
care after radiation therapy. Adv Skin Wound Care 15:216,
2002.
403. Hart GB, Mainous EG: The treatment of radiation necrosis
with hyperbaric oxygen (OHP). Cancer 37:2580, 1976.
404. King GE, Scheetz J, Jacob RF, Martin JW: Electrotherapy
and hyperbaric oxygen: promising treatments for
postradiation complications. J Prosthet Dent 62:331,
1989.
405. Bernstein EF, Harisiadis L, Salomon G, et al: Transforming
growth factor-beta improves healing of radiation-impaired
wounds. J Invest Dermatol 97:430, 1991.
SRPS Volume 10, Number 7, Part 1
406. Kouvaris JR, Kouloulias VE, Plataniotis GA, et al: Dermatitis
during radiation for vulvar carcinoma: prevention and
treatment with granulocyte–macrophage colony-stimulating factor impregnated gauze. Wound Repair Regen
9:187, 2001.
407. Cividalli A, Adami M, de Tomasi F, et al: Orgotein as a
radioprotector in normal tissues. Experiments on mouse
skin and a murine adenocarcinoma. Acta Radiol Oncol
24:273, 1985.
408. Okunieff P: Interactions between ascorbic acid and the
radiation of bone marrow, skin, and tumor. Am J Clin Nutr
54:1281S, 1991.
409. Halperin EC, Gaspar L, George S, et al: A double-blind,
randomized, prospective trial to evaluate topical vitamin
C solution for the prevention of radiation dermatitis. Int
J Radiat Oncol Biol Phys 26:413, 1993.
410. Glees JP, Mameghan-Zadeh H, Sparkes CG: Effectiveness
of topical steroids in the control of radiation dermatitis: a
randomised trial using 1% hydrocortisone cream and
0.05% clobetasone butyrate (Eumovate). Clin Radiol
30:397, 1979.
411. Michalowski AS: On radiation damage to normal tissues
and its treatment. II. Antiinflammatory drugs. Acta Oncol
33:139, 1994.
412. Simonen P, Hamilton C, Ferguson S, et al: Do inflammatory processes contribute to radiation induced erythema
observed in the skin of humans? Radiother Oncol 46:73,
1998.
413. Williams MS, Burk M, Loprinzi CL, et al: Phase III doubleblind evaluation of an aloe vera gel as a prophylactic agent
for radiation-induced skin toxicity. Int J Radiat Oncol Biol
Phys 36:345, 1996.
414. Olsen DL, Raub W Jr, Bradley C, et al: The effect of aloe
vera gel/mild soap versus mild soap alone in preventing
skin reactions in patients undergoing radiation therapy.
Oncol Nurs Forum 28:543, 2001.
415. Schindl A, Schindl M, Pernerstorfer-Schon H, et al: Low
intensity laser irradiation in the treatment of recalcitrant
radiation ulcers in patients with breast cancer. Long term
results of 3 cases. Photodermatol Photoimmunol Photomed
16:34, 2000.
416. Futran ND, Trotti A, Gwede C: Pentoxifylline in the
treatment of radiation-related soft tissue injury: preliminary observations. Laryngoscope 107:391, 1997.
417. O’Reilly R, Blatt G: Accidental high-pressure injection
injuries. Injury 22:467, 1991.
418. Hayes W, Pan HC: High-pressure injection injuries to the
hand. South Med J 75:1491, 1982.
419. Christodoulou L, Melikyan EY, Woodbridge S, Burke FD:
Functional outcome of high-pressure injection injuries of
the hand. J Trauma 50:717, 2001.
420. Peters W: High-pressure injection injuries. Can J Surg
34:511, 1991.
421. Harvey RL, Ashley DA, Yates L, et al: Major vascular
injury from high-pressure water jet. J Trauma 40:165,
1996.
422. Ramos H, Posch JL, Lie KK: High-pressure injection
injuries of the hand. Plast Reconstr Surg 45:221, 1970.
423. Dickson RA: High pressure injection injuries of the hand.
A clinical, chemical and histological study. Hand 8:189,
1976.
424. Kaufman HD: The clinicopathological correlation of
high-pressure injection injuries. Br J Surg 55:214, 1968.
425. Neal NC, Burke FD: High pressure injection injuries. Injury
22:467, 1991.
426. Lewis RC: High-compression injection injuries to the
hand. Emerg Med Clin North Am 3:373, 1985.
427. Schoo M, Scott F, Boswick J: High-pressure injection
injuries of the hand. J Trauma 20:229, 1980.
428. Winemaker M, Douglas L, Peters W: Combination alkali/
thermal burns caused by ‘black liquor’ in the pulp and
paper industry. Burns 18:68, 1992.
429. Fisher AA: Cement injuries. Part II. Cement burns resulting
in necrotic ulcers due to kneeling on wet cement. Cutis
61:121, 1998.
430. Morley SE, Humzah D, McGregor JC, Gilpert PM: Cement-related burns. Burns 22:646, 1996.
431. Boyce DE, Dickson WA: Wet cement: a poorly recognized cause of full-thickness skin burns. Injury 24:615,
1993.
432. Matey P, Allison KP, Sheehan TM, Gowar JP: Chromic
acid burns: early aggressive excision is the best method to
prevent systemic toxicity. J Burn Care Rehabil 21:241,
2000.
433. Terrill PJ, Gowar JP: Chromic acid burns; beware, be
aggressive, be watchful. Br J Plast Surg 43:699, 1990.
434. Chan TC, Williams SR, Clark RF: Formic acid skin burns
resulting in systemic toxicity. Ann Emerg Med 26:383,
1995.
435. Bertolini JC: Hydrofluoric acid: a review of toxicity. J
Emerg Med 10:163, 1992.
