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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. HISTORY The biology of wound healing has been a concern of physicians through the ages. The earliest medical writings dealt extensively with wound careeg, 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 lets-do-something-about-it attitude toward wounds produced disastrous results. In the mid-1500s, the great French army surgeon Ambroise Par by chance rediscovered the value of gentle methods of wound care. During the battle of Villaine the supply of oil was exhausted, and Par 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.

For more than three centuries after Pars observations, our understanding of the biologic processes involved in the healing of wounds was limited to John Hunters experiments with replantation and his musings on the difference between wound contraction and contracture, Joseph Listers writings on wound sepsis, and Alexis Carrels 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. 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 510-minute period of vasoconstriction that serves to slow the blood flow through the area and to aid hemostasis. Vasocon-

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Fig 1. Schematic concept of wound healing. (Annotated from Hunt TK et al (eds): Soft and Hard Tissue RepairBiological and Clinical Aspects, 1st Ed. New York, Praeger, 1984, p 5.)

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 gelground substancethat 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 23 days are synthesized at a highly accelerated rate. Collagen levels rise continuously for

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 2448 hours of injury, gradually disappearing as protein synthesis and chronic inflammation changes become predominant. The inflammatory response of the injured tissues, then, is mediated

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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 equivalentcollagen 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 patients 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.

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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 4896 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-/cachectin (TNF-).17 IL-1 also promotes fibroblast proliferation through the induction of protein-derived growth factor. Both IL-1 and TNF- 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

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 cells 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 20100X 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 otherwiseonly 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.

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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.)

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.3134 Myofibroblasts are the source of contraction within a wound.3134

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

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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 Dupuytrens disease, 39 Peyronies, 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 wounds 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 1421 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

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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

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,

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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.6773 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 patients 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.8183 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

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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 30C, whereas tensile strength decreases by 20% in a cold (12C) wound environment. Induced hypothermia below 28C 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

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.


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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.109111 Chemotherapeutic agents generally decrease fibroblast proliferation and wound contraction,112114 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 1014 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


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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 11.5W/cm2 has been used to improve scar outcome. The nonthermal component at a setting of 0.31W/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.119122 Clinically, the results of ultrasound therapy on the healing of wounds are equivocal.123128 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-

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 3050mmHg). Tissues in wounds that are not healing show oxygen values of 520mmHg. When those wounds are placed in hyperbaric chambers at pressures of 2.4ATA, the tissue oxygen tension rises to 8001100mmHg.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,136138 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-1 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.141144 Electrical current applied to wounded tissue increases the migration of neutrophils and macrophages,145147 and promotes fibroblasts.148150 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


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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.162169 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-) appears to have immunologic properties similar to PDGFie, it stimulates fibroblast mitogenesis and chemotaxis of PMNs, MONOs, and fibroblasts.172 Both PDGF and rPDGF- 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 healingaiming for perfect skin regeneration. Science 276:75, 4 Apr 1997.)


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effects of cytokines on abnormal scars are being investigated.185187 Transforming growth factor beta (TGF-) 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-2 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.)

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

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-), other peptide growth factors,175184 and cytokines,185187 EGF is part of a complex program to orchestrate growth and differentiation of epidermal keratinocytes.174,188 The


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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 adults 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


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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 groups194199 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

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 50100mL/cm of wound length, whereas contaminated wounds and wounds at high risk of becoming infected (marine wounds, farm injuries, and gunshot wounds) require 12L 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 particlesthe 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; Dakins 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


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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, papainurea preparations) (Table 5).208 Autolytic debridement allows the bodys own enzymes and moisture to break down necrotic tissue. It acts in 710 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 13 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


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decrease significantly,211,212 and a complete debridement is achieved in most cases.

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 PRINCIPLES Crikelair216 listed the Halstedian fundamentals of surgical wound closure which apply to the management of any skin wound.

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).219223 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

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. intervention.
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.)

