wound healing reading chapters

WOUND HEALING

The ability to heal wounds by forming scar tissueis essential to the survival of all higher species.Indeed, wound healing is the very foundation ofour specialty. Although we can now intervene insome chronic wounds to accelerate healing, a con-servative and noninterventional approach is still thestandard of care of acute wounds in an otherwisehealthy person.

HISTORY

The biology of wound healing has been a con-cern of physicians through the ages. The earliestmedical writings dealt extensively with woundcare—eg, 7 of 48 case reports in the Smith Papyrus(1700 BC) are about wounds and their manage-ment.1

The ancient physicians of Egypt, Greece, India,and Europe practiced gentle methods for dealingwith wounds and appreciated the importance offoreign body removal, suturing skin edges, and pro-tecting injured tissues from the environment withclean materials. Following the invention of gun-powder and ever-more-frequent gunshot wounds,however, a new philosophy of wound care emergedthat no longer relied on natural processes of soft-tissue repair supplemented with cleanliness, gentlewashing with warm boiled water, and applicationsof mild salves. For the next 250 years, surgeonsaggressively treated persons who had open woundswith the likes of boiling oil, hot cautery, and scald-ing water. This “let’s-do-something-about-it” atti-tude toward wounds produced disastrous results.

In the mid-1500s, the great French army sur-geon Ambroise Paré by chance rediscovered thevalue of gentle methods of wound care. During thebattle of Villaine the supply of oil was exhausted,and Paré was forced to use milder measures onamputation stumps. To his surprise, these woundshealed rapidly without the expected complications,and from this modest beginning the modern era ofwound care evolved.

WOUNDS AND SCARSGeorge Broughton II MD PhD and Rod J Rohrich MD

For more than three centuries after Paré’s obser-vations, our understanding of the biologic processesinvolved in the healing of wounds was limited toJohn Hunter’s experiments with replantation andhis musings on the difference between wound con-traction and contracture, Joseph Lister’s writings onwound sepsis, and Alexis Carrel’s notes on organtransplantation and tissue preservation. The cellularchanges in healing soft-tissue wounds were not elu-cidated until the scientific method was applied inthe 20th century.

CURRENT KNOWLEDGE

The following pages summarize our knowledge ofwound healing. Despite great advances, at presentthere is no “magic bullet” that can be used in themanagement of wounds. Indeed, our current under-standing of the intricate dance of cellular popula-tions, intracellular events, and extracellular factorsthat are involved in a healing wound belies the exist-ence of such a compound or procedure. The myriadmolecular events involved in wound healing are wellreviewed by McGrath,2 Moulin,3 and Martin.4

PHASES OF HEALING

A thorough understanding of the wound healingprocess 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 toinflammation that evokes a nonspecific inflamma-tory response. The stimulus may be physical injury,an antigen-antibody reaction, or infection. Inflam-mation is a cellular and vascular response that servesto clean the wound of devitalized tissue and for-eign material.

The initial changes are vascular. After the injurythere is a transient 5–10-minute period of vaso-constriction that serves to slow the blood flowthrough the area and to aid hemostasis. Vasocon-

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striction is followed by active vasodilation. Vesselwalls (particularly small venules) become lined withleukocytes, platelets, and erythrocytes, and leuko-cytes begin migrating into the wound for thedebriding process. There is a simultaneous increasein permeability of the vessel walls: Endothelial cellsswell and pull away from their neighbors, openinggaps through which the serum gains entry into thewound.

Histamine is responsible for the initial vasodila-tion as well as for the early permeability changes.Hemostatic factors released from the activation ofplatelets, kinin components, complement compo-nents, and the prostaglandin system all participatein sending cellular control signals to initiate theinflammatory phase. At another level, fibronectin, amajor constituent of granulation tissue, seems topromote the adhesion and migration of neutrophils,monocytes, fibroblasts, and endothelial cells intothe wound region. Fibronectin is abundant in thefirst 24–48 hours of injury, gradually disappearingas protein synthesis and chronic inflammationchanges become predominant. The inflammatoryresponse of the injured tissues, then, is mediated

by local substances within the wound, culminatingin a a dynamic cellular milieu at the site of injury.

The precise role that each type of inflammatorycell plays in the wound healing process remainsobscure. Both polymorphonuclear leukocytes(PMNs) and mononuclear leukocytes (MONOs)migrate into the wound in numbers directly pro-portional to the circulating concentrations.7 Althoughthe initial wound exudate contains mainly PMNs,within the wound environment PMNs have a shorterlifespan than MONOs, so that with prolongedinflammation the exudate becomes predominantlymononuclear.

Studies using specific anticellular sera suggest thatwound healing proceeds normally in the absenceof both PMNs and lymphocytes, but monocytes mustbe present to trigger normal fibroblast productionand subsequent invasion of the wound space.

The early wound exudate also contains fragmentsof cells disrupted during the initial injury, togetherwith foreign material and a continued bacterial chal-lenge. There is also a variety of enzymes, both pro-teolytic and collagenolytic, and a number of bio-logically active substances.

Fibroblastic (Proliferative) Phase

Beginning on day 2 or 3 after wounding, fibro-blasts begin to move into the wound along a frame-work of fibrin fibers established during initialhemostasis. This fibrous scaffolding is essential tofibroblast migration from their usual, mostly perivas-cular habitat8 in the tissues surrounding the wound.9

Once in the wound proper, fibroblasts produceseveral substances essential to wound repair,beginning with glycosaminoglycans and ending withfibrillar collagen.10 Glycosaminoglycans are repeat-ing disaccharide units attached to a protein core.Hyaluronic acid is synthesized first, followed in shortorder by chondroitin-4 sulfate, dermatan sulfate,and heparin sulfate. As these are secreted by thefibroblasts, they are hydrated into an amorphousgel—ground substance—that plays an important rolein the subsequent aggregation of collagen fibers.7

The conversion of tropocollagen into fibrillar col-lagen is mediated by the action of two enzymesand calcium.11 Collagen fibrils begin to appear asground substance accumulates, and over the ensu-ing 2–3 days are synthesized at a highly acceler-ated rate. Collagen levels rise continuously for

Fig 1. Schematic concept of wound healing. (Annotated fromHunt TK et al (eds): Soft and Hard Tissue Repair—Biological andClinical Aspects, 1st Ed. New York, Praeger, 1984, p 5.)


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approximately 3 weeks,12 but as increasing quanti-ties of collagen accumulate in the wound, the num-ber of synthesizing fibroblasts begins to decrease,until the rates of collagen degradation and synthesisare equivalent—collagen homeostasis.

The increase in wound tensile strength that takesplace during the fibroblastic phase corresponds tothe increasing levels of collagen within the wound.Gains in tensile strength are thus most rapid whilethe collagen-building curve is climbing, although thewound will continue to get stronger for some time.

In summary, the true fibroblastic phase beginson or about the 4th day after injury and lastsapproximately 2 to 4 weeks, depending on the siteand size of the wound (Fig 2). Toward the end theglycoprotein and mucopolysaccharide content ofscar tissue and the number of synthesizing fibro-blasts will be markedly diminished, although theregion around the wound will remain more cellularthan the surrounding connective tissue for a periodof many months.

Maturation (Remodeling) Phase

The classic maturation phase of wound healingbegins approximately 3 weeks after injury. At thistime collagen synthesis and degradation are accel-

erated (no net increase in collagen content), largenumbers of new capillaries growing into the woundregress and disappear, and collagen fibers initiallydeposited in a haphazard fashion gradually becomemore organized and arranged into a pattern deter-mined by local mechanical forces. The maturationphase is then fully under way.

During this phase the formerly indurated, raised,and pruritic scar becomes a mature scar, while thewound continues to gain tensile strength.12 Most ofthe embryonic Type III collagen laid down early inthe healing process is replaced by Type I collagen,13

until the normal skin ratio of 4:1 Type I:Type IIIcollagen14 is obtained. The macromolecules of theintercellular matrix are progressively degraded, thehyaluronic acid and chondroitin-4 sulfate levelsdecrease to resemble those of normal dermis, andthe water content of the tissues gradually returns tonormal.15 As new collagen is deposited during thisphase, more stable and permanent crosslinks areestablished.

How long the maturation phase lasts dependsupon many variables, including the patient’s ageand genetic background, type of wound, specificlocation on the body, and length and intensity ofthe inflammatory period.

Fig 2. Time sequence of classical wound healing.


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IMMUNE RESPONSE

The inflammatory response to tissue injury is char-acterized by the accumulation of polymorpho-nuclear leukocytes as well as macrophages. Mac-rophages appear at the site of injury within 48–96hours, so that they actively participate in theinflammatory and debridement phases.16 Activatedmacrophages release two monokines known to haveangiogenic properties in vitro: interleukin-1 (IL-1)and tumor necrosis factor-α/cachectin (TNF-α).17

IL-1 also promotes fibroblast proliferation throughthe induction of protein-derived growth factor. BothIL-1 and TNF-α stimulate and inhibit collagen syn-thesis and deposition under various conditions.16,17

A chemical factor in macrophages is necessaryfor proper angiogenesis in early wounds.18,19 Fibrinbreakdown products may provide the signal fordevelopment of vasculature at the appropriate timein the healing process.20,21 Because their halflifewithin the wound is longer, macrophages achievepeak levels somewhat later than PMNs. Neutro-phils in the wound are not necessary for chemo-taxis of fibroblasts nor for eventual fibroplasia.22

T-lymphocytes migrate into wounds following theinflux of macrophages and other inflammatory cells,and produce several lymphokines that influencethe endothelial cells of the wound through theirangiogenic and modulatory properties. These lym-phokines both inhibit and stimulate fibroblastrecruitment and induce fibroblast proliferation viafibroblast-activating factor (FAF). Some can alsoinhibit collagen synthesis.16 Depletion of T-lym-phocytes before or up to 1 week after woundingresults in decreased breaking strength of the woundand impaired collagen synthesis and deposition.23

EPITHELIAL REPAIR

The epithelial portion of wound repair beginswith cell mobilization and migration across thewound. Cellular numbers are thereafter augmentedby mitosis and cellular proliferation, while cellulardifferentiation accounts for maturation into the nor-mal epithelial appearance.

The epithelial cells immediately adjacent to thewound initially undergo a mobilization process dur-ing which they enlarge, flatten, and detach fromneighboring cells and the basement membrane. Asthe cells flatten they tend to flow in a directionaway from adjoining epithelial cells. The stimulus

to migration is an apparent loss of contact inhibi-tion. As the marginal cells begin their migration, thecells 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 advancingcells meet cells coming from the opposite side ofthe wound, whereupon motion stops abruptly—contact inhibition.

During their migration across the wound cellularnumbers are maintained by mitosis. Fixed basalcells away from the wound edge begin mitosis toreplace the migrating cells, and as resurfacing ofthe wound proceeds, the cells that have migratedin turn start to divide and multiply. Increasing num-bers of cells thicken the new epithelial layer.

Upon reepithelialization of the wound, theorderly progression from basal mitotic cells throughlayers of differentiated keratinocytes to stratum cor-neum is again established. In other words, once thewound gap is bridged by advancing cells from theperimeter, the normal cellular differentiation frombasal to surface layers resumes.

Cell receptors called integrins are said to “main-tain integral cell contact through a bridge betweenthe extracellular structural protein matrix and thecell’s internal cytoskeleton.”24 Integrins bind to spe-cific extracellular proteins by recognizing a regionwith a certain amino acid sequence. The integrin-matrix bond can be inhibited by monoclonal anti-bodies and synthetic peptides, which block thereceptors or the sites to which they attach.

SKIN METABOLISM AND PHYSIOLOGY

The blood supply of the skin is far greater than itrequires metabolically. Blood vessels in the skinare capable of carrying 20–100X the amounts ofoxygen and nutrients that are needed for cellularsurvival and function. (Cells above the basal layer ofthe epidermis have largely lost their mitochondriaand respire mainly through glycolysis, contributinglittle to the metabolic needs of the skin.) Despitethe abundant blood supply, skin perfusion is insuffi-cient to support wound healing, which requiresgranulation tissue.

Ryan25 summarizes this paradox as follows:. . . the skin can resist many hours of compres-

sion and obliteration of its blood supply and . . .[yet] nonhealing of the skin is one of the most


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common of problems and is often blamed onimpairment of blood supply. . . .The dilemma isexplained by the fact that exchange between bloodvessels and the supplied tissue services the func-tions of that tissue, and, although it is often statedthat richness of the skin vasculature exceedsnutritional need, this statement is a misconception.. . . The frequent stimuli of scratching, stretching,compressing, heating, or cooling of the skin requiresrestoration of skin stiffness to a status quo. Inrestoring itself to the status quo, the mechanicalproperties of the skin must be instantly repaired andthis repair requires a luxurious blood supply tomaintain not merely cell metabolism but thephysical properties of the interstitium.

Ryan (1995)

COLLAGEN

Collagen is the principal building block of con-nective tissue, accounting for one third of the totalprotein content of the body. Collagen is an unusualprotein in that it is almost devoid of the sulfur-containing amino acids cysteine and tryptophan. Intheir stead, collagen contains hydroxyproline andhydroxylysine, two amino acids with very limiteddistribution otherwise—only in collagen, elastin, theC1q subcomponent of the complement system, andthe tail structure of acetylcholinesterase.26 Collagenhas a very complex tertiary and quaternarymolecular structure consisting of three polypeptidechains, each chain wound upon itself in a left-handed helix and the three chains together woundin a right-handed coil to form the basic collagenunit. The polypeptide chains are held in their rela-tive configurations by covalent bonds. Each triplehelical structure is a tropocollagen molecule. Tro-pocollagen units associate in a regular fashion toform collagen filaments; collagen filaments in turnaggregate as collagen fibrils, and collagen fibrilsunite to form collagen fibers, which are visible underthe light microscope (Fig 3).

Five types of collagen have been identified inhumans on the basis of amino acid sequences. Theirrelative distribution in connective tissues varies, hint-ing at individual properties valuable for specific func-tions (Table 1). Type I collagen is abundant in skin,tendon, and bone. These tissues account for morethan 90% of all collagen in the body. Normal skincontains 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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trophic and immature scars the percentage of TypeIII collagen may be as high as 33% (a 2:1 Type I:IIIratio).27

Collagen synthesis takes place extracellularly aswell as intracellularly. Certain substances inhibitthe formation of collagen either by interfering withits synthesis or activating its degradation (Fig 4).Normal connective tissue is in a state of dynamicequilibrium balanced between synthesis and deg-radation, and this makes it vulnerable to local stimulisuch as mechanical forces on the tissue. Whileexcessive collagen degradation results fromunchecked collagenase synthesis, not enough col-lagenase gives rise to tissue fibrosis. Homeostasis isachieved through activation of collagenase by par-athyroid hormone, adrenal corticosteroids, andcolchicine; and inhibition of collagenase synthesisby serum alpha-2 macroglobulin, cysteine andprogesterone.28

THE MYOFIBROBLASTAND WOUND CONTRACTION

Contraction is an essential part of the repairprocess by which the organism closes a gap inthe soft tissues. Contracture, on the other hand,is an undesirable result of healing, at times due tothe process of contraction and at other times dueto fibrosis or other tissue damage.29

In 1971 Gabbiani, Ryan, and Majno30 firstnoted a type of fibroblast in granulation tissuethat bore some structural similarities to smoothmuscle cells. Myofibroblasts differ from ordinaryfibroblasts by having cytoplasmic microfilamentssimilar to those of smooth muscle cells. Withinthe filamentous system are areas of “dense bod-ies” that serve as attachments for contraction.The nuclei demonstrate numerous surface irregu-larities such as those of smooth muscle cells butunlike those of ordinary fibroblasts. Myofibroblastsare also different from normal fibroblasts in thatthey have well-formed intercellular attachmentssuch as desmosomes and maculae adherens.31–34

Myofibroblasts are the source of contractionwithin a wound.31–34

Fig 4. Collagen synthesis and site of action of common inhibitors.

