wound-healing-reading-chapters

WOUNDS AND SCARS 

George Broughton II MD PhD and Rod J Rohrich MD 

WOUND HEALING 

The ability to heal wounds by forming scar tissue 

is essential to the survival of all higher species. 

Indeed, wound healing is the very foundation of 

our specialty. Although we can now intervene in 

some chronic wounds to accelerate healing, a conservative 

and noninterventional approach is still the 

standard of care of acute wounds in an otherwise 

healthy person. 

HISTORY 

The biology of wound healing has been a concern 

of physicians through the ages. The earliest 

medical writings dealt extensively with wound 

care—eg, 7 of 48 case reports in the Smith Papyrus 

(1700 BC) are about wounds and their management. 

1 

The ancient physicians of Egypt, Greece, India, 

and Europe practiced gentle methods for dealing 

with wounds and appreciated the importance of 

foreign body removal, suturing skin edges, and protecting 

injured tissues from the environment with 

clean materials. Following the invention of gunpowder 

and ever-more-frequent gunshot wounds, 

however, a new philosophy of wound care emerged 

that no longer relied on natural processes of softtissue 

repair supplemented with cleanliness, gentle 

washing with warm boiled water, and applications 

of mild salves. For the next 250 years, surgeons 

aggressively treated persons who had open wounds 

with the likes of boiling oil, hot cautery, and scalding 

water. This “let’s-do-something-about-it” attitude 

toward wounds produced disastrous results. 

In the mid-1500s, the great French army surgeon 

Ambroise Paré by chance rediscovered the 

value of gentle methods of wound care. During the 

battle of Villaine the supply of oil was exhausted, 

and Paré was forced to use milder measures on 

amputation stumps. To his surprise, these wounds 

healed rapidly without the expected complications, 

and from this modest beginning the modern era of 

wound care evolved. 

For more than three centuries after Paré’s observations, 

our understanding of the biologic processes 

involved in the healing of wounds was limited to 

John Hunter’s experiments with replantation and 

his musings on the difference between wound contraction 

and contracture, Joseph Lister’s writings on 

wound sepsis, and Alexis Carrel’s notes on organ 

transplantation and tissue preservation. The cellular 

changes in healing soft-tissue wounds were not elucidated 

until the scientific method was applied in 

the 20th century. 

CURRENT KNOWLEDGE 

The following pages summarize our knowledge of 

wound healing. Despite great advances, at present 

there is no “magic bullet” that can be used in the 

management of wounds. Indeed, our current understanding 

of the intricate dance of cellular populations, 

intracellular events, and extracellular factors 

that are involved in a healing wound belies the existence 

of such a compound or procedure. The myriad 

molecular events involved in wound healing are well 

reviewed by McGrath, 2 Moulin, 3 and Martin. 4 

PHASES OF HEALING 

A thorough understanding of the wound healing 

process is a prerequisite for managing surgical wounds. 

The three classic phases of wound healing are: 

inflammation, fibroplasia, and maturation (Fig 1). 5,6 

Inflammatory Phase 

The sequence of events begins with a stimulus to 

inflammation that evokes a nonspecific inflammatory 

response. The stimulus may be physical injury, 

an antigen-antibody reaction, or infection. Inflammation 

is a cellular and vascular response that serves 

to clean the wound of devitalized tissue and foreign 

material. 

The initial changes are vascular. After the injury 

there is a transient 5–10-minute period of vasoconstriction 

that serves to slow the blood flow 

through the area and to aid hemostasis. Vasocon-

SRPS Volume 10, Number 7, Part 1 

Fig 1. Schematic concept of wound healing. (Annotated from 

Hunt TK et al (eds): Soft and Hard Tissue Repair—Biological and 

Clinical Aspects, 1st Ed. New York, Praeger, 1984, p 5.) 

by local substances within the wound, culminating 

in a a dynamic cellular milieu at the site of injury. 

The precise role that each type of inflammatory 

cell plays in the wound healing process remains 

obscure. Both polymorphonuclear leukocytes 

(PMNs) and mononuclear leukocytes (MONOs) 

migrate into the wound in numbers directly proportional 

to the circulating concentrations. 7 Although 

the initial wound exudate contains mainly PMNs, 

within the wound environment PMNs have a shorter 

lifespan than MONOs, so that with prolonged 

inflammation the exudate becomes predominantly 

mononuclear. 

Studies using specific anticellular sera suggest that 

wound healing proceeds normally in the absence 

of both PMNs and lymphocytes, but monocytes must 

be present to trigger normal fibroblast production 

and subsequent invasion of the wound space. 