Allow time for scars to mature before repeat

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-

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


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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 landmarksthe vermilion border, eyelid, eyebrow, nostril, and auricular helixby 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).227233 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.234238 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


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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 35 days, while elsewhere they are left in place for 710 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

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 patients age and genetic background. The only exception to this rule is when there is loss of functioneg, 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 differenceseg, 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.


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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.)


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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


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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 wateroil 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-


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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.254256 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 patients ulcer. Apligraf is bilayered living skin epidermis and dermisthat 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

Dermagraft vs. Apligraf, although multiple studies attest to a higher percentage of healed diabetic foot ulcers treated with Dermagraft compared with controls.262266


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.270273 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.270273 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-


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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


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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.305307 Unlike normal wounds, fibroplasia in these abnormal scars continues well beyond the third post-injury week without resolution.271 The scars remain imma-

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-,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


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Table 8 Biochemical Alterations in Abnormal Scars

(Adapted from Aston SJ, Beasley RW, Thorne CHM, eds, Grabb and Smiths 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. 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

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--2b or IFN- 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


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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.)

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. 294,296,331333 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.331335 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.

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 23 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


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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 Cushings 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 35 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 1520Gy 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 2430mmHg to avoid excessive compression of peripheral blood vessels. Maximum benefit is achieved from wear-


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ing the pressure appliance for 1824h/d for at least 46 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--2b normalizes the collagen and glycosaminoglycan of the keloid.347 Complications of IFN-2b injection include flu-like symptoms of headache, fever, and myalgias. In a retrospective study, Berman and Flores347 found lower recurrence rates with postexcisional IFN--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--2b injections for keloids of the earlobe. Interferon- is believed to work similarly to IFN-2b. There have been several anecdotal reports regarding the benefits of IFN- 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- 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.

Other researchers have used antitransforming growth factor-beta (anti-TGF-) to decrease scarring in experimental animals. 317 Tredget 353 describes antagonizing the proliferative effects of TGF-2 and histamine with interferon--2b. Imiquimod is an immune response modifier that stimulates innate and cell-mediated immune pathways, enhancing the bodys 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.358360 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%


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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 therapyeg, surgery and corticosteroidsis 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 pressure can be easily applied

skin grafts should be harvested from areas where

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


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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 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

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.)

Fig 14. The running Y-V-plasty. (Reprinted with permission from Olbrisch RR: Running Y-V plasty. Ann Plast Surg 26:52, 1991.)


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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.

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.


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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.388390 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 46 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:

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.395398 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


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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-1, 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 60012,000psi.417,418 The substance enters the skin through a seemingly insignificant


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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

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


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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 8595C. 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 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

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; 510% 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. 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


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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 12 hours, then gray areas followed by necrosis and deep ulceration within 624 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

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-


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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 23X 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 surgeons 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


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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 3090 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.

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


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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):

signs and symptoms of systemic envenomation; and for children under age 12.454,456458 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, 812 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

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

Compartment pressure release.

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 46 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. 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

Antivenom. Indications for the use of antivenom


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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 marksthe 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-

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 (100200mg q.d. x 1025d) 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

tion of calcium gluconate is administered intravenously over 1520 minutes. If this is effective in controlling pain, the diagnosis of black widow envenomation is confirmed. carbamol (Robaxin) or 510mg of diazepam (Valium) may be given.

Muscle relaxants. One ampule of metho-

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.


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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 victims 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


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1. 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 healingAiming 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. 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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. 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: Wolffs 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. 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94. 95. 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. 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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 (Raynauds 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. 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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. 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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 healingan 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.


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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.


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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. 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 repaira 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.


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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 scarsimmunological 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 Dupuytrens 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- in thermally injured patients with hypertrophic scars: effects of interferon -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.


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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. 384. 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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. 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406. Kouvaris JR, Kouloulias VE, Plataniotis GA, et al: Dermatitis during radiation for vulvar carcinoma: prevention and treatment with granulocytemacrophage 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). 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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. 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.