Table 1Types and Distribution of Collagen

(Annotated from Prockop DJ et al: The biosynthesis of collagen andits disorders. N Engl J Med 301:13, 1979.)


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Rudolph35,36 found a direct relationship betweenthe rate of wound contraction and the number ofmyofibroblasts within a wound.35 Rudolph36 alsodemonstrated the presence of myofibroblaststhroughout the wound, not just adjacent to thewound margins. McGrath and Hundahl37 confirmedthe parallel paths of wound contraction and num-ber of myofibroblasts in the wound and the rela-tively even distribution of myofibroblasts in granu-lation tissue except at the wound bed (fewer) andadjacent to foci of inflammation (more). Their find-ings support the “pull theory” of wound contrac-tion, which holds that the entire granulating surfaceof the wound acts as a contractile organ. This con-cept implies contraction of individual myofibroblaststo shorten the wound, followed by collagen deposi-tion and crosslinking to maintain the shortening, ina lock-step mechanism.

Prostaglandin inhibitors do not inhibit myofibro-blast production, therefore wound contraction isnot altered.38 Although present in a number of con-tracture disorders like Dupuytren’s disease,39

Peyronie’s, and lederhosen disease,32 myofibroblastshave not been implicated in their etiology.

TENSILE STRENGTH

The tensile strength of a wound is a measure-ment of its load capacity per unit area. A wound’sbreaking strength is defined as the force requiredto break it regardless of its dimensions. Dependingsolely on different skin thicknesses, breaking strengthcan vary severalfold; tensile strength, on the otherhand, is constant for wounds of similar size.

Experimental studies give evidence that collagenfibers are largely responsible for the tensile strengthof wounds.13,40 The rate at which a healing woundregains strength varies not only among species, butalso among individuals and even among differenttissues in the same individual.29 The healing patternof the various tissues, however, is remarkably simi-lar within a philogenetic family.

All wounds gain strength at approximately the samerate during the first 14–21 days, but thereafter thecurves may diverge significantly according to thetissue involved. In skin, the peak tensile strength isachieved at approximately 60 days after injury41 (Fig5). Given optimal healing conditions, the tensilestrength of a wound never reaches that of the origi-nal, unwounded skin, leveling off at about 80%.

FACTORS IN WOUND HEALING

Numerous local or systemic, physical conditionsor chemical agents either enhance collagen remod-eling or impair wound healing. Some of these arediscussed below.

Oxygen. Hunt and Pai42 showed that fibroblastsare oxygen-sensitive: At partial pressures of 30–40mmHg, fibroblast replication is potentiated.Because collagen synthesis cannot take place unlessthe PO2 is >40mmHg, both myofibroblast and col-lagen production can be stimulated by maintainingthe wound in a state of hyperoxia.43 Oxygen alsoconverts regenerating epithelial cells to aerobicmetabolism.44

The most common cause of wound infection orfailure of wounds to heal properly is deficientwound PO2.

45 Adequate tissue oxygenation im-plies sufficient inspired oxygen as well as compo-nent transfer of oxygen to hemoglobin, amplehemoglobin for oxygen transport, satisfactory vas-cularity of the tissues to keep oxygen diffusion dis-tances small, etc. The arterial pressure of oxygenalone is not indicative of tissue oxygenation; despitesupplemental inspired oxygen, the wound itself mayremain ischemic if perfusion is inadequate. Mosthealing problems associated with diabetes mellitus,irradiation, small vessel atherosclerosis, chronicinfection, etc. can be ascribed to a faulty oxygendelivery system at some point.45

Fig 5. Tensile strength of a healing skin incision as a function oftime. (Reprinted with permission from Levenson SM et al: Thehealing of rat skin wounds. Ann Surg 161:293, 1965.)


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Hematocrit. The quantity of hemoglobin that isavailable to carry oxygen to the tissues would beexpected to be a critical factor in maintaining tissueoxygenation, yet the data regarding the effect ofanemia on the tensile strength of a wound are con-tradictory.29 When the hematocrit is reduced to50% of normal as a result of hemorrhage and theblood volume has been replaced by plasma, someinvestigators report a marked decrease in tensilestrength46 while others report no change.47,48

Mild or moderate anemia does not appear to bedetrimental to healing in a well-perfused wound,with collagen deposition being proportional to tis-sue oxygenation and perfusion.48 The reperfusionof injured tissue itself can be deleterious to woundhealing, however, with release of anaerobicmetabolites and reactive oxygen species creatingadditional oxidative stresses.

Steroids and Vitamin A. One of the more fre-quent disorders of wound healing is arrest ofinflammation as a result of the administration ofsteroids. The steroid seems to inhibit wound mac-rophages and also interferes with fibrogenesis,angiogenesis, and wound contraction.45,49

Through a poorly understood mechanism, bothvitamin A and anabolic steroids will restore mono-cytic inflammation that has been retarded by anti-inflammatory steroids.50,51 The exact dose of vita-min A required is not known, but oral ingestion of25,000IU/d or topical application of 200,000IU oint-ment q. 8h is effective in most cases.

Vitamin A deficiency retards repair.52 Conversely,ingestion of vitamin A stimulates collagen deposi-tion and contributes to increased breaking strengthof wounds, while topically applied vitamin A accel-erates wound reepithelialization. Hunt52 hypoth-esizes that retinoids are particularly important inmacrophagic inflammation to initiate reparativebehavior in tissue.

Supplemental estrogen applied topically improveshealing in elderly women.53

Vitamin C. Ascorbic acid is an essential cofactorin the synthesis of collagen, a fact known since thesailing days of the 16th century. Vitamin C is themain vitamin associated with poor healing due toits influence on collagen modification.54 L-arginineis required in a variety of metabolic functions,wound healing, and endothelial function. It is

important in the synthesis of nitric oxide, and defi-ciency is linked to immune dysfunction and failureof wound repair. The effects of vitamin C defi-ciency on healing wounds include proliferation ofimmature fibroblasts; failure of formation of matureextracellular material; production of alkaline phos-phatase; and formation of defective capillaries thatcan lead to local hemorrages. Even healed woundsdeprived of vitamin C for long periods show dimin-ished tensile strength. Nevertheless, high concen-trations of ascorbic acid do not promote supranormalhealing.

Vitamin E. Although vitamin E has been used tocontrol various problems of wound overhealing,55,56

its therapeutic efficacy and indications remain tobe defined. Large doses of vitamin E inhibit heal-ing, as reflected by decreased tensile strength andlower accumulations of collagen.57 The mechanismby which vitamin E exerts this effect is related to itsmembrane-stabilizing properties. Vitamin E doesnot reverse the delaying action of glucocorticoidson wound healing and is in turn reversed by vita-min A.

Vitamin E increases the breaking strength ofwounds exposed to preoperative irradiation.58 Asan antioxidant, vitamin E neutralizes the lipidperoxidation caused by ionizing radiation, thus lim-iting the levels of free radicals, peroxidases, andother products of lipid peroxidation that are knownto cause cellular damage.

Zinc and Other Minerals. Many trace metalsincluding manganese, magnesium, copper, cal-cium, and iron are cofactors in collagen produc-tion and deficiencies in these minerals impair col-lagen synthesis.54 Zinc is essential for normalwound healing. Zinc influences reepithelializationand collagen deposition.59 Epithelial and fibro-blastic proliferation is impaired in patients withlow serum zinc levels.60 Zinc also influences Band T lymphocyte activity, but many other nutri-ents including copper and selenium have beenimplicated in immune system dysfunction.61 Zincaccelerates healing only when there is a preexist-ing zinc-deficiency state, otherwise it is of no ben-efit.62

Tissue Adhesives. Logic dictates that fibrin-basedtissue adhesives might be useful in wound healing,


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since deposition of the fibrin network during clot-ting has been implicated in many aspects of cellularevents after injury. A report on mechanical proper-ties of rat skin wounds treated with a fibrin gluenotes increased breaking strength, energy absorp-tion, and elasticity of the healing wounds.63

Antiinflammatory Agents. Nonsteroidal anti-inflammatory drugs (aspirin and ibuprofen) havebeen shown by Kulick et al64,65 to decrease collagensynthesis an average of 45% even at ordinary thera-peutic doses. The effect is dose-dependent andmediated through prostaglandins.66

Smoking. Smoking is harmful to a healingwound.67–73 The mechanism of action is likely tobe multifactorial. Nicotine is a vasoconstrictive sub-stance that decreases proliferation of erythrocytes,macrophages, and fibroblasts.74,75 Hydrogen cya-nide inhibits oxidative enzymes. Carbon monox-ide decreases the oxygen-carrying capacity ofhemoglobin by competitively inhibiting oxygenbinding.72,76 This pathophysiologic triad reducesthe cellular response and efficiency of the healingprocess. Smoking also increases platelet aggrega-tion, increases blood viscosity, decreases collagendeposition, and decreases prostacyclin formation,which all negatively affect wound healing.73

The vasoconstriction associated with smoking isnot a transient phenomenon. Smoking a single ciga-rette may cause cutaneous vasoconstriction for upto 90 minutes, and a pack-a-day smoker sustainstissue hypoxia for most of each day. Tobacco-usingpatients are therefore at risk of cutaneous hypoxiafrom decreased arterial O2 and decreased tissueperfusion as well as increased carboxyhemoglobinlevels.

Lathyrogens. As a group, lathyrogens preventthe formation of aldehyde intermediates in the cross-linking process of collagen, reducing the strength ofthe collagen bundles. This dramatic effect on col-lagen is brought about by beta-aminopropionitrile(BAPN). BAPN and another lathyrogenic agent,d-penicillamine, have been used in the pharmaco-logic control of scar tissue.

Nitric Oxide. Nitric oxide is suspected of play-ing a role in the early phases of wound healing,possibly serving as a modulatory/demodulatory sec-

ond messenger for several of the polypeptide growthfactors.77

Oxygen-derived Free Radicals. Univalentreductions of oxygen generate highly reactive, po-tentially cytotoxic free radicals.78 When releasedinto the extracellular matrix, these oxygen-derivedmetabolites may cause cellular injury by 1) degrad-ing hyaluronic acid and collagen; 2) destroying cellmembranes; 3) disrupting organelle membranes;and 4) interfering with important protein enzymesystems. Oxygen free radical production can betriggered by radiation, chemical agents, ischemia,and inflammation. Several studies seem to supporta direct involvement of oxygen radicals in woundhealing.78

Age. Wound healing is a function of age. Thepatient’s age affects a number of elements in woundhealing, notably the rate of multiplication of cellsand the rate of production of various substances bycells.79 Both tensile strength and wound closure ratesdecrease with age.80 As the individual gets olderthe phases of healing are protracted, so that eventsbegin later, proceed more slowly, and often do notreach the same level.81–83

Some authors84 propose that the real factor con-tributing to delayed healing in the elderly is intoler-ance to ischemia, rather than any inherent alter-ation in the normal processes of wound healing as aconsequence of age. Although increasing age istypically linked with delayed healing, it is difficult toseparate the effects of age alone from those of dis-eases commonly associated with age.85

Mechanical Stress. Mechanical stresses on thehealing wound affect the quantity, aggregation, andorientation of collagen fibers.86 Abnormal tensionon the skin can give rise to blanching and subse-quent necrosis, rupture of the dermis, and perma-nent stretching.87 The effect of mechanical stresson wound healing has been studied on expandedskin wounds in rabbits.88 The expanded woundsshowed significant increases in breaking strengthand energy absorption compared with the implantedbut non-expanded control wounds. The collagen inexpanded wounds was found to be better orga-nized than in controls, and was oriented parallel tothe force vector. The authors conclude that themechanical stress of subcutaneous expansion


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“accelerates wound healing by producing strongerand more organized scars” at the expense of scarstretching.88

Nutrition. Malnutrition manifests as delayed ten-sile strength of wounds in the rat model.89 Theeffect is particularly marked early in the healingprocess, but eventually levels off and ultimately boththe control and starved animals heal equally.

Serum protein levels <2g% in humans areassociated with a prolonged inflammatory phaseand impaired fibroplasia.90 Of the essential aminoacids, methionine, which is later converted to cys-teine, is critical to restoring inflammation andincreasing production of fibroblasts to reverse theeffects of protein depletion.91

Much less is known about the role of carbohy-drates and fats in the healing process. Glucose isrequired as an energy source by leukocytes duringthe inflammatory phase of wound healing, whilefats are necessary for the synthesis of new cells.Essential fatty acid deficiency does not appear tohave any detrimental effect on wound healing.92

Hydration. A well hydrated wound will epithe-lialize faster than a dry one,18,93,94 explaining whyocclusive wound dressings and grafts hasten epi-thelial repair and control the proliferation of granu-lation tissue.

Environmental Temperature. Wound healingis accelerated at environmental temperatures of30°C, whereas tensile strength decreases by 20%in a cold (12°C) wound environment. Inducedhypothermia below 28°C in animals resulted indecreased wound tensile strength up to the fifthpostoperative day,95 presumably through reflex vaso-constriction and perhaps blood sludging.

Denervation. Denervation has no effect oneither wound contraction or epithelialization. Den-ervated skin, however, is less susceptible to localtemperature changes and more prone to ulceratethan normal skin because of high rates of collage-nase activity. Paralyzed persons tend to developmassive, rapidly destructive ulcers over anestheticareas, and these ulcers are up to 5X worse than theusual pressure sores seen in debilitated patients withintact nervous systems.96

Ischemia. The initial anaerobic conditions in awound following injury stimulate cells to adoptanaerobic production of ATP via glycolysis.97 Theincreased metabolism and protein synthesis duringthe proliferative phase of healing require large quan-tities of ATP via oxidative phosphorylation, and theseare provided by glucose and oxygen through a richblood supply. Hypoxia potentially slows or halts thehealing process.98

The physiologic response of the vascular endo-thelium to localized hypoxia in the early phase ofhealing is to precipitate vasodilation and stimulatefibrin deposition, proinflammatory activity, capil-lary leak, and neovascularization. The endothelialcell response to sustained hypoxia is apoptosisinduced by tumor necrosis factor. Wound neutro-phil activity is also impaired at lower oxygen ten-sions.99 Collagen synthesis is disrupted in hypoxicconditions, and fibroblasts may not participate inthe formation of the extracellular matrix.100

Foreign Bodies. Foreign bodies, including non-viable tissue, are a physical obstacle to wound heal-ing and an asylum for bacteria. Like infection, for-eign bodies prolong the inflammatory phase andwounds fail to contract, repopulate the area withcapillaries, or completely epithelialize. Woundswith necrotic tissue will not heal until all the necrotictissue is removed.101

Infection. Infection prolongs the inflammatoryphase of healing, while subinfective bacterial levelsappear to accelerate wound healing and the forma-tion of granulation tissue.102,103 Bacterial counts>105 or the presence of any beta-hemolytic strep-tococcus inhibits healing by prolonging the inflam-matory phase and interfering with epithelialization,contraction, and collagen deposition.104 Bacterialendotoxins decrease tissue PO2 and stimulatephagocytosis and the release of collagenase andreactive oxygen species, further degrading collagenand contributing to the destruction of previouslynormal tissue adjacent to the wound.

In the presence of significant infection, leuko-cyte chemotaxis and migration, phagocytosis, andintercellular killing are decreased. Excessive bacte-rial colonization likewise impairs angiogenesis andepithelialization. The granulation tissue of infectedwounds is more edematous, somewhat hemor-rhagic, and more fragile than that of clean wounds.