The early wound exudate also contains fragments 

of cells disrupted during the initial injury, together 

with foreign material and a continued bacterial challenge. 

There is also a variety of enzymes, both proteolytic 

and collagenolytic, and a number of biologically 

active substances. 

striction is followed by active vasodilation. Vessel 

walls (particularly small venules) become lined with 

leukocytes, platelets, and erythrocytes, and leukocytes 

begin migrating into the wound for the 

debriding process. There is a simultaneous increase 

in permeability of the vessel walls: Endothelial cells 

swell and pull away from their neighbors, opening 

gaps through which the serum gains entry into the 

wound. 

Histamine is responsible for the initial vasodilation 

as well as for the early permeability changes. 

Hemostatic factors released from the activation of 

platelets, kinin components, complement components, 

and the prostaglandin system all participate 

in sending cellular control signals to initiate the 

inflammatory phase. At another level, fibronectin, a 

major constituent of granulation tissue, seems to 

promote the adhesion and migration of neutrophils, 

monocytes, fibroblasts, and endothelial cells into 

the wound region. Fibronectin is abundant in the 

first 24–48 hours of injury, gradually disappearing 

as protein synthesis and chronic inflammation 

changes become predominant. The inflammatory 

response of the injured tissues, then, is mediated 

Fibroblastic (Proliferative) Phase 

Beginning on day 2 or 3 after wounding, fibroblasts 

begin to move into the wound along a framework 

of fibrin fibers established during initial 

hemostasis. This fibrous scaffolding is essential to 

fibroblast migration from their usual, mostly perivascular 

habitat 8 in the tissues surrounding the wound. 9 

Once in the wound proper, fibroblasts produce 

several substances essential to wound repair, 

beginning with glycosaminoglycans and ending with 

fibrillar collagen. 10 Glycosaminoglycans are repeating 

disaccharide units attached to a protein core. 

Hyaluronic acid is synthesized first, followed in short 

order by chondroitin-4 sulfate, dermatan sulfate, 

and heparin sulfate. As these are secreted by the 

fibroblasts, they are hydrated into an amorphous 

gel—ground substance—that plays an important role 

in the subsequent aggregation of collagen fibers. 7 

The conversion of tropocollagen into fibrillar collagen 

is mediated by the action of two enzymes 

and calcium. 11 Collagen fibrils begin to appear as 

ground substance accumulates, and over the ensuing 

2–3 days are synthesized at a highly accelerated 

rate. Collagen levels rise continuously for 

2


approximately 3 weeks, 12 but as increasing quantities 

of collagen accumulate in the wound, the number 

of synthesizing fibroblasts begins to decrease, 

until the rates of collagen degradation and synthesis 

are equivalent—collagen homeostasis. 

The increase in wound tensile strength that takes 

place during the fibroblastic phase corresponds to 

the increasing levels of collagen within the wound. 

Gains in tensile strength are thus most rapid while 

the collagen-building curve is climbing, although the 

wound will continue to get stronger for some time. 

In summary, the true fibroblastic phase begins 

on or about the 4th day after injury and lasts 

approximately 2 to 4 weeks, depending on the site 

and size of the wound (Fig 2). Toward the end the 

glycoprotein and mucopolysaccharide content of 

scar tissue and the number of synthesizing fibroblasts 

will be markedly diminished, although the 

region around the wound will remain more cellular 

than the surrounding connective tissue for a period 

of many months. 

Maturation (Remodeling) Phase 

The classic maturation phase of wound healing 

begins approximately 3 weeks after injury. At this 

time collagen synthesis and degradation are accelerated 

(no net increase in collagen content), large 

numbers of new capillaries growing into the wound 

regress and disappear, and collagen fibers initially 

deposited in a haphazard fashion gradually become 

more organized and arranged into a pattern determined 

by local mechanical forces. The maturation 

phase is then fully under way. 

During this phase the formerly indurated, raised, 

and pruritic scar becomes a mature scar, while the 

wound continues to gain tensile strength. 12 Most of 

the embryonic Type III collagen laid down early in 

the healing process is replaced by Type I collagen, 13 

until the normal skin ratio of 4:1 Type I:Type III 

collagen 14 is obtained. The macromolecules of the 

intercellular matrix are progressively degraded, the 

hyaluronic acid and chondroitin-4 sulfate levels 

decrease to resemble those of normal dermis, and 

the water content of the tissues gradually returns to 

normal. 15 As new collagen is deposited during this 

phase, more stable and permanent crosslinks are 

established. 