436. Kirkpatrick JJ, Enion DS, Burd DA: Hydrofluoric acid
burns: a review. Burns 21:483, 1995.
437. Sheridan RL, Ryan CM, Quinby WC Jr, et al: Emergency
management of major hydrofluoric acid exposures. Burns
21:62, 1995.
438. Horch R, Spilker G, Stark GB: Phenol burns and intoxications. Burns 20:45, 1994.
439. Konjoyan TR: White phosphorus burns: case report and
literature review. Mil Med 148:881, 1983.
440. Santucci RA, Chang YJ: Ballistics for physicians: myths
about wound ballistics and gunshot injuries. J Urol
171:1408, 2004.
441. McGoldrick J, Marx JA: Marine envenomations. Part 1:
Vertebrates. J Emerg Med 9:497, 1991.
442. Flandry F, Lisecki EJ, Domingue GJ, et al: Initial antibiotic
therapy for alligator bites: characterization of the oral flora
of Alligator mississippiensis. South Med J 82:262, 1989.
443. Patten BM, More on catfish stings. JAMA 232:248, 1975.
444. McGoldrick J, Marx JA: Marine envenomations. Part 2:
Invertebrates. J Emerg Med 10:71, 1992.
445. Wingert WA, Wainschel J: Diagnosis and management of
envenomation by poisonous snakes. South Med J 68:1015,
1975.
446. Gold BS, Dart RC, Barish RA: Bites of venomous snakes.
N Engl J Med 347(5):347, 1 Aug 2002.
447. Greene MA: Clinical Toxicology, 3rd ed. London, Pittman
Books, 1983, pp 581-585.
448. Seiler JG III, Sagerman SD, Geller RJ, et al: Venomous snake
bite: current concepts of treatment. Orthopedics 17:707,
1994.
449. Butner AN: Envenomation coagulopathy from snake
bites. N Engl J Med 305:1347, 1981.
450. Stewart ME, Greenland S, Hoffman JR: First-aid treatment
of poisonous snakebite: are currently recommended
procedures justified? Ann Emerg Med 10:331, 1981.
53
SRPS Volume 10, Number 7, Part 1
451. Ledbetter EO, Kutscher AE: The aerobic and anaerobic
flora of rattlesnake fangs and venom: therapeutic implications. Arch Environ Health 19:771, 1969.
452. Grace TG, Omer GE. The management of upper extremity
pit viper wounds. J Hand Surg 5:168, 1980.
453. Huang TT, Blackwell SJ, Lewis SR: Tissue necrosis in
snakebite. Texas Med 77:53, 1981.
454. Pennell TC, Babu SS, Meredith JW: The management of
snake and spider bites in the Southeastern United States.
Am Surg 53:198, 1987.
455. Russell FE: Rattlesnake bite (letter). JAMA 245:1579,
1981.
456. Kurecki BA III, Brownlee HJ Jr: Venomous snakebites in the
United States. J Fam Pract 25:386, 1987.
457. White RR IV, Weber RA: Poisonous snakebite in Central
Texas. Ann Surg 213:466, 1991.
458. Hardy DL: Fatal rattlesnake envenomation in Arizona:
1969-1984. J Toxicol Clin Toxicol 24:1, 1986.
459. Ruha AM, Curry SC, Beuhler M, et al: Initial postmarketing
experience with crotalidae polyvalent immune Fab for
treatment of rattlesnake envenomation. Ann Emerg Med
39:609, 2002.
460. Jurkovich GJ, Luterman A, McCullar K, et al: Complications of Crotalidae antivenin therapy. J Trauma 28:1032,
1988.
461. McCullough NC, Gennaro JF. Treatment of venomous
snake bite in the United States. Clin Toxicol 3:483, 1980.
462. Kitchens CS, Van Mierop LHS: Envenomation by the
Eastern coral snake (Micrurus fulvius fulvius). A study of 39
victims. JAMA 258:1615, 1987.
463. Harwood RF, James MT: Entomology in Human and Animal
Health, 7th ed. New York, Macmillan, 1979, pp 445-447.
54
464. Miller TA: Latrodectism: Bite of the black widow spider.
Am Fam Physician 45:181, 1992.
465. Pennell TC, Babu SS, Meredith JW: The management of
snake and spider bites in the Southeastern United States.
Am Surg 53:198, 1987.
466. Kunkel DB: Arthropod envenomations. Emerg Med Clin
North Am 2:579, 1984.
467. Young VL, Pin P: The brown recluse spider bite. Ann Plast
Surg 20:447, 1988.
468. Murray LM, Seger DL: Hemolytic anemia following a
presumptive brown recluse spider bite. Clin Toxicol 32:451,
1994.
469. Young RA: Thrombocytopenia associated with brown
recluse spider bite (letter). J Emerg Med 12:389, 1994.
470. King LE Jr, Rees RS: Dapsone treatment of a brown recluse
bite. JAMA 250:648, 1983.
471. Diekema DS, Reuter DG: Environmental emergencies:
arthropod bites and stings. Clin Ped Emerg Med 2:155,
2001.
472. Watson WA, Litovitz TL, Rodgers GC Jr, et al: 2002 annual
report of the American Association of Poison Control
Centers Toxic Exposure Surveillance System. Am J Emerg
Med 21:353, 2003.
473. Saucier JR: Arachnid envenomation. Emerg Med Clin
North Am 22:405, 2004.
474. Pinson RT, Morgan JA: Envenomation by the puss caterpillar (Megalopyge opercularis). Ann Emerg Med 20:562,
1991.
475. McGovern IP, Barkin GB, McElhenney TR, et al:
Megalopyge opercularis. Observation of its life history,
natural history of its sting to man, and reports of an
epidemic. JAMA 175:1155, 1961.