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Epithelialization does not proceed in the presenceof a significant bacterial load because the toxinsand metabolites of bacteria inhibit epidermalmigration and even digest tissue proteins andpolysaccharides in the dermis.102,105,106 Finally, heavybacterial contamination promotes collagenolyticactivity through the action of microbial collagenaseand endotoxins capable of cleaving the collagenmolecule, ultimately resulting in decreased woundstrength and contraction.102

Edema. Edema further compromises tissue per-fusion and interferes with wound healing. Mastcells in skeletal muscle produce most of the NOassociated with ischemia-reperfusion injury.107 Mastcells are inflammatory cells that, when stimulated,release histamine and numerous cytokines respon-sible for the intense inflammatory reaction andedema. In addition, tissue edema due to loweredplasma oncotic pressures, a leaky endothelium, andimpaired peripheral perfusion may further com-promise tissue perfusion by raising interstitial pres-sures.108 In turn, raised tissue pressure, eitherexternal (compression) or internal (compartment syn-drome), induces capillary closure through its effecton critical closing pressures.

Idiopathic Manipulation. The degree of tissuenecrosis 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 ofinflammation and retard healing.

Chemotherapy. Antimetabolic, cytotoxic, andsteroidal agents are all associated with compromisedimmunity, increased susceptibility to sepsis, and fail-ure of tissue repair.109–111 Chemotherapeutic agentsgenerally decrease fibroblast proliferation andwound contraction,112–114 although thio-TEPA andchloroquine mustard do not seem to affect woundhealing when administered in therapeutic doses.Actinomycin D, bleomycin, and BCNU are moredetrimental to wound strength than vincristine,methotrexate, 5-fluorouracil, or cyclophospha-mide.112 Cyclophosphamide inhibits the earlyvasodilatory phase of inflammation, while metho-trexate apparently does not act directly upon thewound but does potentiate infection. When che-motherapy is begun 10–14 days postoperatively,

little effect is noted on wound healing over the longterm despite a demonstrable early decrease inwound strength.

Radiation Therapy. Acute radiation injury ismanifested by stasis and occlusion of small vessels,with a consequent decrease in wound tensilestrength and total collagen deposition. Althoughdecreased blood flow to the wound tissues cer-tainly contributes to poor healing, Miller andRudolph115 cite evidence of a direct adverse effectof ionizing radiation on fibroblast proliferation, withpossible permanent damage to the fibroblasts. Irra-diated skin is thus irreversibly injured, and the injuryitself may be progressive.115

Diabetes Mellitus. Diabetes mellitus affects softtissue healing via metabolic, vascular, and neuro-pathic pathways.116 Small vessel occlusive diseaseis no longer considered to be a component of dia-betes mellitus.117 Rather, it is the larger arteries, notthe arterioles, that are typically affected in diabeticpatients. Factors that affect the microcirculation indiabetes include stiffened red blood cells andincreased blood viscosity; susceptibility of the tibialand peroneal arteries to atherosclerosis; high venousback-pressure in the lower extremities that increasestransudation and edema; affinity of glycosylatedhemoglobin for oxygen contributing to low oxygendelivery at the capillary; and impaired phagocytosisand bacterial killing, which along with neuropathyand ischemia make the patient vulnerable to infec-tion.117

Other Systemic Conditions. Obesity, cardio-vascular disease, COPD, cancer, endocrine disor-ders, small vessel disease, and renal or hepatic fail-ure all delay wound healing. Local hypoperfusiondue to small vessel occlusion secondary to emboli,vasculitis, and arterial or venous thrombosis, orlocally raised tissue pressures due to extrinsic orintrinsic factors (eg, hematoma or extravasation) ren-der the wound ischemic and retard healing. Thestress of a critical illness may further impair healingby 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-emittingdiode (LED) therapy, growth factors, and bio-engineered skin.

Hydrotherapy. Whirlpool treatments are amongthe oldest adjunct therapies still in use for the man-agement of chronic wounds. Hydrotherapy is mosteffective when given once or twice a day withconcomitant dressing changes. Antibacterial agentscan be added to the whirlpool water to increasethe bactericidal effect on the wound.

A new form of hydrotherapy is replacing thewhirlpool; it is called pulsed lavage. Pulsed lavagedelivers an irrigating solution under pressure (4–15psi) that stimulates formation of granulation tis-sue.118

Clean, nondraining wounds with healthy redgranulation tissue should never be subjected tohydrotherapy. Even minimal water agitation canmechanically damage the fragile new cells.

Ultrasound. Ultrasound is the result of electri-cal energy that is converted to sound waves atfrequencies >20,000Hz. Sound waves are trans-mitted to the tissue through a hydrated mediumsandwiched between the tissue and the transducer.The depth of penetration of the ultrasound energydepends on the frequency: the lower the fre-quency, the deeper the penetration.

The therapeutic effects of ultrasound therapy stemfrom its thermal and nonthermal properties. Thethermal component at a setting of 1–1.5W/cm2 hasbeen used to improve scar outcome. Thenonthermal component at a setting of 0.3–1W/cm2

produces both cavitation (formation of gas bubbles)and streaming (a steady unidirectional force), whichin the laboratory cause changes in cell membranepermeability, increase cellular recruitment, collagensynthesis, tensile strength, angiogenesis, wound con-traction, fibrinolysis, and stimulate fibroblast andmacrophage production.119–122 Clinically, the resultsof ultrasound therapy on the healing of wounds areequivocal.123–128

Negative Pressure Therapy (V.A.C.). Vacuum-assisted closure consists of using a subatmosphericpressure dressing to convert an open wound into acontrolled closed wound.129,130 The negative pres-sure relieves interstitial fluid and edema to improvetissue oxygenation; removes inflammatory media-

tors that suppress the normal progression of heal-ing;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 hos-tile wound into a manageable one.

Hyperbaric Oxygen (HBO). Dividing cells in awound require a minimum oxygen tension of30mmHg (normal range 30–50mmHg). Tissues inwounds that are not healing show oxygen values of5–20mmHg. When those wounds are placed inhyperbaric chambers at pressures of 2.4ATA, thetissue oxygen tension rises to 800–1100mmHg.119

Besides providing more oxygen to the wound site,HBO also increases expression of NO, which iscrucial for wound healing.132 Many reports attest tothe benefit of HBO therapy in amputations,133

osteoradionecrosis,134,135 surgical flaps,136 and skingrafts,136–138 but the results are not impressive innecrotizing soft-tissue infections.

Hyperbaric oxygen administration increases tis-sue oxygenation considerably as long as the woundvessels are not obliterated, but cannot alter woundischemia in the absence of satisfactory perfusion.In an ischemic rabbit ear model, HBO in combina-tion with PDGF or TGF-β1 had a synergistic effectthat totally reversed the healing impairment causedby ischemia.139 In severely compromised wounds,Mathes, Feng, and Hunt140 recommend surgicaltransplantation of a blood supply to bring O2 intothe ischemic tissues and enhance the healing pro-cess.

Electrostimulation. Electrostimulation isbelieved to accelerate the wound healing processby imitating the natural electrical current that occursin skin when it is injured.141–144 Electrical currentapplied to wounded tissue increases the migrationof neutrophils and macrophages,145–147 and promotesfibroblasts.148–150 Electrostimulation results in a 109%increase in collagen149 and 40% increase in tensilestrength151 and may also improve blood flow in awound.152,153

Four types of electrostimulation are commonlyused: direct current, low-frequency pulsed cur-rent, high-voltage pulsed current, and pulsed elec-tromagnetic fields.119

Lasers. Low-energy laser management of openwounds has been used for over 35 years in Europe


13

and Russia, where it is called “biostimulation.”154

Weak biostimulation excites physiologic processesand results in increased cellular activity in woundedskin.155,156 The mechanism is believed to be thestimulation of ascorbic acid uptake by cells, stimula-tion of photoreceptors in the mitochondria, changesin cellular ATP, and cell membrane stabilization.157–

159 The common types of low-energy lasers used inwound management are the helium-neon laser andthe gallium-arsenide (or infrared) lasers.

Lasers accelerate healing of ischemic, hypoxic,and infected wounds, especially when combinedwith hyperbaric oxygen treatments.160 Low-energylasers promote epithelialization for wound closure161

and better tissue healing.162–169 Laser biostimulationhas different effects at different wavelengths, andoptimal treatment requires several applications atvarious wavelengths.

LED. The treatment area for a laser is limited;that is, large areas must be treated in a grid-likepattern. In contrast, light-emitting diodes (LED) pro-duce multiple wavelengths (680, 730, and 880nmsimultaneously159 or 670, 720, and 880nm170 in large,flat arrays to treat large wounds. NASA developedLED based on their research on wound healing in a

weightless environment. Work done on spaceshuttle missions, on the international space station,and aboard submarines shows significant improve-ment in wound healing with LED therapy alone orin combination with hyperbaric oxygen treatment.

Growth Factors. McGrath2 defines growth fac-tors as follows: “A polypeptide growth factor is anagent promoting cell proliferation. . . . These pro-teins also induce the migration of cells, and thus arenot only mitogens but are also chemoattractantsthat recruit leukocytes and fibroblasts to the injuredarea.” Of particular importance to wound healingare the fibroblast growth factors (Table 2).4 Theireffect on the repair process is illustrated in Figure 6.

Platelets contain growth factors that stimulateangiogenesis, fibroplasia, and collagen production.These are called platelet-derived wound healingfactors (PDWHF).171 A beta-chain recombinantc-sis homodimer of platelet-derived growth factor(rPDGF-β) appears to have immunologic propertiessimilar to PDGF—ie, it stimulates fibroblast mitoge-nesis and chemotaxis of PMNs, MONOs, and fibro-blasts.172 Both PDGF and rPDGF-β acceleratewound healing by augmenting the inflammatoryresponse and the accumulation of granulation tissue.

Table 2Growth Factor Signals at the Wound Site

(Reprinted with permission from Martin P: Wound healing—aiming for perfect skin regeneration. Science 276:75, 4 Apr 1997.)


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Brown and associates173 studied epidermal growthfactor (EGF) added to silver sulfadiazine in the heal-ing of wounds. The cream mixture was applied toskin-graft donor sites of 12 patients. Complete heal-ing was noted 1.5 days sooner in the experimentalwounds than in the control wounds, which receivedsilver sulfadiazine alone. In a separate study onchronic wounds, EGF applied topically b.i.d. resultedin complete healing in 8/9 wounds at a mean 34days.

In vitro, EGF is a growth-promoting protein forskin fibroblasts and other cell types. In vivo, EGFstimulates epithelial proliferation in the skin, lung,cornea, trachea, and gastrointestinal tract. Epider-mal growth factor affects keratinocyte proliferationmainly by increasing their rate of migration, whichin turn increases the number of dividing cells,growth rate, culture lifetime, and the ability to beginnew colonies.174 Along with transforming growthfactor alpha (TGF-α), other peptide growth fac-tors,175–184 and cytokines,185–187 EGF is “part of acomplex program to orchestrate growth and differ-entiation of epidermal keratinocytes.”174,188 The

effects of cytokines on abnormal scars are beinginvestigated.185–187

Transforming growth factor beta (TGF-β) has beenlinked clinically and experimentally to dermal pro-liferative disorders. Polo and colleagues189 foundan abnormal dose response by fibroblasts of prolif-erative scars to TGF-β2 stimulation. This responsewas not demonstrated by nonburn hypertrophicscars.

The commercially available growth factor prod-ucts and their uses are summarized in Table 3.

Bioengineered Skin. Skin equivalents providea living supply of growth factors and cytokines and acollagen matrix for a wound to build upon. Theunderlying principles and specific benefits of theseproducts are discussed elsewhere in this overview.The bioengineered skin replacements currently onthe market are shown in Table 4.

FETAL WOUND HEALING

Tissue repair in the mammalian fetus is funda-mentally different from normal postnatal healing.“In adult humans, injured tissue is repaired by col-lagen deposition, collagen remodeling, and even-tual scar formation. [In contrast], fetal wound heal-ing seems to be more of a regenerative processwith minimal or no scar formation.”190

Siebert et al191 examined healing fetal woundshistologically and biochemically and found that theycontained a small amount of collagen identical tothat found in the exudate from wounds in adults, ie,Type III collagen but no Type I. The fetal woundmatrix was also rich in hyaluronic acid, which hasbeen associated experimentally with decreased scar-ring postnatally. The authors propose a mechanismof hyaluronic acid-collagen-protein complex actingin fetal wound healing to check scar formation, andconcluded that healing in fetuses involved a muchmore efficient process of matrix reorganization thanthat which takes place after birth. True regenera-tion apparently does not play a role in fetal healing,based on the few appendageal elements seen.

Rowsell192 suggests that the collagen present infetal wounds is “structural” rather than “scar tissue”collagen. The amounts of collagen deposited in fetaland in adult wounds are not only markedly differ-ent, but the deposited collagen is also handled dif-ferently. The fetal pattern of wound healing “is

Fig 6. Peptide growth factors released by the cells recruitedinto the injured area. (Reprinted with permission from McGrathMH: Peptide growth factors and wound healing. Clin Plast Surg17(3):421, 1990.)


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characterized, at least in the early fetus, by thedeposition of glycosaminoglycans at the wound siteinto which rapidly proliferating mesenchymal cellsof all types migrate, differentiate, and mature.”193

The transition from fetal to adult patterns of woundhealing for different tissues probably occurs at dif-ferent times during gestation.

In their review of scarless wound healing in themammalian fetus, Mast and coworkers190 state that“a striking difference between postnatal and fetalrepair is the absence of acute inflammation in fetalwounds,” and offer several hypotheses to explainthis phenomenon. Epithelialization occurs at a muchfaster rate in fetal wounds, but adult-like angiogen-

esis is absent. More important, the fetal woundmatrix is markedly different from the adult’s in thatit lacks collagen and instead contains predominantlyhyaluronic acid. The fetal wound contains a persis-tent abundance of HA while collagen deposition israpid, nonexcessive, and highly organized, so thatthe normal dermal structure is restored and scarringdoes not occur. The authors speculate about theapplications of scarless fetal healing, namely forintrauterine repair and in the treatment of patho-logic, postnatal processes.

Whitby and Ferguson193 studied the distributionof growth factors in healing fetal wounds in anattempt to identify the mechanism controlling the

Table 3Commercially Available Growth Factors, Indications and Benefits

Table 4Bioengineered Skin Replacements


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healing process in fetuses. They found platelet-derived growth factor (PDGF) in fetal, neonatal,and adult wounds, but transforming growth factorbeta and basic fibroblast growth factor (bFGF) werenot detected in the fetal wounds. They concludethat it may be possible to manipulate the adultwound to produce more fetal-like, scarless woundhealing by therapeutically altering the levels ofgrowth substances and their inhibitors. This hope isshared by other groups194–199 though it has not yetmaterialized in the clinical setting. Other growthfactors are under study also.200

Tenascin (cytotactin) is a large, extracellular matrixglycoprotein synthesized by fibroblasts that ispresent during embryogenesis but only sparsely dis-tributed in the connective tissue papillae of adults.The protein is re-expressed, however, in healingwounds, particularly close to the basement mem-branes at the wound edges beneath the proliferat-ing and migrating epithelium, and later on duringhealing in the regenerating connective tissue area.This expression subsided later on during healing.201

Compared with adult wounds, tenascin is presentearlier in fetal wounds, and may be responsible forinitiating cell migration and the rapid epithelializa-tion of fetal wounds.202 Some investigators201,202

believe that tenascin could be a modulator of cellgrowth and movement and that it may influencethe deposition and organization of other extracel-lular matrix glycoproteins during tissue repair.

WOUND CARE

Cleaning and Irrigation

The general surgical principles of cleanliness andgentleness in managing wounds remain the main-stay of accepted medical practice. Next to debri-dement, cleaning the wound is the most importantthing one can do to prepare the wound. It is notenough to simply soak the affected part; irrigationwith at least 7psi of pressure is needed to flush outany bacteria in a wound.203 High-pressure irriga-tion, however, may injure adjacent healthy tissueand cause lateral spread of the irrigating fluid, withresultant postoperative edema, therefore high-pres-sure irrigation should be reserved for highly con-taminated wounds.

Hollander looked at wound infection rates andcosmetic appearance of 1923 facial lacerations 1

week after repair.204 The infection rate was similarin 1090 lacerations that were irrigated (0.9%) vs833 that were not irrigated (1.4%), but there was atrend toward better early cosmetic appearance inthe nonirrigated wounds.