How long the maturation phase lasts depends 

upon many variables, including the patient’s age 

and genetic background, type of wound, specific 

location on the body, and length and intensity of 

the inflammatory period. 

Fig 2. Time sequence of classical wound healing. 

3


IMMUNE RESPONSE 

The inflammatory response to tissue injury is characterized 

by the accumulation of polymorphonuclear 

leukocytes as well as macrophages. Macrophages 

appear at the site of injury within 48–96 

hours, so that they actively participate in the 

inflammatory and debridement phases. 16 Activated 

macrophages release two monokines known to have 

angiogenic properties in vitro: interleukin-1 (IL-1) 

and tumor necrosis factor-α/cachectin (TNF-α). 17 

IL-1 also promotes fibroblast proliferation through 

the induction of protein-derived growth factor. Both 

IL-1 and TNF-α stimulate and inhibit collagen synthesis 

and deposition under various conditions. 16,17 

A chemical factor in macrophages is necessary 

for proper angiogenesis in early wounds. 18,19 Fibrin 

breakdown products may provide the signal for 

development of vasculature at the appropriate time 

in the healing process. 20,21 Because their halflife 

within the wound is longer, macrophages achieve 

peak levels somewhat later than PMNs. Neutrophils 

in the wound are not necessary for chemotaxis 

of fibroblasts nor for eventual fibroplasia. 22 

T-lymphocytes migrate into wounds following the 

influx of macrophages and other inflammatory cells, 

and produce several lymphokines that influence 

the endothelial cells of the wound through their 

angiogenic and modulatory properties. These lymphokines 

both inhibit and stimulate fibroblast 

recruitment and induce fibroblast proliferation via 

fibroblast-activating factor (FAF). Some can also 

inhibit collagen synthesis. 16 Depletion of T-lymphocytes 

before or up to 1 week after wounding 

results in decreased breaking strength of the wound 

and impaired collagen synthesis and deposition. 23 

EPITHELIAL REPAIR 

The epithelial portion of wound repair begins 

with cell mobilization and migration across the 

wound. Cellular numbers are thereafter augmented 

by mitosis and cellular proliferation, while cellular 

differentiation accounts for maturation into the normal 

epithelial appearance. 

The epithelial cells immediately adjacent to the 

wound initially undergo a mobilization process during 

which they enlarge, flatten, and detach from 

neighboring cells and the basement membrane. As 

the cells flatten they tend to flow in a direction 

away from adjoining epithelial cells. The stimulus 

to migration is an apparent loss of contact inhibition. 

As the marginal cells begin their migration, the 

cells immediately behind them also tend to flatten, 

break their cellular connections, and drift along; 

epithelium thus flows across the gap of the wound. 

The epithelial stream continues until the advancing 

cells meet cells coming from the opposite side of 

the wound, whereupon motion stops abruptly— 

contact inhibition. 

During their migration across the wound cellular 

numbers are maintained by mitosis. Fixed basal 

cells away from the wound edge begin mitosis to 

replace the migrating cells, and as resurfacing of 

the wound proceeds, the cells that have migrated 

in turn start to divide and multiply. Increasing numbers 

of cells thicken the new epithelial layer. 

Upon reepithelialization of the wound, the 

orderly progression from basal mitotic cells through 

layers of differentiated keratinocytes to stratum corneum 

is again established. In other words, once the 

wound gap is bridged by advancing cells from the 

perimeter, the normal cellular differentiation from 

basal to surface layers resumes. 

Cell receptors called integrins are said to “maintain 

integral cell contact through a bridge between 

the extracellular structural protein matrix and the 

cell’s internal cytoskeleton.” 24 Integrins bind to specific 

extracellular proteins by recognizing a region 

with a certain amino acid sequence. The integrinmatrix 

bond can be inhibited by monoclonal antibodies 

and synthetic peptides, which block the 

receptors or the sites to which they attach. 

SKIN METABOLISM AND PHYSIOLOGY 

The blood supply of the skin is far greater than it 

requires metabolically. Blood vessels in the skin 

are capable of carrying 20–100X the amounts of 

oxygen and nutrients that are needed for cellular 

survival and function. (Cells above the basal layer of 

the epidermis have largely lost their mitochondria 

and respire mainly through glycolysis, contributing 

little to the metabolic needs of the skin.) Despite 

the abundant blood supply, skin perfusion is insufficient 

to support wound healing, which requires 

granulation tissue. 

Ryan 25 summarizes this paradox as follows: 

. . . the skin can resist many hours of compression 

and obliteration of its blood supply and . . . 