Wounds can be effectively cleansed with ordi-nary tap water.205 Potent antibacterial agents likehydrogen peroxide, povidone-iodine, alcohol, etc.are unnecessary and will destroy healthy tissue. Ifthey are used on a wound, they must be thoroughlyrinsed out with sterile saline before the wound issutured or bandaged. Most uncomplicated woundscan be irrigated with 50–100mL/cm of woundlength, whereas contaminated wounds and woundsat high risk of becoming infected (marine wounds,farm injuries, and gunshot wounds) require 1–2L ofirrigation.

Debridement

Adequate debridement is perhaps the mostimportant step to produce a wound that will healrapidly and without infection. Necrotic tissue is asafe haven for bacteria and the physical presenceof the dead cells prevents the wound from con-tracting and healing.

Scrubbing with a saline-soaked sponge is a veryeffective way of removing bacteria, proteinaceouscoagulum and debris.206 Scrubbing can also signifi-cantly damage healthy tissue and widen the area ofinjury. Scrubbing is best reserved for highly con-taminated wounds with embedded particles—theso-called “road rash.”

Nonselective debridement is also calledmechanical debridement and may include any oneor a combination of dry-to-dry, wet-to-dry, and/orwet-to-wet dressing changes; Dakin’s solution orhydrogen peroxide; and hydrotherapy or high-pow-ered wound irrigation. Non-selective debridementis used for wounds with large amounts of necrotictissue and debris. Once granulation tissue beginsto develop, a more selective form of debridementshould be used.

Selective debridement can be sharp, enzymatic,autolytic, or biologic. Surgical debridement is themost effective, aggressive, and rapid means ofremoving large quantities of devitalized tissue.Clearly demarcated areas of living and dead tissuesneed to be appreciated or else too much viabletissue can be removed.207


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Enzymatic debridement takes advantage of natu-rally occurring enzymes that will selectively digestdevitalized tissue. Enzymatic debridement has theadvantage of working continuously while the patientis at home or in the hospital. This form of debride-ment is slower and less aggressive than surgicaldebridement. Depending on the thickness of theeschar or fibrinous material to be debrided, cross-hatching of the surface might speed the process byincreasing the available surface area. The enzymesare typically applied daily and covered with gauze.They can be used for weeks and may need up to 1month of treatment for success. Silver sulfadiazine(Silvadene) should not be used concurrently becauseit will deactivate the enzyme. Some agents digestnecrotic tissue from the bottom up (eg, collage-nase) while others work from the top down (eg,papain–urea preparations) (Table 5).208

Autolytic debridement allows the body’s ownenzymes and moisture to break down necrotic tis-sue. It acts in 7–10 days under semiocclusive andocclusive dressings, but not under gauze dressings.209

Transparent films, hydrocolloids, and calcium algi-nates may all be used to enhance autolytic debride-

ment. Hydrogels hasten the autolytic process byquickly rehydrating necrotic tissue. Autolyticdebridement is usually ineffective in malnourishedpatients.

Biologic debridement with maggots was firstintroduced in the US in 1931 and was routinelyused until the mid-1940s. With the advent of anti-bacterials maggot therapy became rare until theearly 1990s, when it once again became popular.Up to 1000 sterile maggots of the green bottle fly,Lucilia (Phaenicia) sericata, are placed in the woundand left for 1–3 days. Maggot debridement can beused for any kind of purulent, sloughy wound onthe skin, independent of the underlying diseases orthe location on the body, and for ambulatory aswell as for hospitalized patients. In addition to stimu-lating host healing through debridement and result-ant cytokine release, the maggots secrete calciumsalts and bactericidal peptides (defensins)210 that pro-vide an antimicrobial benefit. One of the majoradvantages of this type of debridement is that themaggots separate the necrotic tissue from the livingtissue, making surgical debridement easier. Offen-sive odors and pain associated with the wound

Table 5Enzymatic Debridement Agents


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decrease significantly,211,212 and a complete debri-dement is achieved in most cases.

WOUND CLOSURE

INTRODUCTION

Ancient Hindu medicine described the use ofinsect mandibles to approximate skin wounds.213

From these modest beginnings, increasingly sophis-ticated wound closure materials and techniqueshave evolved.

Healing by primary intention is achieved bydirect approximation of the wound margins and ispreferable in most instances. However, wheninfection or excessive tension precludes primaryclosure, spontaneous contraction and epithelial-ization of open wounds (secondary intention) ordelayed surgical closure (tertiary intention) maybe necessary.214,215

PRINCIPLES

Crikelair216 listed the Halstedian fundamentals ofsurgical wound closure which apply to the manage-ment of any skin wound.

• Place incisions to follow tension lines and natu-ral folds in the skin.

• Handle tissues gently and debride only as muchas 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 closerto 90 than to 9 years.

• Allow time for scars to mature before repeatintervention.

PREOPERATIVE EVALUATION

Hunt and Hopf217 indicate the importance ofsimple, inexpensive, and readily available interven-tions in the perioperative setting. Their paperfocuses on correcting for hyperglycemia and ste-roid use before surgery, preventing vasoconstric-

tion by maintaining normothermia, and addressingmalnutrition when present.

Scars are generally less conspicuous if they canbe made to follow a skin line.218 The surgical inci-sions are planned so that the final scar lies parallelor adjacent to the relaxed skin tension lines(RSTL).219–223 The RSTL in the face are the lines offacial expression.223 In young, unlined persons, theRSTL can be visualized by pinching the skin in vari-ous directions. In older people the RSTL coincidewith the nadir of wrinkles.

Elective incisions for the removal of skin lesionsshould be planned as a long ellipse approximatelyfour times longer than wide (Fig 7). If the ellipse istoo short, the skin will bunch at the ends in a dog-ear.163

Fig 7. Elliptical excision. A, If the ellipse is too short, dog ears willform at the ends. B, Correct method. (Reprinted with permissionfrom Grabb WC: Basic Techniques of Plastic Surgery. In: GrabbWC and Smith JW (eds), Plastic Surgery, 3rd Ed. Boston, LittleBrown, 1979.)

When the orientation of the RSTL cannot bedetermined, the lesion can be excised as a circleprovided the margins are undermined in all direc-tions. The natural skin tension will pull the woundinto an elliptical configuration and one may thenproceed with suturing.218

Semicircular lacerations, if sutured linearly, tendto yield a trapdoor deformity. Gahhos and


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Simmons224 recommend immediate Z-plasty for therepair of curved lacerations. Borges225 disagrees,arguing that (1) most lacerations go beyond the skinand therefore it is difficult to decide what may beviable tissue; (2) patients may not like a zigzag scarif they have not had an opportunity to compare itwith the scar produced by linear closure; and (3)the risk of infection or hematoma after a traumaticlaceration is greater than after elective scar revi-sion.

WOUND PREPARATION

Local anesthesia in the face is induced with adilute anesthetic solution injected at key points overthe nerve to the wounded area using a 25-gauge orsmaller needle.226 The syringe should be small andthe pressure on the plunger no more than neededfor a slow but steady flow.

Traumatic wounds must be rid of all devitalizedtissue and foreign material. Only minimal debride-ment is recommended in the head and neckbecause of the ample blood supply of the area andthe mutilating consequences of overly aggressivedebridement. After sharp debridement the woundshould be thoroughly cleansed with normal salineor with povidone iodine for antisepsis.

If primary closure is contemplated, the woundedges are trimmed to make them perpendicular tothe bed. The exception is in hair-bearing areas,where they should parallel the hair shafts. Everyeffort should be made to preserve key anatomiclandmarks—the vermilion border, eyelid, eyebrow,nostril, and auricular helix—by precisely aligningthe wound edges during closure.

SURGICAL TECHNIQUES

Meticulous surgical technique is required toobtain an inconspicuous scar. Critical elementsinclude the obliteration of dead space, layered tis-sue closure, and eversion of skin margins.

Deep dermal sutures align the skin edges andhelp decrease tension on the skin closure. Evertingskin sutures are placed by encompassing a largeramount of deep dermis than epidermis in the clo-sure (Fig 8). They are tied under the minimal ten-sion necessary to oppose the skin margins.

Nonabsorbable synthetic monofilament sutures(nylon, Prolene, Novafil) are minimally reactive and

thus preferred for skin closure when cosmesis isessential. 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 byphagocytosis. They are useful where suture removalis difficult and cosmesis is not critical (eg, in the oralcavity, nasal cavity, and non-facial wounds in chil-dren).227–233

The simple interrupted suture is the most com-mon skin closure method. Horizontal mattress suturesfacilitate tissue eversion with the use of 50% fewersutures, whereas vertical mattress sutures are usefulin wounds under significant tension. Runningsutures speed the closure of uncomplicated, linearwounds. Unlike interrupted sutures, they do notallow the differential adjustment of suture tensionthat is required in complex wounds. Subcuticularrunning sutures yield cosmetically pleasing resultsin wounds under mild tension.234–238

Tissue bonding with cyanoacrylate adhesives isbecoming an increasingly popular method of woundclosure in Canada and Europe. Mizrahi239 reportedthe use of cyanoacrylate glue in more than 1500simple pediatric lacerations, with a 2.4% complica-tion rate. Applebaum240 cites the advantages of rapid

Fig 8. Technique of layered wound closure everting the skinedges. (Modified from Spicer TE: Techniques of facial lesionexcision and closure. J Dermatol Surg Oncol 8:551, 1982.)


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and painless application at an average materials costof $2.86 per patient. These products are not cur-rently in mainstream use in the United States.

A skin-stretching device has been developedrecently by Hirschowitz.241 Marketed in the U.S.as the Sure-Closure device, it uses the skin prop-erty of mechanical creep242 to achieve primaryclosure of large wounds that would otherwiserequire grafts or flaps. Promising results have beendemonstrated in the closure of fasciotomies,amputation stumps, and other wounds of the trunkand lower extremity.

For difficult wound closure in the acute setting,Abramson and colleagues243 describe a simple tech-nique of intraoperative skin stretching with 18-gaugespinal needles placed parallel to the wound marginsaided by a rib approximator.

Markovchick244 lists his recommendations forsuture repair of soft-tissue injuries in an emergencydepartment, including preferred anesthetic, suturematerial, surgical technique, wound dressing, andtiming of suture removal (Table 6).

POSTOPERATIVE CARE

Immediately after completing the closure, anti-biotic ointment is applied to the suture line withoutfurther occlusive covering. Most surgeons recom-mend that the wound be kept dry for the first 2days, after which gentle washing is encouraged.Borges,245 however, questions the wisdom of keep-ing a wound dry, and instead recommends imme-diate application of a light dressing to prevent scabformation and to maintain a moist wound environ-ment. In support of this practice Noe and Keller246

report no suture disruption, wound dehiscence, orinfection in 100 patients who washed their woundswith soap and water twice a day beginning themorning after surgery.

In the head and neck surgical sutures areremoved in 3–5 days, while elsewhere they areleft in place for 7–10 days. To remove it, thesuture is cut close to the skin edge and its freeend is pulled across the wound, not away from it.Crikelair216 notes that the two most commoncauses of unsightly suture marks are delayedremoval beyond 10 days and excessive tension

of the closure. The size of the individual “bites”,type of needle, and suture material are not sig-nificant to the esthetic outcome.

The eventual width of a scar is proportional tothe force required for closure. Wray247 suggestsprolonged support of the wound edges with tape toeffectively minimize scar width. Nonwovenmicroporous tape is superior in terms of breakingstrength, extensibility, adhesive capacity, porosity,and resistance to infection.248

For a wound to heal as a good scar withouthypertrophy, adhesion, or contracture, the pro-cesses of scar formation and remodeling must fol-low a precisely chartered, finely tuned course.Parsons249 makes the following points regardingscar prognosis:

• A scar usually looks its worst between 2 weeksand 2 months after injury. Scar revision shouldawait scar maturation, which can take from 4 to24 months depending on the type of injury aswell as on the patient’s age and genetic back-ground. The only exception to this rule is whenthere is loss of function—eg, scars crossing con-cave surfaces or the flexor aspects of joints, whichtend to contract into tethering bands that pre-vent full extension.

• A scar becomes noticeable if it interrupts thehomogeneous flow of tissue planes through color,contour, or texture differences—eg, hyperpig-mented, depressed, or shiny scars.

• The final appearance of a scar depends more onthe 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 pooroutcome.

• Differences among suture materials are of negli-gible importance to the result, but other techni-cal factors of suture placement and removal doaffect the final scar.

• Immobilization is as important in soft-tissue heal-ing as it is in bone fractures. Tension across thewound causes minute wound disruptions andsubsequent excessive scarring. Adhesive stripsacross the suture line should be kept in place for1 or 2 weeks after the sutures are removed.


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Table 6Suture 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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WOUND DRESSINGS

There are more than 2000 wound dressing ma-terials available commercially. See the Appendixfor an overview of their respective properties, indi-cations, advantages, and disadvantages.

The red-yellow-black classification of wounds hasremoved the mystery in choosing a dressing. TheRYB system is used for wound healing by secondaryintention and is based on the balance of healthygranulation tissue and necrotic tissue (Table 7).When treating a wound with multiple colors, theworst problem should be treated first: black beforeyellow before red.

Semipermeable Occlusive Dressings

There is evidence that debridement, angiogen-esis, dermal repair, and epithelialization areaccelerated under occlusive dressings. The mecha-nisms involved include thermal insulation, changesin wound pH, PO2 and PCO2, and maintenance ofgrowth factors in the moist environment.250

Because occlusive dressings can cause skin mac-eration from excessive fluid accumulation, manypopular modern dressings are semipermeable,allowing escape of moisture vapor and passage ofgases but preventing entry of bacteria and liquidwater.250 Carver and Leigh250 review the varioustypes of commercially available occlusive dressings,

Table 7Wound Management Protocol: The Red-Yellow-Black Classification


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including alginates, adhesive-coated films, hydro-colloids, hydrogels, foams, and absorptive powdersand pastes.

Katz et al251 compared the effects of 6 commer-cially available semiocclusive dressings on the heal-ing of contaminated surface wounds. All the mate-rials tested were equally effective in increasingthe rate of reepithelialization; all, however, pro-duced microenvironments that were conduciveto the growth of bacteria. Although occlusive dress-ings may provide a physical barrier to exogenousmicroorganisms, by themselves they are unable toprevent infection once pathogens are introduced,and may actually promote infection by encourag-ing bacterial proliferation, particularly with pro-longed occlusion.

Alginates are particularly well suited for use inwounds with heavy exudates. Upon contact withthe wound exudate, the alginate is converted toa sodium salt, which results in a hydrophilic geland an occlusive environment that promoteswound healing. The dressing must be changedwhen the gel-like substance begins to weep exu-date.252

Creams are opaque, soft solids or thick liquidsintended for external application. Medications aredissolved or suspended in the emulsion base, awater–oil substance. Creams are usually applied tomoist, weeping lesions and have a slight dryingeffect. Creams can be formulated to aid in drugpenetration into or through the skin. Ointmentsare semisolid preparations that melt at body tem-perature and are used for their emollient proper-ties. Their primary role in wound healing is to aidin rehydrating the skin and for topical application ofdrugs.

Foam dressings consist of hydrophobic polyure-thane sheets with a nonabsorbent, adhesiveocclusive cover. Foam dressings are very absor-bent and nonadherent to the wound. Becausethey absorb environmental water, reepitheli-alization does not occur as readily as under mois-ture-promoting dressings.

Film dressings are transparent polyurethane mem-branes with water-resistant adhesives. They arehighly elastic and conform easily to body contours.Film dressings are semipermeable to moisture andoxygen and impermeable to bacteria. The trappedmoisture promotes autolytic debridement, but canalso macerate the wound in the event of heavy

exudate. Because the membrane is transparent,film dressings are best for visual monitoring ofwounds. They do not hold up well in friction areas,and the adhesive can tear the skin in elderlypatients.253

Gauze dressings are highly permeable to air andallow rapid moisture evaporation. They can stick tonewly formed granulation tissue and damage itwhen dressing is removed, and dressing changescan be painful. In addition, both woven and non-woven gauze will leave behind some lint and fiberswhich can harbor bacteria.

Hydrocolloid dressings are completely imperme-able and therefore should not be used for dressingwounds with anaerobic infections. These dressingsadhere well, are comfortable for the patient, andare effective in absorbing minimal to moderateamounts of exudate. Hydrocolloid dressings arewell suited for wounds over high-friction areas.

Hydrogel dressings are simply starch and waterpolymers that are manufactured as gels, sheets, orimpregnated gauze. They rehydrate a wound, andbecause of their high water content, they do notabsorb large amounts of wound exudate.

Vacuum-assisted Closure (V.A.C.) Dressing

V.A.C. dressings provide a negative-pressureenvironment around the wound that helps removeinterstitial fluid and edema and improve tissue oxy-genation. They also remove inflammatory media-tors that suppress the normal progression of woundhealing.130,131 Granulation tissue forms more rap-idly and bacterial counts decrease to <105 organ-isms per gram of tissue.129 V.A.C. dressings areconvenient to use and associated with few compli-cations. V.A.C. dressings are employed in a varietyof situations such as soft-tissue loss, exposed boneand hardware, osteomyelitis, weeping wounds,infected wounds, and as a skin graft bolster.

Silver-impregnated Dressings

Silver-impregnated dressings offer an excellentway to kill bacteria without antibiotics while stillproviding a moist environment for wound healing.Some of the brand names and manufacturers areActicoat (Smith & Nephew), Arglaes (MedlineIndustries), AcryDerm Silver (Acrymed Portland),and Silveron (Silveron). The silver in these prod-


24

ucts must be in the Ag+ nonmetallic, ionic form toinhibit cell wall synthesis, ribosome activity, mem-brane transport, and transcription in bacteria. Silver-impregnated dressings provide broad-spectrumantimicrobial coverage and are effective againstmethicillin-resistant S. aureus and vancomycin-resistant enterococci as well as against yeast andfungi.254–256

Oasis (Cook Surgical) is a unique wound dressingmade from porcine small intestinal submucosa. Oasisis simple to use and appears to act as a scaffold forcollagen to stimulate wound healing in chronic andpossibly in acute wounds.257 Oasis is relativelyinexpensive, easy to handle, safe, and appears tohave a sound scientific basis for its claim that itpromotes healing.258

Apligraf

For several years, Apligraf has been associatedwith improved healing over conventional therapyin skin ulcers from venous insufficiency or diabeticneuropathy. Apligraf is cultured human skin deliv-ered “fresh” on a culture medium to be placed ona patient’s ulcer. Apligraf is bilayered living skin—epidermis and dermis—that contains no Langer-hans cells, melanocytes, macrophages, lymphocytes,hair, or blood vessels. Cytokines have been identi-fied in it, including interleukin, platelet-derivedgrowth factor, tumor necrosis factor, vascularendothelial growth factor, and fibroblast growth fac-tor. It is derived from human foreskin that hasundergone extensive viral and genetic process-ing.259,260

Treatment with Apligraf is expensive, but whenall factors are taken into consideration (the actualcost of the bandage plus all health care resourcessuch as office visits, home visits, laboratory tests,treatment failures and complications, and subse-quent hospitalizations), Apligraf therapy is less costlythan traditional therapies for chronic ulcers.261

Dermagraft

Dermagraft is a human fibroblast-derived dermalsubstitute that consists of neonatal dermal fibroblastscultured in vitro on bioabsorbable mesh to producea living, metabolically active tissue containing thenormal dermal matrix proteins and cytokines.262 Todate there are no trials comparing the efficacy of

Dermagraft vs. Apligraf, although multiple studiesattest to a higher percentage of healed diabeticfoot ulcers treated with Dermagraft compared withcontrols.262–266

HYPERTROPHIC SCARSAND KELOIDS

INTRODUCTION

“A preferred scar is one that has matured rapidlywithout contracture or increase in width, andwithout forming more collagen than is necessary forits strength.”

van den Helder and Hage (1994)267

While most modern societies perceive promi-nent scars as disfiguring, some primitive societiescontinue to use scarification for ornamental pur-poses.268 The existence of surface scarring was prob-ably recognized centuries before Jean-Louis Alibertdescribed the cheloide.269 However, the wide vari-ety of current theories and proposed treatments forthese abnormal scars demonstrates how inadequateour understanding remains.

Gross Morphology

Hypertrophic scars are characteristically elevatedabove the skin surface but limited to the initialboundaries of the injury. The severity of the initialtissue injury determines the extent of scar. Hyper-trophic scars may occur at any age or site and tendto regress spontaneously. They are more commonthan keloids and are generally more responsive totreatment.270–273 Hypertrophic scars may regress withtime and occur earlier after injury (usually within 4weeks).

Keloids are distinguished clinically from hyper-trophic scars by their extension beyond the originalwound and lack of regression. They may developfrom either superficial or deep injuries, are bettercorrelated with young age and dark skin color, andare frequently resistant to treatment.270–273 Mostkeloids form within 1 year of wounding, althoughsome may begin to grow years after the initialinjury.271 Symptoms associated with keloid forma-


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tion include pain, pruritus, hyperpigmentation, dis-figurement, and decreased self-esteem (especiallyin teenagers). Persistent pruritus is associated withkeloid formation.274 Areas of the head and neckthat are spared include the eyelids and the mucousmembranes.274

Rudolph275 described a third type of abnormalscar, the widespread scar, which apparently resultsnot from excessive collagen deposition but ratherfrom a mishap occurring during the third phase ofhealing as a consequence of continued tension andmobility of the wound. The typical widespreadscar is flat, wide, and often depressed.

ETIOLOGY AND PATHOGENESIS

The underlying mechanism of abnormal scars isan excessive accumulation of collagen from increasedcollagen synthesis or decreased collagen degrada-tion.276,277 A number of genetic and environmentalfactors have been implicated in the pathogenesis ofhypertrophic scars and keloids (Fig 9).

Fig 9. Factors implicated in the pathogenesis of hypertrophicscarring. (Reprinted with permission from Thomas DW et al: Thepathogenesis of hypertrophic/keloid scarring. Int J Oral MaxillofacSurg 23:232, 1994.)

The most common triggering mechanism forkeloid formation is earlobe piercing, althoughlocalized skin trauma, vaccination, hormonal excess,increased skin tension, genetic factors, and otherminor factors have also been implicated.278 Virtu-ally all abnormal scars are associated with trauma,including surgery, lacerations, tattoos, burns, injec-tions, bites, vaccinations, and occasionally bluntimpact.271 Skin tension is frequently implicated,

especially in hypertrophic scar formation. Areas ofhigh skin tension, such as the anterior chest, shoul-ders, and upper back are commonly involved.279,280

Brody and colleagues281 point out that hypertrophicscars may result from compressive forces across thescar rather than excessive tension, as hypertrophicscar contractures occur only on the flexor surfacesof joints. Other local etiologic factors include woundinfection or anoxia, prolonged inflammatoryresponse, and a wound orientation different fromthe relaxed skin tension lines.

Tissue hypoxia has been implicated in keloidalscar formation.282 The mechanism by whichhypoxia may lead to keloidal scar formation isunclear. Vascular endothelial growth factor (VEGF)is released from fibroblasts in response to hypoxia.Gira et al283 found that VEGF production wasabundant in keloids and the source of the VEGFwas the overlying epidermis. In contrast,Steinbrech et al284 found no difference in levelsof VEGF between keloidal fibroblasts and normaldermal fibroblasts.

There is a theory that keloidal scars are causedby an immune reaction to sebum.285 Proponentssuggest random damage to pilosebaceous structuresin the skin.286 This theory is supported by the fol-lowing observations: keloids are more common inadolescence; they rarely occur on the palms andsoles; spontaneous keloids occur in skin areas withsebaceous activity; and one scar may be keloidalwhereas an adjacent scar may be normal.

Keloids can be considered a mesenchymal neo-plasm. Keloid fibroblast have been shown to con-tain the oncogene gli-1 and express the proteinGli-1,287 and in this regard are similar to basal cellcarcinomas. This oncogene is not expressed infibroblasts from normal tissue and non-hypertrophicscars (no reports in the literature whether it isexpressed in fibroblasts of hypertrophic scars).

A detailed review of keloids, their etiology, patho-genesis, and treatment by Shaffer et al288 is highlyrecommended. A brief discussion of the differ-ences between keloids and hypertrophic scars ispresented.

EPIDEMIOLOGY

Keloids are far more common in blacks than inother races, whereas other abnormal scars do notexhibit an ethnic predilection. Even though they


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can occur at any age, keloids are prevalent in patientsbetween 10 and 30 years of age,289 while youngchildren290 and older adults291 are rarelyaffected.294 There are many reports of keloidsbeing more frequent in women, but this may justbe a reflection of which sex seeks correction.292

A study of rural Africans reveals a similar inci-dence of keloids in men and women.293 Althoughkeloids can occur in persons of all races, darklypigmented skin is affected 15X more often thanlighter skin.295,296

Keloids show racial and familial heritability, indi-cating a genetic component. A predisposition tokeloid formation is inherited as an autosomal domi-nant297 or autosomal recessive trait.298 Keloids tendto have accelerated growth during puberty or preg-nancy and to resolve after menopause.299,300

HISTOLOGY

Microscopic analysis reveals large collagenbundles in keloidal scars but not in hypertrophicscars.301,302 Collagen bundles are “crisp” inhypertrophic scars and more “glazed” in keloidalscars.303 Keloidal scars may have few macroph-ages but abundant eosinophils, mast cells, plasmacells, and lymphocytes.301 Keloidal scars are asso-ciated with a mucopolysaccharide ground sub-stance and hypertrophic scars have only scantamounts.301

Hypertrophic scars have nodules containingcells and collagen within the mid-to-deep part ofthe scar.304 Within these nodules are smoothmuscle actin-staining myofibroblasts which areabsent from normal dermis, normal scars, and88% of keloids. On electron microscopy, Ehrlichet al304 found an amorphous substance aroundkeloidal fibroblasts that separate them from thecollagen bundles. This substance was not seen inhypertrophic scars.

BIOCHEMICAL AND METABOLIC ACTIVITY

The increased metabolic activity of hyper-trophic scars and keloids is reflected in elevatedglycolytic enzyme activity, fibronectin deposition,and collagen MRNA expression.305–307 Unlike nor-mal wounds, fibroplasia in these abnormal scarscontinues well beyond the third post-injury weekwithout resolution.271 The scars remain imma-

ture, with an abnormally high content of Type IIIcollagen and a disorganized pattern of collagendeposition.308 The scars are initially hypoxic butlater exhibit increased blood flow that is three tofour times greater than that of normal scars.309

Although hypertrophic scars and keloids are his-tologically indistinguishable by light microscopy,279

Ehrlich et al304 have recently demonstrated a num-ber of electron microscopic and immunochemi-cal differences. Keloids contain thick collagenfibers with increased epidermal hyaluron con-tent,310 whereas hypertrophic scars exhibit nodu-lar structures with fine collagen fibers andincreased 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) andfibroblasts than hypertrophic scars. Nakaoka et al313

found a higher density of fibroblasts in both keloi-dal scars and hypertrophic scars, but keloidal scarshad a higher expression of proliferating cell nuclearantigen, which may help explain the tendency ofkeloidal scars to grow beyond the boundary of theoriginal wound.

Immunologic alterations have been demonstratedin abnormal scars, including irregular immunoglo-bulin and complement levels,314,315 increased mastcells and TGF-β,316,317 and decreased TNF andinterleukin-1.318,319

Antinuclear antibodies against fibroblasts andepithelial and endothelial cells have been found inpatients with keloidal scars but not in those withhypertrophic scars.320

Lower rates of apoptosis have been observed inkeloidal fibroblasts.321 It has been suggested thatkeloidal fibroblasts resist physiological cell death,continuing to proliferate and produce collagen.322

Keloidal fibroblasts have increased levels of PAI-1 and low levels of urokinase.323 This may lead toreduced collagen removal and contribute to scarformation.288

TREATMENT

Prevention is the best therapy for keloids. Pre-ventive measures include avoiding nonessentialcosmetic surgery, closing wounds with minimal ten-sion following skin creases, and using cuticular,monofilament, synthetic permanent sutures in aneffort to decrease tissue reaction.274 One should


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also avoid Z-plasties or any wound-lengthening tech-niques and any incisions that cross joints.

No universally effective treatment for keloidsexists. A “shotgun approach” to treatment is mostoften used, and specific modalities are chosen on apatient-to-patient basis.278 For example, althoughinjected triamcinolone is considered to be effica-cious as a first-line therapy, silicone gel sheetingmay be more useful in children and others whocannot tolerate the pain of other therapies.324

Lindsey and Davis325 reported a 15% overall recur-rence rate in 202 patients with head and neckkeloids treated with excision, intralesional steroids,silicone sheeting, and radiation therapy. All patientshad more than 2-years of follow-up.

The following is a list of current treatment optionsfor keloids:278

Excision and closure by direct approximation, localflap, homograft, or keloid skin suturing

CryosurgeryLaser excision — argon, CO2, or Nd:YAG laserRadiation therapy — as primary treatment or surgi-

cal adjuvant

Steroids — intralesional injection, topical ointment,or as a surgical adjuvant

Pressure therapyRetinoic acid (topical)Verapamil (intralesional injection)5-fluorouracil (intralesional injection)PenicillamineColchicineThiopetaHyaluronidaseVitamin E (oral)Silicone sheet or gelInterferon — IFN-α-2b or IFN-γ

Excision Alone. Excision alone has not beensuccessful in eliminating keloids. Recurrence ratesrange from 45% to 93%.296,326 Apfelberg et al327

proposed using the keloid epidermis as an autograftafter keloid excision to avoid donor site morbidity,decrease the amount of tension on the closure, andto lessen the cosmetic deformity. Weimar andCeilley328 used the autograft technique with

Table 8Biochemical Alterations in Abnormal Scars

(Adapted from Aston SJ, Beasley RW, Thorne CHM, eds, Grabb and Smith’s Plastic Surgery, ed5. Philadelphia, Lippincott-Raven,1997, Ch 1.)


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adjunctive pressure therapy and steroid injections.Adams and Gloster329 recommend excision andsuprakeloid flap closure (Fig 10) with postoperativeradiation therapy for the successful treatment of anearlobe keloid.

Fig 10. Keloid of the earlobe: dissection from the epidermis andclosure with suprakeloid flap. The excision is followed byradiotherapy to the site to prevent recurrence. (Reprinted withpermission from Adams BB, Gloster HM: Surgical pearl: excisionwith suprekeloid flap and radiation therapy for keloids. J Am AcadDermatol. 47:307, 2002.)

Surgical Excision and Steroids. Treatment ofan earlobe keloid consists of a single intralesionalinjection of triamcinalone acetonide, 40mg/mL,through a 27-gauge needle. It should be verydifficult to inject the medication; if it injects freely,then the needle is incorrectly positioned. Approxi-mately 0.3mL of steroid is injected into the lesion.If the response is significant, the injection is re-peated after 1 month. If there is no response at 1month, the keloid is excised by the core tech-nique278 (Fig 11). Approximately 5mg of triam-cinalone acetonide, 10 mg/mL, is deposited in thewound at the time of excision. The wound is closedanteriorly and is allowed to granulate posteriorly.After reepithelialization has occurred, the patientis instructed to begin use of silicone gel twicedaily. Monthly steroid injections of the 40mg/mLconcentration are performed for 2–3 months toprevent recurrence.

Core excision of a dumbbell keloid on the ear-lobe with adjuvant steroids shows excellent curerates. The anterior wound is closed primarily andthe posterior wound is allowed to granulate.Salasche330 reports successful treatment of 6 patients

without recurrence at the 1-year follow-up period.Adjuvant therapy has become the standard of careto effect improved outcomes.