[yet] nonhealing of the skin is one of the most 

4


common of problems and is often blamed on 

impairment of blood supply. . . .The dilemma is 

explained by the fact that exchange between blood 

vessels and the supplied tissue services the functions 

of that tissue, and, although it is often stated 

that richness of the skin vasculature exceeds 

nutritional need, this statement is a misconception. 

. . . The frequent stimuli of scratching, stretching, 

compressing, heating, or cooling of the skin requires 

restoration of skin stiffness to a status quo. In 

restoring itself to the status quo, the mechanical 

properties of the skin must be instantly repaired and 

this repair requires a luxurious blood supply to 

maintain not merely cell metabolism but the 

physical properties of the interstitium. 

Ryan (1995) 

COLLAGEN 

Collagen is the principal building block of connective 

tissue, accounting for one third of the total 

protein content of the body. Collagen is an unusual 

protein in that it is almost devoid of the sulfurcontaining 

amino acids cysteine and tryptophan. In 

their stead, collagen contains hydroxyproline and 

hydroxylysine, two amino acids with very limited 

distribution otherwise—only in collagen, elastin, the 

C1q subcomponent of the complement system, and 

the tail structure of acetylcholinesterase. 26 Collagen 

has a very complex tertiary and quaternary 

molecular structure consisting of three polypeptide 

chains, each chain wound upon itself in a lefthanded 

helix and the three chains together wound 

in a right-handed coil to form the basic collagen 

unit. The polypeptide chains are held in their relative 

configurations by covalent bonds. Each triple 

helical structure is a tropocollagen molecule. Tropocollagen 

units associate in a regular fashion to 

form collagen filaments; collagen filaments in turn 

aggregate as collagen fibrils, and collagen fibrils 

unite to form collagen fibers, which are visible under 

the light microscope (Fig 3). 

Five types of collagen have been identified in 

humans on the basis of amino acid sequences. Their 

relative distribution in connective tissues varies, hinting 

at individual properties valuable for specific functions 

(Table 1). Type I collagen is abundant in skin, 

tendon, and bone. These tissues account for more 

than 90% of all collagen in the body. Normal skin 

contains Type I and Type III collagen in a 4:1 ratio, 

the latter mainly in the papillary dermis. In hyper- 

Fig 3. Molecular and fibrillar structure of collagen. 

5


Table 1 

Types and Distribution of Collagen 

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

(Annotated from Prockop DJ et al: The biosynthesis of collagen and 

its disorders. N Engl J Med 301:13, 1979.) 

trophic and immature scars the percentage of Type 

III collagen may be as high as 33% (a 2:1 Type I:III 

ratio). 27 

Collagen synthesis takes place extracellularly as 

well as intracellularly. Certain substances inhibit 

the formation of collagen either by interfering with 

its synthesis or activating its degradation (Fig 4). 

Normal connective tissue is in a state of dynamic 

equilibrium balanced between synthesis and degradation, 

and this makes it vulnerable to local stimuli 

such as mechanical forces on the tissue. While 

excessive collagen degradation results from 

unchecked collagenase synthesis, not enough collagenase 

gives rise to tissue fibrosis. Homeostasis is 

achieved through activation of collagenase by parathyroid 

hormone, adrenal corticosteroids, and 

colchicine; and inhibition of collagenase synthesis 

by serum alpha-2 macroglobulin, cysteine and 

progesterone. 28 

THE MYOFIBROBLAST 

AND WOUND CONTRACTION 

Contraction is an essential part of the repair 

process by which the organism closes a gap in 

the soft tissues. Contracture, on the other hand, 

is an undesirable result of healing, at times due to 

the process of contraction and at other times due 

to fibrosis or other tissue damage. 29 

In 1971 Gabbiani, Ryan, and Majno 30 first 

noted a type of fibroblast in granulation tissue 

that bore some structural similarities to smooth 

muscle cells. Myofibroblasts differ from ordinary 

fibroblasts by having cytoplasmic microfilaments 

similar to those of smooth muscle cells. Within 

the filamentous system are areas of “dense bodies” 

that serve as attachments for contraction. 