Laser Excision. Lasers are believed to wound insuch a way so as to minimize scar contraction. Bothcarbon dioxide and argon lasers showed early prom-ise in keloid excision, but long-term studies revealedrecurrence rates of up to 92% when used as asingle treatment modality.294,296,331–333 The mostpromising form of laser therapy seems to be the585nm flashlamp-pumped pulsed-dye laser (PDL),which has been effective in reducing pruritus,erythema, and the height of keloids, with improve-ment in 57% to 83% of cases.331–335 The best resultsare obtained when laser excision is combined withadjunctive therapy.

Steroids. Intralesional steroids are used oftenfor the initial treatment of keloids, but more com-monly they are the adjuvant treatment of choiceperioperatively. Steroids suppress the inflamma-tory phase of wound healing, decrease collagenproduction by the fibroblast, and control fibro-blast proliferation. Triamcinolone acetonide,40mg/mL, is the usual agent, and is administeredpreoperatively, intraoperatively, and/or postop-eratively. No single regimen has proved to bemost effective.

Fig 11. Core excision of a dumbbell keloid of the ear having botha posterior and anterior component. (Reprinted with permissionfrom Porter JP: Treatment of the keloid: What is new? OtolaryngolClin North Am 35:207, 2002.)


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Adverse reactions to the use of intralesional ste-roids may include local depigmentation orhypopigmentation, epidermal atrophy, telangiecta-sia, and skin necrosis. Systemic side effects andCushing’s syndrome are rare and associated withimproper dosages. Ketchum and colleagues336

injected up to 120mg triamcinolone intralesionallyat the time of excision, and noted 88% regressionto varying degrees and disappearance of prurituswithin 3–5 days. Complications included atrophy,depigmentation, and recurrence. Currently mostpractitioners do not administer such high doses;rather, monthly doses of ~12mg are recom-mended.337

Radiation Therapy. Radiation therapy has beenused for treating keloids since 1906.296 Used alone,radiation therapy is associated with a wide range ofcure rates (15%–94%).326

Radiotherapy is best used in conjunction withsurgical excision. When the lesions are first excisedand subsequently radiated, the response ratesincrease to 33%–100%.326 More recent studies showeven better response rates (64%–98%).326 In largekeloids resistant to treatment, radiotherapy offers areduction in recurrence rate, from 50%–80% with

surgery alone, to ~25% with combined surgeryand early postoperative radiotherapy (Table 9).338,339

Success seems to depend on the number of radsdelivered to the surgical site and start of RT imme-diately postoperatively. Preoperative irradiationdoes not offer any advantage. The usual dosage is15–20Gy administered over 5 or 6 treatment ses-sions. Possible complications include scar hyper-pigmentation and, rarely, malignant degenera-tion.340

Controversy abounds regarding the safety ofdelivering radiation to a benign tumor,341 fueled byanecdotal reports of malignant tumors developingafter RT of a keloid. Although the recommendeddose for the treatment of keloids is low, long-termfollow-up is needed to put this issue to rest.

Pressure Therapy. Pressure therapy is effec-tive in the treatment of hypertrophic scars andkeloids, especially after burn injury.342 This thera-peutic strategy is used in combination with othertreatment modalities (eg, silicone gels or sheets).The applied pressure should be 24–30mmHg toavoid excessive compression of peripheral bloodvessels. Maximum benefit is achieved from wear-

Table 9Reports 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 literaturereview. Plast Reconstr Surg 95:1051, 1995.)


30

ing the pressure appliance for 18–24h/d for at least4–6 months.296,343,344

Pressure is thought to decrease tissue metabo-lism and increase collagenase activity within thewound.272 Pressure techniques include various com-pression wraps and custom garments for large areas,or the use of large clip-on earrings after excision ofearlobe keloids.345 Pressure therapy requirespatience and perseverance, as continuous applica-tion of pressure is required for several months toobtain a satisfactory result.

Several authors report good response rates of90%–100% in patients treated with keloid excisionfollowed by pressure therapy,296,343,344 especiallywhen the keloid was located on the earlobe.Intralesional verapamil combined with 6 months ofpressure therapy after keloid excision resulted in a55% cure rate in one series.346

Interferon. Interferons interfere with the abilityof fibroblasts to synthesize collagen. Specifically,IFN-α-2b normalizes the collagen and glycosami-noglycan of the keloid.347 Complications of IFN-α-2b injection include flu-like symptoms of headache,fever, and myalgias. In a retrospective study, Bermanand Flores347 found lower recurrence rates withpostexcisional IFN-α-2b (18.7%) than with eitherexcision alone (51.1%) or postexcisional triam-cinalone injections (58.4%). Conejo-Mir et al348

report 0% recurrence at 3 years with the combina-tion of CO2 laser excision and IFN-α-2b injectionsfor keloids of the earlobe.

Interferon-γ is believed to work similarly to IFN-α-2b. There have been several anecdotal reports re-garding the benefits of IFN-γ in treating the keloid.Pittet et al349 reported improvement of hypertrophicscars in 7 patients who were given human recombi-nant gamma-interferon in twice-weekly intralesionalinjections for 4 weeks. Granstein350 and Larrabee351

have also reported modest success with gamma-interferon in a small number of patients.

A small pilot study by Broker et al352 followedthe course of patients with two keloids, one ofwhich was treated with IFN-γ injections and theother with placebo injections after excision. Only7 patients were enrolled in the study and 3dropped out by the 1-year follow-up examination.Both experimental and control groups had uni-formly poor results, with an approximate 75%recurrence.

Other researchers have used antitransforminggrowth factor-beta (anti-TGF-β) to decrease scar-ring in experimental animals.317 Tredget353

describes antagonizing the proliferative effects ofTGF-β2 and histamine with interferon-α-2b.

Imiquimod is an immune response modifier thatstimulates innate and cell-mediated immune path-ways, enhancing the body’s natural ability to heal.354

Imiquimod also induces the local synthesis andrelease of cytokines, including IFN[alpha],IFN[gamma], tumor necrosis factor-[alpha], andinterleukins-1, -6, -8, and -12 when topicallyapplied.355 A number of recent case reports andclinical studies document success with imiquimodunder conditions where interferons are also suc-cessful. Nightly application of topical imiquimod5% cream for 8 weeks after surgical excision of 13keloids from 12 patients resulted in no recurrenceof keloidal growth at 24 weeks.356

Silicone Gel Sheeting. The mechanism of actionof silicone gel sheeting is not known. Histologicexamination reveals no evidence of silicone leak-age into the tissues. Hydrocolloid dressings areocclusive and facilitate scar hydration, and are con-sidered to be safe in the treatment of wounds in theinitial stages of healing.357

Depending on the series, between 80% and 100%of patients show significant improvement of theirhypertrophic scars with silicone gel.358–360 In patientswith keloids, however, silicone gel is successful only35% of the time.360 Silicone gel sheeting may reducerecurrence rates after excision of keloids. It is a benignintervention that does not cause any problems andmay be useful as an adjunctive measure. In humantrials, topical silicone gel was used to treat 22 keloidsin 18 patients, with a significant response rate of86%.361 Possible drawbacks to silicone gel includepatient noncompliance (especially children) andoccasional rashes, skin breakdown, or difficultyobtaining adherence to the scar.362

The review by Shaffer et al288 summarizes andcompares all keloid treatments in the literature.

SURGICAL TREATMENT

Keloids that are resistant to corticosteroid injec-tion, pressure therapy, or other topical therapyshould be considered for surgical excision. Surgeryalone is associated with recurrence rates of 50%–


31

80% and is therefore indicated only in compliantpatients who are willing to undergo adjuvant therapypostoperatively to try to avoid a recurrence.363

Hypertrophic scars, although more responsive toappropriate surgery, also frequently require adju-vant treatment.

Guidelines for the surgical management ofabnormal scars are as follows:

• combination therapy—eg, surgery and corticos-teroids—is more effective in preventing recur-rence than any single modality

• for small scars, surgical excision and corticoster-oids are appropriate therapy

• for moderately large scars, pressure therapy shouldbe added to the surgery-steroid combination

• for very large, treatment-resistant scars, the bestresults are reported with a combination of sur-gery and postoperative radiotherapy

• pressure and irradiation are useful surgical adju-vants but are ineffective in the treatment ofestablished lesions

• skin grafts should be harvested from areas wherepressure can be easily applied

The goals of excisional scar revision are to redi-rect the scar, divide it into smaller segments, andmake it level with the adjacent skin. The locationand size of the scar will also influence the choice ofrevision procedure.364

Fusiform Excision

Fusiform excision is the most commonly usedtechnique of scar revision because of its simplicityand because it does not add to scar length. Ideallyan ellipse at least four times as long as it is wideshould be removed to prevent dog-ears. Fusiformexcision is indicated for short, linear, minimallywide but unsatisfactory scars that approximate theRSTLs. The technique is much less effective inaddressing depressed scars or wide hypertrophicscars resulting from primary wound closure.365

Bowen and Charnock366 recently described adouble-blade scalpel for excising long, linear scars,and reported excellent results in 27 widespreadabdominal scars.

Z-plasty

A Z-plasty entails creation of triangular transpo-sition flaps which are used to lengthen a contractedscar or to reorient a scar parallel to the RSTLs (Fig12). Although a single large Z-plasty often givesmore length, multiple small Z-plasties may bettercamouflage the scar.

Fig 12. Z-plasty angles and their theoretical gain in length. (AfterGrabb 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 gainlength at the expense of increased tension. Theusual Z-plasty angle is 60° and the resulting scar will


32

be 75% longer than the original minus 25%–45%lost to skin elasticity.218,367,368 Z-plasty scar revisionis 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 inclinationto the RSTLs

• severe trapdoor and depressed scars

• small linear scars not amenable to fusiform exci-sion

• most areas of multiple scarring

W-plasty

Unlike Z-plasties, a W-plasty breaks up thestraight-line configuration of a scar without addinglength to its axis (Fig 13). Since it requires excisionof additional tissue, it should not be used in scarsunder significant tension. W-plasty scar revision isindicated 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 sameplane across a scar to break up the scar cord andlengthen it.371 The tongue at the top of the Y stemcan be advanced to form a V without raising thedermis (Fig 14). This ensures a good blood supply.Running Y-V plasties are indicated in the manage-ment of some contracted burns scars and may beused in conjunction with W-plasties to break up alinear scar.

Serial Excision

Staged excision is appropriate for wide scarsthat cannot be excised completely without ten-sion. Although largely supplanted by tissueexpansion, serial excision remains simpler andmore 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 lengthof the limbs of the flap is tapered to avoid puckering. B, Ona curved scar, the angles of the inner aspect of the curve shouldbe 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 toPlastic Surgery. In: McCarthy JG (ed), Plastic Surgery. Philadel-phia, WB Saunders, 1990. Vol 1, Ch 1, pp 1-68.)

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


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Tissue Expansion

Full-thickness unscarred skin can be recruitedfrom areas adjacent to large hypertrophic scars andburn scar contractures by placement and gradualinflation of expanders. In a second stage, the scar isexcised and the expanded skin is used to resurfacethe tissue deficit.372 Tonnard et al373 described atechnique for scar-length reduction by circumfer-ential adjacent tissue recruitment using two semi-circular expanders.

Skin Stretching

The Sure-Closure device is discussed in theWound Closure section. The device has been pro-posed to excise and primarily close large scars onthe trunk and extremities.241

Miscellaneous

Dermabrasion. Dermabrasion removes the epi-dermis and partial-thickness dermis and smoothessurface irregularities. It is most effective for mildlyelevated or depressed scars, particularly acne scars.Dermabrasion is often used as an adjunct to scarexcision.374,375

Scalpel Sculpturing. Snow et al376 reported usinga #15 scalpel blade to microshave and feather theskin edges as an alternative to dermabrasion. Otherauthors have used razor blades to contour small,mildly elevated scars.377

Cryosurgery. The first prospective study ofcryosurgery for abnormal scars was recently reportedby Zouboulis et al.378 Good-to-excellent responseswere seen in 57 of 93 White patients treated withnitrous oxide once a month for at least 3 months.Significant pain occurred in 32% of patients andlesional pigmentary changes were seen in 11%.

Laser. Lasers have been applied to the manage-ment of abnormal scars because of their ability toremove lesions precisely with minimal injury tonormal adjacent tissue. The Nd:YAG, CO2, andargon lasers have been used with modest suc-cess.379,380 Dierickx et al381 reported 80% improve-ment in 26 patients with erythematous or pigmentedscars after treatment with the flashlamp-pumpedpulsed dye laser. Alster and Nanni382 report symp-

tomatic improvement of hypertrophic burn scarsafter treatment with the 585nm pulsed dye laser,namely improved scar pliability and texture anddecreased erythema.

EXOTIC WOUNDS

This section will address some of the more exoticwounds, includingExtravasation injuriesRadiation burnsHigh-pressure injuriesChemical burnsBallistics and high-velocity missile woundsAquatic animal woundsBites — snakes, spiders, centipedesStings — scorpions and caterpillars

EXTRAVASATION INJURIES

Leakage of solution from a vein into the sur-rounding tissue spaces during intravenous adminis-tration may lead to severe local tissue injury. Adultpatients 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. Theinjury can be classified as necrotic, irritant, or vesi-cant. The most common agents involved areosmotically active chemicals (eg, total parenteralnutrition), cationic solutions (eg, potassium ion [K+],calcium ion [Ca2+]), and cytotoxic drugs.385

Certain groups of patients are prone to extrava-sation injury: Babies in special care units are atgreater risk because of their immature skin andtheir frequent need for antibiotics or intravenouselectrolyte and nutritional support. Elderly patientsmay be unable to report the pain from extravasa-tion injury and the general fragility of their skin andveins make them more susceptible to injury.386

Cancer patients often have fragile veins that aredifficult to cannulate. Patients who are unable tocommunicate or have a decreased level of con-sciousness may have extravasation injuries that gounnoticed.


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The sequelae of extravasation are often moreserious than the original injury and are oftenunderestimated. Common sites of injury are thedorsum of the hand and the antecubital fossa, wherethere is little soft-tissue coverage.385 Extravasationmay result in large wounds that require debride-ment and coverage with a split skin graft or localflap, and when next to a major artery in the fore-arm or leg, extravasation may lead to amputation.Severe damage to the underlying nerves and ten-dons can also happen. Chemotherapeutic agentsmay produce an insidious injury because they spreadto the surrounding tissue and produce indolentulcers that resemble radiation necrosis.385

The extent of damage after extravasation injurydepends on the toxicity of the drug, the site ofextravasation, the amount that has leaked out, andthe general nutrition of the patient. The clinicalpresentation varies. There may be a loss of bloodreturn at the cannula site, which may be accompa-nied by pain (a burning sensation). Persistent painsuggests a more severe injury.387 Erythema may bepresent, accompanied by swelling of the surround-ing area and local blistering, suggesting at least apartial-thickness injury, which may also be associ-ated with mottling and darkening of the skin. Early,firm induration and pain are good indicators of even-tual ulceration, which may lead to eschar beneathwhich is the ulcer cavity.

A wide array of treatments has been proposed,ranging from no intervention to early aggressiveexcision.388–390 If the extravasated drug is an antibi-otic or hypertonic solution, application of ice to thearea, elevation, and monitoring the patient for 48hours are usually sufficient.391 Scuderi and Onesti392

recommend local injection of copious amounts ofsaline and topical application of corticosteroids ifonly a few hours have elapsed since injury.

Extravasated high osmolarity contrast medium(such as is commonly used for contrast CT scans) istreated with 4–6 small incisions around the areaof extravasation. A blunt-ended liposuction can-nula with side holes is inserted in the incisions andused to aspirate extravasated material and subcu-taneous fat. Saline is then injected through thesame cannula, up to 200mL. After extensive irri-gation, the saline is aspirated using the liposuctiondevice.393

Khan and Holmes394 list five mechanisms ofextravasation necrosis:

1) direct cellular toxicity (chemotherapeutic agents,pentathol)

2) osmotically active substances with an osmolalitygreater than that of serum (parenteral nutrition,contrast dye)

3) ischemic necrosis from vasopressors and cationicsolutions (epinephrine, dopamine)

4) mechanical compression5) bacterial colonization

The authors devised a kit and protocol for therapid treatment of extravasations caused by cyto-toxic drugs.394 The kit contains hydrocortisonecream, injectable hyaluronidase and lidocaine,sodium chloride infusion, and a number of syringesand needles. The aim is to flush out as much of thecytotoxic agent as possible.

When preventive measures and drug therapyare insufficient to avert tissue necrosis, or if theinjury is extensive or more than a few hours old,early surgery is indicated. Gault386 reviewed a seriesof 96 patients with extravasation injuries seen attwo London hospitals during a 6-year period. Ofthe 44 patients treated by either saline flushout(37), liposuction (1), or both (6), 86% healed with-out soft-tissue loss. Examination of the flushout fluidconfirmed the presence of the extravasated mate-rial. Early treatment was associated with a goodoutcome. Patients who were referred late sufferedskin necrosis and significant scarring around ten-dons, nerves, and joints, and many required exten-sive reconstruction.

Most authors now recommend early detectionand excision of all affected tissue followingAdriamycin extravasation.395–398 The excision maybe guided by fluorescence microscopy;396,397

delayed closure is indicated.

RADIATION INJURY

The morphologic and functional changes thatoccur in noncancerous tissue as a direct result ofionizing radiation can range from mild to extremelydebilitating or life-threatening. Ionizing radiationcauses damage to tissue by means of energy trans-ference. Free radicals are formed and cause intrac-ellular and molecular damage. The primary targetsof ionizing radiation are cellular and nuclear mem-branes and DNA. The susceptibility of an individual


35

cell to radiation damage is directly proportional toits mitotic rate. The most sensitive cells are thosewhich divide rapidly, such as cells of the skin, bonemarrow, and gastrointestinal tract. In addition tosensitivity of the exposed cell, morbidity fromradiation depends on the dose received, time overwhich the dose is received, volume of tissue irradi-ated, and type of radiation.399 Cellular changesresulting from low-dose radiation are probably dueto an apoptotic mechanism, whereas changesrelated to high-dose radiation are probably due todirect cellular necrosis.

The direct effects of radiation can be immedi-ate, acute (days to weeks), or delayed (months toyears). Acute effects result from necrosis of the rap-idly proliferating cell lines. A transient, faint erythemamay appear during the first week of treatment dueto dilation of capillaries and may be associated withan increase in vascular permeability. Radiationinhibits mitotic activity in the germinal cells of theepidermis, hair follicles, and sebaceous glands. Epi-lation and dryness of the skin occur. By the third orfourth week of radiation, typical erythema is local-ized to the radiation field and the skin is noticeablyred, edematous, warm, and tender. Larger vesselsmay be obstructed by fibrin thrombi, edema isprominent, and there may be small foci of hemor-rhage.400 Cellular exudate is rare. If the total radia-tion dose to the skin does not exceed 30Gy, theerythema phase is followed during the fourth orfifth week by a dry desquamation phase character-ized by pruritus, scaling, and an increase in mela-nin pigmentation in the basal layer. Within 2 monthsthe inflammatory exudate and edema have sub-sided, leaving an area of brown pigmentation.

If the total radiation dose to the skin is >40Gy,the erythema phase is followed by a moist desqua-mation phase. This stage usually begins in the fourthweek and is often accompanied by considerablediscomfort. Bullous formation occurs above the basallayer and sometimes just below the epidermis. Even-tually the roofs of the bullae are shed and the entireepidermis may be lost in portions of the irradiatedarea. Edema and fibrinous exudate persist. In theabsence of infection, reepithelization of thedenuded skin usually begins within 10 days. Ulcersmay appear 2 weeks or more after radiation expo-sure. These ulcers are a result of direct necrosis ofthe epidermis; they usually heal but tend torecur.399,401

Approximately 1 year after radiation treatmentthe epidermis is thin, dry, and semitranslucent, withvessels easily seen. Hair follicles and sebaceousglands are usually absent. Some sweat glands mayalso have been destroyed. In time, increasing fibro-sis of the skin is present. Much of the collagen andsubcutaneous adipose tissue are replaced by atypi-cal fibroblasts and dense fibrous tissue that maycause induration of the skin and may limit move-ment. In radiation injury of soft tissue, fibrinousexudate accumulates under the epidermis. Char-acteristic features of delayed radiation lesions areeccentric myointimal proliferation of the smallarteries and arterioles as well as telangiectasia. Thesechanges may progress to thrombosis or completeobstruction. Delayed ulcers are more common thanacute ulcers and result from ischemic changes insmall arteries and arterioles; they heal slowly andmay persist for several years. Irradiated skin in thechronic stage is thin, hypovascularized, extremelypainful, and easily injured by any slight trauma orinfection.399,401

Skin reactions to radiation should be treated earlyto prevent complications later. Keeping the skinmoist and pliable to prevent fissures and cracks andfree of infection is extremely important. Mendel-sohn et al402 has compiled a list of products to treatradiation-induced skin changes (Table 10). If anulcer develops, the normal wound care protocolsshould be initiated. In severe cases, widedebridement and a skin graft or flap coverage maybe necessary.

Treatment with hyperbaric oxygen accelerateshealing in some patients,403,404 but its effectivenessin soft-tissue necrosis from radiation injury isunproven. Experimental therapies include topicalTGF-β1,405 granulocyte-macrophage colony-stimulating factor (GM-CSF),406 orgotein (a Cu/Znchelate with superoxide dismutase),407 topical vita-min C,408,409 topical corticosteroids,410 glucor-ticoids,411 NSAIDs,412 aloe vera gel,413,414 helium-neon laser treatments,415 and oral pentoxifyllinetreatment.416

HIGH-PRESSURE INJECTION INJURIES

High-pressure injection devices such as are usedfor painting, cleaning, degreasing, etc. can producepressures of 600–12,000psi.417,418 The substanceenters the skin through a seemingly insignificant


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wound and rapidly spreads through the tissues alongfascial planes. In the hand, the injected materialcan course volar to the tendon sheath and extendinto the forearm. The tendon sheath is rarelybreached. The degree of injury varies with theinjection pressure and type of injected material.With high injection pressures and large amounts ofcaustic substances, tissue damage can be so exten-sive that salvage may not be possible. Amputationrates after high-pressure injection injuries range upto 48% in the literature.419

Water, low volume vaccines, and air generallycause no serious damage.420,421 In these cases medi-cal treatment with wide spectrum antibiotics andtetanus prophylaxis are usually all that is needed.422

Other times the pressure itself is responsible for theinitial damage; a compartment syndrome may beinduced immediately by the amount of materialinjected and later by the inflammation elicited.423

Digital injection injuries do worse than palmarinjuries because of the limited space available forexpansion.423,424

An immediate progressive toxic effect has beenshown to take place in cases of paint and paintthinners,425 and a foreign body reaction occurs if

the material is not removed, leading to fibrosis anddraining sinuses.424

The nature of the injected material is probablythe most important factor in the subsequent injury.Injected paint wounds have a worse outcome thanthose injected with oil or grease. Spirit-based paintscause damage by disintegration of cell membranes,whereas oil-based paints cause an intense inflam-matory response. Latex paints in a water base arethe least noxious.419

Not surprisingly, delayed and conservative treat-ment of high pressure injection injuries is associ-ated with very poor results and frequent amputa-tion.424,426,427 The proper management of theselesions is primarily surgical, with immediate removalof the foreign material, debridement, cleansing ofnecrotic areas, and insertion of a drain. X-ray evalu-ation should precede the surgical treatment, bothto detect fractures and to guide the decompres-sion. Angiograms are also useful to show any areasthat are not being perfused. Medical treatmentincludes tetanus and antimicrobial prophylaxis andantibiotic administration. A postoperative physicalrehabilitation program will help reduce the degreeof functional impairment.426

Table 10Skin 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.)


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CHEMICAL BURNS

The proper treatment of chemical burns is tai-lored 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 Itconsists of a mixture of sodium bicarbonate (10%),sodium hydroxide (60%), sodium sulfide (4%), so-dium thiosulfate (5%), and sodium sulfate (4%) at atemperature of 85–95°C. Surgical treatment beginswith irrigation with tap water. Silver sulfadiazinecream and sodium chloride solution occlusive dress-ings are applied twice daily. Debridement and skingrafting procedures may be necessary.428

Cement

Cement burns are either alkaline or heat related.Wet cement is roughly 64% calcium oxide and21% silicon oxide and has a pH of ~12.5. Abra-sions by the coarse cement allow the alkali to enterthe skin and cause increased tissue destruction. Themost frequently affected areas are the knees, calves,and feet. Because the initial contact is typicallypainless, the injury progresses from prolonged con-tact with the skin.429,430 In time there is reddishdiscoloration of the contact areas, followed by agradual change to a deep purple-blue color and thismay go on to painful burns, blistering, and ulcer-ation.429,431 Treatment consists of removing the agentwith a cloth followed by washing the affected areawith soap and copious amounts of running water.431

Chromic Acid

Chromic acid is an industrial chemical used forelectroplating in alloy and dye production. Chro-mic acid burns produce coagulative necrosis andmay lead to systemic toxicities, including gastrointes-tinal hemorrhage, vomiting, diarrhea, renal orhepatic failure, CNS disorders, anemia, andcoagulopathies. An exchange transfusion may berequired to remove hexavalent chromium boundto hemoglobin from the circulation. Circulatingchromium may also be removed by peritonealdialysis or by hemodialysis the day after the burnoccurs.432,433

Treatment initially involves water irrigation oruse of phosphate buffer or 5% thiosulfate soaks,which convert hexavalent chromic ion into a lesstoxic trivalent form. Topical use of 10% calciumethylenediamine tetraacetic acid (EDTA) ointment;5–10% sodium citrate; lactate- or tartrate-soakeddressings; or cream containing ascorbic acid, sodiumpyrosulfate, ammonium chloride, tartaric acid, andglucose is recommended to prevent further absorp-tion. Dimercaprol, ascorbic acid, or sodium cal-cium edetate are often used as systemic treat-ment.432,433

If the burn is <2% TBSA and is superficial, cal-cium EDTA dressings may be used.432,433 For burns>2% TBSA, immediate wide excision reduces sys-temic chromium absorption, and should be followedby split-skin grafts. Peritoneal dialysis in the first 24hours prevents parenchymal chromium uptake.

Formic Acid

Formic acid or formate is used industrially as adescaling agent, as a rubber processor, and as atextile tanning substance. The main concern incases of formic acid burn is systemic acidosis, whichimpairs the elimination of formic acid because ofincreased reabsorption in the proximal tubule.434

Patients often present with hypotension, intravas-cular hemolysis (because of cytotoxic formateeffects), hematuria, hemoglobinuria, kidney failure,CNS depression, and evidence of other organ dam-age.434

Treatment is similar to that of other acid burns.All clothing is removed and the patient is thoroughlywashed with water. Internally, the formate isremoved or neutralized with intravenous hydrationand aggressive bicarbonate therapy. Folic acid canbe administered to accelerate formate breakdown.Dialysis may be necessary.

Hydrofluoric Acid (HF)

HF is used to frost, etch, and polish glass andceramics; to remove sand from metal castings; toclean stone and marble; and to treat textiles. HF isalso prevalent in the manufacture of fertilizers, pes-ticides, solvents, dyes, plastics, refrigerants, high-octane fluids, rust removers, aluminum brighten-ers, and heavy-duty cleaners.435,436 Although anacid, HF causes injury similar to an alkali because it


38

reaches deeply into tissue. Because of its ability topenetrate lipid membranes, HF breaches cell mem-branes and binds calcium and magnesium ions withinthe cell. The initial corrosive burn causes little dam-age compared with the secondary damage pro-duced by the fluoride ions. The F ions produceextensive liquefaction of soft tissues and decalcifi-cation and corrosion of bone. Most exposuresinvolve dilute HF on small spots. Exposure of con-centrated HF to even small areas (~2%) of the bodyoften has a fatal outcome.435,436

The clinical presentation is of blanched tissuewith surrounding erythema and immediate severepain. Edema and blistering occur within 1–2 hours,then gray areas followed by necrosis and deepulceration within 6–24 hours and possible tenos-ynovitis and osteolysis. Even burns from dilute HF,if left untreated, will progress to similar destruc-tion.436 In addition to the obvious burn, systemiceffects of hypocalcemia and hyponatremia must alsobe addressed. Cardiac arrhythmia often results fromhypocalcemia, and free fluoride ions may causerespiratory arrest and ventricular arrhythmia.436

Treatment consists of copious irrigation for about20 minutes to clean the wound of any unreactedchemicals and to dilute the chemical that is in con-tact with the skin. Washing is extremely importantin HF burns because the toxic properties derivefrom complex ions that are not present at concen-trations of <10%. Some authors advocate the useof neutralizing agents such as sodium bicarbonateand phosphate buffer.437 After washing, the freefluoride ions must be converted to an insolublefluoride salt by means of benzalkonium chloride,either 0.2% (Hyamine 1622) or 0.13% (Zephiran).Use of these compounds is controversial becauseof the discomfort they cause, the potential toxicityof Hyamine, and the possible ineffectiveness ofHyamine in deeper tissues.437

Minor burns may be treated with topical 2.5%calcium gluconate jelly. If calcium carbonate gel isused, large amounts may be required for treatmentand it may stain the skin. Some authors recom-mend a subcutaneous injection of 10% calciumgluconate on the periphery of the burn, but gener-ally this treatment is reserved for patients who havea central, hard, gray area with surrounding erythemaand those with severe, throbbing pain.437 Infiltra-tion therapy is invasive and may introduce infec-tion and hypercalcemia. In patients with severe

hand burns, consider an arterial infusion of calciumsolution via the brachial, ulnar, or radial arteries.Monitoring of serum calcium and magnesium lev-els is extremely important.437

The role of surgery is to debride blisters and toexcise any necrotic tissue from the burned area sothat treatment with topical agents or infiltration maybe effective. Excision of the involved tissue is oftenattempted to reduce systemic toxicity and to aid inwound treatment.437

Phenol

Phenol has antiseptic properties and is used inchemical face peels, nerve injections, and as a topi-cal anesthetic for skin and mucous membranes.438

Acute poisoning may occur from phenol absorp-tion. The patient experiences initial bradycardia,followed by tachycardia and a decrease in bloodpressure. Systemic toxicity is proportional to theplasma concentration of free phenol. Phenoldepresses the CNS and may lead to respiratory arrest;it may also produce peripheral nerve demyeliniza-tion and RBC lysis, central lobular necrosis of theliver, and renal failure through direct damage tothe glomeruli.438 Skin damage of acute phenol poi-soning includes denaturation and necrosis followedby gangrene. Typically there is a partial-thicknesschemical burn accompanied by severe pain, swell-ing, and redness. Phenol may have some localanesthetic properties, which allow extensive dam-age to occur before the patient feels pain.438

Treatment consists of decontamination with a50% concentration of PEG 300 or 400 and exten-sive lavage with soapy water. A solvent cleanermay also be used to remove phenol from the skin.Irrigation with water, glycerin, or Zephiran has alsobeen recommended. The burn wounds are cov-ered with a silver sulfadiazine dressing.438

White Phosphorus

White phosphorus is used in the manufacture ofvarious insecticides, fertilizers, and incendiaryweapons. Phosphorus burns may be caused byeither liquid or solid white phosphorus. When whitephosphorus contacts the skin, a painful, necrotic,yellow chemical burn with a garlic-like odor results.The phosphorus is extremely lipid-soluble andreadily penetrates the dermal layers. As skin pen-


39

etration progresses, white phosphorus continues tobe oxidized until it is removed by debridement orconsumed by oxidation.439

White phosphorus is difficult to remove and oftenbecomes embedded in the skin. Immediate treat-ment consists of prompt removal of all clothing incontact with the agent. The skin is then washedwith cool water to end oxidation of the white phos-phorus. Greasy dressings should be avoided becausethey contribute to tissue permeability. The phos-phorus is then neutralized with a dilute solution ofcopper sulfate (1%–5%) briefly applied to the wound(because of the danger of copper toxicity). Bicar-bonate may be used to neutralize the pH of thewound.439

BULLET WOUNDS

Santucci and Chang440 reviewed the tissue effectsof different bullet types, as follows:

Jacketed bullets travel faster than 2000ft/secand are used primarily in assault rifles. They aremore likely to wound than to kill. Hollow-pointbullets are designed so that the tip flattens andexpands on impact, to 2–3X the original diameter.They cause more tissue damage and a larger per-manent wound cavity. These bullets are prohibitedby the Geneva Convention for military use but aresold legally to U.S. civilians. Exploding bullets aredesigned to detonate on impact, but do not explodereliably. Surgeons must be careful when handlingthese bullets, which should always be grasped withforceps. PTFE (cop killer) bullets have a steel ortungsten core coated with PTFE and are intendedto penetrate Kevlar vests. Similarly, armor pierc-ing rounds have a hardened steel or tungsten coredesigned to penetrate light military armor of trucksand other vehicles. Black talon bullets have areverse-tapered hollow point designed to open intopetal-like blades that cut tissue as it spins into thewound. These bullets should always be graspedwith forceps or hemostats because the razor-sharpblades will easily cut the surgeon’s fingers. Fran-gible bullets, eg, the Glaser Safety Slugs, use alightweight cup of jacketed lead filled with smalllead shots. When the bullet hits its target, the cupcollapses and empties its shot contents into tissue,causing massive destruction at a relatively superfi-cial level. A large caliber round at close rangecauses severe, widespread tissue damage.