The nuclei demonstrate numerous surface irregularities 

such as those of smooth muscle cells but 

unlike those of ordinary fibroblasts. Myofibroblasts 

are also different from normal fibroblasts in that 

they have well-formed intercellular attachments 

such as desmosomes and maculae adherens. 31–34 

Myofibroblasts are the source of contraction 

within a wound. 31–34 

6


Rudolph 35,36 found a direct relationship between 

the rate of wound contraction and the number of 

myofibroblasts within a wound. 35 Rudolph 36 also 

demonstrated the presence of myofibroblasts 

throughout the wound, not just adjacent to the 

wound margins. McGrath and Hundahl 37 confirmed 

the parallel paths of wound contraction and number 

of myofibroblasts in the wound and the relatively 

even distribution of myofibroblasts in granulation 

tissue except at the wound bed (fewer) and 

adjacent to foci of inflammation (more). Their findings 

support the “pull theory” of wound contraction, 

which holds that the entire granulating surface 

of the wound acts as a contractile organ. This concept 

implies contraction of individual myofibroblasts 

to shorten the wound, followed by collagen deposition 

and crosslinking to maintain the shortening, in 

a lock-step mechanism. 

Prostaglandin inhibitors do not inhibit myofibroblast 

production, therefore wound contraction is 

not altered. 38 Although present in a number of contracture 

disorders like Dupuytren’s disease, 39 

Peyronie’s, and lederhosen disease, 32 myofibroblasts 

have not been implicated in their etiology. 

TENSILE STRENGTH 

The tensile strength of a wound is a measurement 

of its load capacity per unit area. A wound’s 

breaking strength is defined as the force required 

to break it regardless of its dimensions. Depending 

solely on different skin thicknesses, breaking strength 

can vary severalfold; tensile strength, on the other 

hand, is constant for wounds of similar size. 

Experimental studies give evidence that collagen 

fibers are largely responsible for the tensile strength 

of wounds. 13,40 The rate at which a healing wound 

regains strength varies not only among species, but 

also among individuals and even among different 

tissues in the same individual. 29 The healing pattern 

of the various tissues, however, is remarkably similar 

within a philogenetic family. 

All wounds gain strength at approximately the same 

rate during the first 14–21 days, but thereafter the 

curves may diverge significantly according to the 

tissue involved. In skin, the peak tensile strength is 

achieved at approximately 60 days after injury 41 (Fig 

5). Given optimal healing conditions, the tensile 

strength of a wound never reaches that of the original, 

unwounded skin, leveling off at about 80%. 

Fig 5. Tensile strength of a healing skin incision as a function of 

time. (Reprinted with permission from Levenson SM et al: The 

healing of rat skin wounds. Ann Surg 161:293, 1965.) 

FACTORS IN WOUND HEALING 

Numerous local or systemic, physical conditions 

or chemical agents either enhance collagen remodeling 

or impair wound healing. Some of these are 

discussed below. 

Oxygen. Hunt and Pai 42 showed that fibroblasts 

are oxygen-sensitive: At partial pressures of 30– 

40mmHg, fibroblast replication is potentiated. 

Because collagen synthesis cannot take place unless 

the PO 2 

is >40mmHg, both myofibroblast and collagen 

production can be stimulated by maintaining 

the wound in a state of hyperoxia. 43 Oxygen also 

converts regenerating epithelial cells to aerobic 

metabolism. 44 

The most common cause of wound infection or 

failure of wounds to heal properly is deficient 

wound PO 2 

. 45 Adequate tissue oxygenation implies 

sufficient inspired oxygen as well as component 

transfer of oxygen to hemoglobin, ample 

hemoglobin for oxygen transport, satisfactory vascularity 

of the tissues to keep oxygen diffusion distances 

small, etc. The arterial pressure of oxygen 

alone is not indicative of tissue oxygenation; despite 

supplemental inspired oxygen, the wound itself may 

remain ischemic if perfusion is inadequate. Most 

healing problems associated with diabetes mellitus, 

irradiation, small vessel atherosclerosis, chronic 

infection, etc. can be ascribed to a faulty oxygen 

delivery system at some point. 45 

7


Hematocrit. The quantity of hemoglobin that is 

available to carry oxygen to the tissues would be 

expected to be a critical factor in maintaining tissue 

oxygenation, yet the data regarding the effect of 

anemia on the tensile strength of a wound are contradictory. 

29 When the hematocrit is reduced to 

50% of normal as a result of hemorrhage and the 

blood volume has been replaced by plasma, some 

investigators report a marked decrease in tensile 

strength 46 while others report no change. 47,48 

Mild or moderate anemia does not appear to be 

detrimental to healing in a well-perfused wound, 

with collagen deposition being proportional to tissue 

oxygenation and perfusion. 48 The reperfusion 

of injured tissue itself can be deleterious to wound 

healing, however, with release of anaerobic 

metabolites and reactive oxygen species creating 

additional oxidative stresses. 