Shotshells are meant to turn handguns and smallrifles into minishotguns. Shotgun injuries are dev-astating at close range. Air bursting ammunitionwill be fired from US Army M-16 rifles in the nearfuture. When fired, high explosive, air burstingammunition will detonate at a prescribed distanceto send shrapnel to multiple targets. The projectedincrease in wounding power is 4-fold over standardrifle rounds.

The authors440 dispelled some misconceptionsabout high velocity projectiles, primarily that ballis-tic wounds require massive debridement. Theirextensive review of the literature led them to thefollowing conclusions:1) It is not true that high velocity weapons always

cause more tissue damage than low velocityweapons. In fact, the fastest bullets are just aslikely to keep traveling past the victim after leav-ing the body and impart little wounding energyonto the target.

2) It is not a good idea to debride the bullet pathup to 30X the diameter of the bullet; this mayactually harm the patient. Overdebridement isto be avoided.

3) The current recommendation is to debrideobviously detached and nonviable tissue, thenreexamine the wound after 2 days for additionaldebridement if necessary.

WOUNDS BY AQUATIC ANIMALS

The treatment of wounds inflicted by some marinevertebrates, from stingrays to sea snakes, is summa-rized in Table 11.

Marine wounds easily become infected, and assuch most wounds should be left to heal second-arily. Special culture media are required for isola-tion of certain marine organisms. Infected woundsshould also be cultured for routine aerobes andanaerobes. Management of marine acquired infec-tions should include therapy against Vibrio spp. Anypatient with a marine acquired wound who devel-ops rapidly progressive cellulitis or myositis shouldbe suspected of having Vibrio parahemolyticus orVibrio vulnificus infection.441

Soft-tissue infections are common after alligatorand crocodile bites, and broad-spectrum antibio-tics should be administered prophylactically. A vari-ety of gram-negative aerobes including Aeromonas


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hydrophila, Acinetobacter, Citrobacter, Entero-bacter, Yersinia, Proteus, and Pseudomonas; anaer-obes such as Bacteroides, Clostridium, Fusobacte-rium, and Peptococcus; and fungi such as Candida,Aspergillus, and Torulopsis have been cultured fromthe mouths of alligators.442 The same principles ofdiagnosis and treatment apply for alligators bites asfor shark attacks, including the administration oftetanus toxoid vaccine.

Wounds from stinging animals should be soakedin hot water as soon as possible to inactivate anyheat-labile components of the venom and perhapsto help reverse local toxin-induced vasospasm andtissue ischemia.441,443,444 This should be continuedfor 30–90 minutes or until the pain is relieved. Ifpain is not controlled with the hot water soak, aregional nerve block or local infiltration withbupivacaine can be performed.441 Delayed pri-mary wound closure may be performed later.

BITES

Snakes

Venomous snakes are responsible for 8000 ofthe 45,000 snake bites reported in the U.S. annu-ally,445 yet fewer than 15 cases per year are fatal.446

In other parts of the world, however, approximately30,000 fatal snake bites are sustained annually.447

These figures underscore the importance of promptand appropriate treatment of snake bites.

A regional poison-control center (which in theU.S. may be reached through the national hotline,800-222-1222) should be contacted for assistancein treating patients who have been bitten by a snake.These centers are staffed by persons who have beentrained in all types of poisoning and maintain a listof consulting physicians throughout the country whoare experienced in the management and treatmentof bites from venomous snakes.

Pit Vipers

The vast majority of venomous snake bites inNorth America are by pit vipers (Crotalidae). Pitvipers are distinguished by a heat-sensing pit locatedbetween the eye and the nostril, and are most com-mon in the southern U.S. This family of snakesincludes the cottonmouth, copperhead, and rattle-snakes. Pit viper venom contains at least 26 enzymesand 69 enzymatic peptides capable of producingextensive local tissue necrosis.448 Systemic enveno-mation increases capillary permeability, which mayinduce coagulopathy, shock, and acute renal fail-ure.449

Proper patient assessment should include identi-fication of the species of snake, its size, the pres-ence or absence of discrete fang marks, and anyevidence of local or systemic toxicity. The easternand western diamondback rattlesnakes account formost fatalities. Deaths typically occur in children,in the elderly, and in people who are either not

Table 11Emergency 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.)


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given antivenom or receive too little of it or toolate.446

The current treatment for snake bite is summa-rized by Seiler et al448 as follows (Table 12):

• Incision and suction. This technique is onlyeffective if perfomed within 45 minutes of thebite, and thus is of limited value in the emer-gency department. A linear incision should bemade through skin only, across the fang marksand slightly beyond.450 Suction is applied with aSawyer venom extractor.

• Loose tourniquet. A loosely applied tourniquet willreduce venom dissemination from the affectedlimb by 50%. The tourniquet should be applied 1hour after the snake bite only if a significant delayin hospital transport time is anticipated. Tourni-quets that are too tight will exacerbate tissue lossfrom the injured extremity.448

• Antibiotics and tetanus prophylaxis. Both mea-sures are appropriate. Rattlesnake fangs may har-bor gram negative organisms, and clostridialinfections have been reported.451,452

• Surgical debridement. Wound debridement isindicated for the removal of all necrotic tissue.Because most of the injected venom remains inthe subcutaneous tissue for a few hours, someauthors recommend aggressive early local exci-sion to remove the contaminated tissues.452,453

Others advocate a more conservative ap-proach.454,455

• Compartment pressure release. Severeenvenomations by rattlesnakes may be associ-ated with increased compartment pressure.The clinical diagnosis requires objective evi-dence of elevated compartment pressure to>30mmHg. The bite site should be elevatedand the patient given an additional 4–6 vials ofFabAV in 1h.446 The extra antivenom shouldeffectively neutralize the venom componentsand reduce compartment pressure. Fasciotomiesare controversial and may actually prolong therecovery.

• Antivenom. Indications for the use of antivenomhave not been strictly defined. Most authorsreserve antivenom administration for confirmedcases of envenomation by a medium to largesnake, particularly a rattlesnake; for patients with

signs and symptoms of systemic envenomation;and for children under age 12.454,456–458

After rattlesnake bites, signs of worsening localinjury (pain, swelling, and ecchymosis), coagulo-pathy, or systemic effects (hypotension and alteredmental status) dictate administration of anti-venom. FabAV is a lyophilized antivenom. Eachdose must be reconstituted and then diluted to avolume of 250mL in a crystalloid fluid before beingadministered. The initial dose is given by slowinfusion for the first 10min, and the infusion ofthe rest of the dose is completed over the courseof 1h. The dose of antivenomn is correlated withthe clinical severity of envenomation. In mostreported cases, 8–12 vials are sufficient to estab-lish initial control.459 Skin testing is unreliable inpredicting the development of immediate (ana-phylaxis) or delayed (serum sickness) hypersensi-tivity reactions to antivenom. Because the com-plications of antivenom administration can be life-threatening, it should be used selectively andjudiciously.460,461

Other types of therapy for crotalid bites includehyperbaric oxygen, cryotherapy, corticosteroids, andelectroshock. None of these has proved efficacy.448

Coral Snakes

Only one other snake indigenous to NorthAmerica poses any serious threat to man, andthat is the coral snake. Unlike pit vipers, coralsnakes possess a potent neurotoxic venom con-sisting chiefly of acetylcholinesterase. Coral-snakeenvenomations produce little or no pain but mayresult in tremors, marked salivation, and changesin mental status, including drowsiness andeuphoria. The neurologic manifestations are usu-ally cranial-nerve palsies such as ptosis, dysar-thria, dysphagia, dyspnea, and respiratory paraly-sis.

The onset of neurotoxic effects may be delayedup to 12h.446 Once manifestations appear, it maynot be possible to prevent further effects or reversethe changes that have already occurred. Althoughlocal tissue destruction is minimal, envenomationmay cause respiratory paralysis and immediate death(Table 12). Subacute deaths are usually due toaspiration pneumonia.462


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Spiders

Although all spiders are venomous, only a hand-ful of spiders are dangerous to man from among themore than 100,000 species worldwide. Two NorthAmerican species, the black widow and the brownrecluse, are capable of penetrating the skin andinjecting sufficient venom to inflict serious injury.

Black Widow

The black widow spider (Latrodectus mactans)is widely distributed throughout the continentalUnited States. Although both sexes carry venom,only the female spider is large enough to causesignificant envenomation in man.463 The venom isa potent neurotoxin that causes an irreversible block-ade of nerve conduction. The initial sharp pain atthe envenomation site is often accompanied bytwo small red marks—the fang punctures. Within20 to 30 minutes of the bite, neurologic signs andsymptoms begin to manifest, including first local-ized and then generalized muscle cramps, abdomi-nal pain, restlessness, perspiration, and occasionallyconvulsions or shock. If the patient is not treated,milder symptoms may linger for days or weeks.464

Pennell et al465 recommend the following thera-peutic regimen (Table 12):

• Calcium gluconate. A 10mL dose of a 10% solu-tion of calcium gluconate is administered intra-venously over 15–20 minutes. If this is effectivein controlling pain, the diagnosis of black widowenvenomation is confirmed.

• Muscle relaxants. One ampule of metho-carbamol (Robaxin) or 5–10mg of diazepam(Valium) may be given.

• Black widow antivenin. A single 2.5mL vial ofLyovac is administered intravenously in severelyenvenomated patients.

At greatest risk of an adverse outcome from blackwidow bites are young children, the elderly, andpeople who have underlying medical problems.These patients should be monitored closely andtreated aggressively.466

Brown Recluse

The brown recluse spider (Loxosceles reclusa) iscommon throughout the southern United States.

Although nondescript in appearance, the spider maybe distinguished by its long slender legs, fiddle-likemarkings on its dorsal thorax, and shiny brownexoskeleton.467 The bite usually goes unnoticed atfirst. Within several hours, however, increasing painis accompanied by erythema and blistering at thepuncture site, which frequently has a pale halo.Over the next few days, a central ulceration mayspread to adjacent skin, resulting in extensive tissuedestruction and occasional limb loss.

Systemic envenomation is uncommon but maycause hemolytic anemia, thrombocytopenia, anddisseminated intravascular coagulation. Five of thesix reported deaths from brown recluse bites havebeen in children.468,469

Treatment remains controversial. Dapsone, ananti-leprosy drug, has been advocated for the pre-vention of tissue necrosis. Oral administration ofdapsone (100–200mg q.d. x 10–25d) inhibits neu-trophil migration. Patients must be selected care-fully and monitored closely, since dapsone mayinduce a dose-dependent hemolytic anemia oragranulocytosis.467,470 Surgical excision may resultin significant scarring and soft-tissue defects anddoes not appear to inhibit the spread of venom.Conservative surgical debridement limited toinfected or obviously necrotic tissues is appropriate(Table 12).

Centipedes

Like spiders, centipedes are venomous, and anycentipede with large-enough fangs to penetratehuman skin has the ability to envenomate humans.Centipede envenomation usually results in burningpain, local swelling, lymphangitis, and lymphaden-opathy. Symptoms may persist for weeks and thendisappear, only to recur. Systemic reactions in theUnited States are rare. Treatment is symptomatic,and infiltration of the bitten area with lidocaine orother anesthetic agent promptly relieves pain. Teta-nus prophylaxis should be provided.471

STINGS

Scorpions

In 2002 there were 15,687 calls to U.S. poisoncontrol centers related to scorpion stings. Of these,485 (3%) required medical attention, 2 resulted in


43

death, and 8 had major complications.472 World-wide there are an estimated 5000 deaths from scor-pion stings every year.

Scorpions have a stinger at the end of their tailthrough which they introduce venom that immobi-lizes their prey. The size of a scorpion does notcorrelate with its aggressiveness or the potency ofits venom. Scorpions can control the amount ofvenom released per sting depending on the victim’ssize, and can sting repeatedly and rapidly whenfaced with large prey. In the United States andMexico, the small Centruroides scorpions accountfor the majority of severe human envenomations.473

Scorpion venom varies among species, butgenerally is a mixture of single-chain polypeptidescontaining neurotoxins that block ion channels,particularly sodium and potassium. A pronouncedacetylcholine and catecholamine release triggerssecondary effects. The most notable aspect of ascorpion sting is significant pain at the puncture sitewith little redness and edema. Typical adults expe-rience local pain and some paresthesias extendingalong the affected limb that can last for several hours,but have minimal systemic effects. Systemicenvenomation is the cause of most deaths in chil-dren and the elderly. Initially there is a transientexcess cholinergic tone at the neuromuscular junc-tion resulting in salivation, lacrimation, urinaryincontinence, defecation, gastroenteritis, and eme-sis (SLUDGE syndrome). The subsequent norepi-nephrine release causes tachycardia, hypertension,

hyperpyrexia, myocardial depression, and pulmo-nary edema that can be fatal. The pain, paresthesias,and tachycardia can persist for 2 weeks.473

Caterpillars

Caterpillars are the larval stages of moths andbutterflies. There are approximately 50 species ofcaterpillar in the United States that can causeenvenomation, with symptoms that range from apainful sting to dermatitis and conjunctivitis. Thepuss caterpillar, Megalopyge opercularis, is one ofthe more toxic species, sometimes resulting in epi-demics of envenomation. It is common in the south-eastern United States and its body has toxin-containing spines. A person who brushes againstthis caterpillar experiences an intense burning sen-sation at the contact site, followed shortly by red-ness, swelling, and proximally radiating pain.Vesicles usually appear, and pain and pruritus canlast for days.474 The swelling can be impressiveand involve an entire limb. Some patients go intoshock or have seizures.475

Treatment consists of local wound care and cleans-ing, immobilization and elevation of the affectedextremity and tetanus prophylaxis. Any embeddedbroken-off spines are removed with adhesive tape.Diphenhydramine may be necessary for the reliefof pruritus. Early application of ice may providepain relief, but morphine or meperidine may benecessary in more severe cases.475

Table 12Symptoms and Treatment of Patients after Snake and Spider Bites


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