Steroids and Vitamin A. One of the more frequent 

disorders of wound healing is arrest of 

inflammation as a result of the administration of 

steroids. The steroid seems to inhibit wound macrophages 

and also interferes with fibrogenesis, 

angiogenesis, and wound contraction. 45,49 

Through a poorly understood mechanism, both 

vitamin A and anabolic steroids will restore monocytic 

inflammation that has been retarded by antiinflammatory 

steroids. 50,51 The exact dose of vitamin 

A required is not known, but oral ingestion of 

25,000IU/d or topical application of 200,000IU ointment 

q. 8h is effective in most cases. 

Vitamin A deficiency retards repair. 52 Conversely, 

ingestion of vitamin A stimulates collagen deposition 

and contributes to increased breaking strength 

of wounds, while topically applied vitamin A accelerates 

wound reepithelialization. Hunt 52 hypothesizes 

that retinoids are particularly important in 

macrophagic inflammation to initiate reparative 

behavior in tissue. 

Supplemental estrogen applied topically improves 

healing in elderly women. 53 

Vitamin C. Ascorbic acid is an essential cofactor 

in the synthesis of collagen, a fact known since the 

sailing days of the 16th century. Vitamin C is the 

main vitamin associated with poor healing due to 

its influence on collagen modification. 54 L-arginine 

is required in a variety of metabolic functions, 

wound healing, and endothelial function. It is 

important in the synthesis of nitric oxide, and deficiency 

is linked to immune dysfunction and failure 

of wound repair. The effects of vitamin C deficiency 

on healing wounds include proliferation of 

immature fibroblasts; failure of formation of mature 

extracellular material; production of alkaline phosphatase; 

and formation of defective capillaries that 

can lead to local hemorrages. Even healed wounds 

deprived of vitamin C for long periods show diminished 

tensile strength. Nevertheless, high concentrations 

of ascorbic acid do not promote supranormal 

healing. 

Vitamin E. Although vitamin E has been used to 

control various problems of wound overhealing, 55,56 

its therapeutic efficacy and indications remain to 

be defined. Large doses of vitamin E inhibit healing, 

as reflected by decreased tensile strength and 

lower accumulations of collagen. 57 The mechanism 

by which vitamin E exerts this effect is related to its 

membrane-stabilizing properties. Vitamin E does 

not reverse the delaying action of glucocorticoids 

on wound healing and is in turn reversed by vitamin 

A. 

Vitamin E increases the breaking strength of 

wounds exposed to preoperative irradiation. 58 As 

an antioxidant, vitamin E neutralizes the lipid 

peroxidation caused by ionizing radiation, thus limiting 

the levels of free radicals, peroxidases, and 

other products of lipid peroxidation that are known 

to cause cellular damage. 

Zinc and Other Minerals. Many trace metals 

including manganese, magnesium, copper, calcium, 

and iron are cofactors in collagen production 

and deficiencies in these minerals impair collagen 

synthesis. 54 Zinc is essential for normal 

wound healing. Zinc influences reepithelialization 

and collagen deposition. 59 Epithelial and fibroblastic 

proliferation is impaired in patients with 

low serum zinc levels. 60 Zinc also influences B 

and T lymphocyte activity, but many other nutrients 

including copper and selenium have been 

implicated in immune system dysfunction. 61 Zinc 

accelerates healing only when there is a preexisting 

zinc-deficiency state, otherwise it is of no benefit. 

62 

Tissue Adhesives. Logic dictates that fibrin-based 

tissue adhesives might be useful in wound healing, 

8


since deposition of the fibrin network during clotting 

has been implicated in many aspects of cellular 

events after injury. A report on mechanical properties 

of rat skin wounds treated with a fibrin glue 

notes increased breaking strength, energy absorption, 

and elasticity of the healing wounds. 63 

Antiinflammatory Agents. Nonsteroidal antiinflammatory 

drugs (aspirin and ibuprofen) have 

been shown by Kulick et al 64,65 to decrease collagen 

synthesis an average of 45% even at ordinary therapeutic 

doses. The effect is dose-dependent and 

mediated through prostaglandins. 66 

Smoking. Smoking is harmful to a healing 

wound. 67–73 The mechanism of action is likely to 

be multifactorial. Nicotine is a vasoconstrictive substance 

that decreases proliferation of erythrocytes, 

macrophages, and fibroblasts. 74,75 Hydrogen cyanide 

inhibits oxidative enzymes. Carbon monoxide 

decreases the oxygen-carrying capacity of 

hemoglobin by competitively inhibiting oxygen 

binding. 72,76 This pathophysiologic triad reduces 

the cellular response and efficiency of the healing 

process. Smoking also increases platelet aggregation, 

increases blood viscosity, decreases collagen 

deposition, and decreases prostacyclin formation, 

which all negatively affect wound healing. 73 

The vasoconstriction associated with smoking is 

not a transient phenomenon. Smoking a single cigarette 

may cause cutaneous vasoconstriction for up 

to 90 minutes, and a pack-a-day smoker sustains 

tissue hypoxia for most of each day. Tobacco-using 

patients are therefore at risk of cutaneous hypoxia 

from decreased arterial O 2 

and decreased tissue 

perfusion as well as increased carboxyhemoglobin 

levels. 

Lathyrogens. As a group, lathyrogens prevent 

the formation of aldehyde intermediates in the crosslinking 

process of collagen, reducing the strength of 

the collagen bundles. This dramatic effect on collagen 

is brought about by beta-aminopropionitrile 

(BAPN). BAPN and another lathyrogenic agent, 

d-penicillamine, have been used in the pharmacologic 

control of scar tissue. 

Nitric Oxide. Nitric oxide is suspected of playing 

a role in the early phases of wound healing, 

possibly serving as a modulatory/demodulatory second 

messenger for several of the polypeptide growth 

factors. 77 

Oxygen-derived Free Radicals. Univalent 

reductions of oxygen generate highly reactive, potentially 

cytotoxic free radicals. 78 When released 

into the extracellular matrix, these oxygen-derived 

metabolites may cause cellular injury by 1) degrading 

hyaluronic acid and collagen; 2) destroying cell 

membranes; 3) disrupting organelle membranes; 

and 4) interfering with important protein enzyme 

systems. Oxygen free radical production can be 

triggered by radiation, chemical agents, ischemia, 

and inflammation. Several studies seem to support 

a direct involvement of oxygen radicals in wound 

healing. 78 

Age. Wound healing is a function of age. The 

patient’s age affects a number of elements in wound 

healing, notably the rate of multiplication of cells 

and the rate of production of various substances by 

cells. 79 Both tensile strength and wound closure rates 

decrease with age. 80 As the individual gets older 

the phases of healing are protracted, so that events 

begin later, proceed more slowly, and often do not 

reach the same level. 81–83 

Some authors 84 propose that the real factor contributing 

to delayed healing in the elderly is intolerance 

to ischemia, rather than any inherent alteration 

in the normal processes of wound healing as a 

consequence of age. Although increasing age is 

typically linked with delayed healing, it is difficult to 

separate the effects of age alone from those of diseases 

commonly associated with age. 85 

Mechanical Stress. Mechanical stresses on the 

healing wound affect the quantity, aggregation, and 

orientation of collagen fibers. 86 Abnormal tension 

on the skin can give rise to blanching and subsequent 

necrosis, rupture of the dermis, and permanent 

stretching. 87 The effect of mechanical stress 

on wound healing has been studied on expanded 

skin wounds in rabbits. 88 The expanded wounds 

showed significant increases in breaking strength 

and energy absorption compared with the implanted 

but non-expanded control wounds. The collagen in 

expanded wounds was found to be better organized 

than in controls, and was oriented parallel to 

the force vector. The authors conclude that the 

mechanical stress of subcutaneous expansion 

9


“accelerates wound healing by producing stronger 

and more organized scars” at the expense of scar 

stretching. 88 

Nutrition. Malnutrition manifests as delayed tensile 

strength of wounds in the rat model. 89 The 

effect is particularly marked early in the healing 

process, but eventually levels off and ultimately both 

the control and starved animals heal equally. 

Serum protein levels 10 5 or the presence of any beta-hemolytic streptococcus 

inhibits healing by prolonging the inflammatory 

phase and interfering with epithelialization, 

contraction, and collagen deposition. 104 Bacterial 

endotoxins decrease tissue PO 2 

and stimulate 

phagocytosis and the release of collagenase and 

reactive oxygen species, further degrading collagen 

and contributing to the destruction of previously 

normal tissue adjacent to the wound. 

In the presence of significant infection, leukocyte 

chemotaxis and migration, phagocytosis, and 

intercellular killing are decreased. Excessive bacterial 

colonization likewise impairs angiogenesis and 

epithelialization. The granulation tissue of infected 

wounds is more edematous, somewhat hemorrhagic, 

and more fragile than that of clean wounds. 

10


Epithelialization does not proceed in the presence 

of a significant bacterial load because the toxins 

and metabolites of bacteria inhibit epidermal 

migration and even digest tissue proteins and 

polysaccharides in the dermis. 102,105,106 Finally, heavy 

bacterial contamination promotes collagenolytic 

activity through the action of microbial collagenase 

and endotoxins capable of cleaving the collagen 

molecule, ultimately resulting in decreased wound 

strength and contraction. 102 

Edema. Edema further compromises tissue perfusion 

and interferes with wound healing. Mast 

cells in skeletal muscle produce most of the NO 

associated with ischemia-reperfusion injury. 107 Mast 

cells are inflammatory cells that, when stimulated, 

release histamine and numerous cytokines responsible 

for the intense inflammatory reaction and 

edema. In addition, tissue edema due to lowered 

plasma oncotic pressures, a leaky endothelium, and 

impaired peripheral perfusion may further compromise 

tissue perfusion by raising interstitial pressures. 

108 In turn, raised tissue pressure, either 

external (compression) or internal (compartment syndrome), 

induces capillary closure through its effect 

on critical closing pressures. 

Idiopathic Manipulation. The degree of tissue 

necrosis increases with the severity of the trauma. 

Rough tissue handling, overzealous cauterization, 

abundant blood clots, tight sutures, tissue ischemia, 

and subsequent necrosis extend the period of 

inflammation and retard healing. 

Chemotherapy. Antimetabolic, cytotoxic, and 

steroidal agents are all associated with compromised 

immunity, increased susceptibility to sepsis, and failure 

of tissue repair. 109–111 Chemotherapeutic agents 

generally decrease fibroblast proliferation and 

wound contraction, 112–114 although thio-TEPA and 

chloroquine mustard do not seem to affect wound 

healing when administered in therapeutic doses. 

Actinomycin D, bleomycin, and BCNU are more 

detrimental to wound strength than vincristine, 

methotrexate, 5-fluorouracil, or cyclophosphamide. 

112 Cyclophosphamide inhibits the early 

vasodilatory phase of inflammation, while methotrexate 

apparently does not act directly upon the 

wound but does potentiate infection. When chemotherapy 

is begun 10–14 days postoperatively, 

little effect is noted on wound healing over the long 

term despite a demonstrable early decrease in 

wound strength. 

Radiation Therapy. Acute radiation injury is 

manifested by stasis and occlusion of small vessels, 

with a consequent decrease in wound tensile 

strength and total collagen deposition. Although 

decreased blood flow to the wound tissues certainly 

contributes to poor healing, Miller and 

Rudolph 115 cite evidence of a direct adverse effect 

of ionizing radiation on fibroblast proliferation, with 

possible permanent damage to the fibroblasts. Irradiated 

skin is thus irreversibly injured, and the injury 

itself may be progressive. 115 

Diabetes Mellitus. Diabetes mellitus affects soft 

tissue healing via metabolic, vascular, and neuropathic 

pathways. 116 Small vessel occlusive disease 

is no longer considered to be a component of diabetes 

mellitus. 117 Rather, it is the larger arteries, not 

the arterioles, that are typically affected in diabetic 

patients. Factors that affect the microcirculation in 

diabetes include stiffened red blood cells and 

increased blood viscosity; susceptibility of the tibial 

and peroneal arteries to atherosclerosis; high venous 

back-pressure in the lower extremities that increases 

transudation and edema; affinity of glycosylated 

hemoglobin for oxygen contributing to low oxygen 

delivery at the capillary; and impaired phagocytosis 

and bacterial killing, which along with neuropathy 

and ischemia make the patient vulnerable to infection. 

117 

Other Systemic Conditions. Obesity, cardiovascular 

disease, COPD, cancer, endocrine disorders, 

small vessel disease, and renal or hepatic failure 

all delay wound healing. Local hypoperfusion 

due to small vessel occlusion secondary to emboli, 

vasculitis, and arterial or venous thrombosis, or 

locally raised tissue pressures due to extrinsic or 

intrinsic factors (eg, hematoma or extravasation) render 

the wound ischemic and retard healing. The 

stress of a critical illness may further impair healing 

by placing high demands on tissue oxygen. 108 

ADJUNCTS TO WOUND HEALING 

Adjuncts to wound healing include hydrotherapy, 

ultrasound, negative pressure therapy, hyperbaric 

11


oxygen, electrostimulation, lasers, light-emitting 

diode (LED) therapy, growth factors, and bioengineered 

skin. 

Hydrotherapy. Whirlpool treatments are among 

the oldest adjunct therapies still in use for the management 

of chronic wounds. Hydrotherapy is most 

effective when given once or twice a day with 

concomitant dressing changes. Antibacterial agents 

can be added to the whirlpool water to increase 

the bactericidal effect on the wound. 

A new form of hydrotherapy is replacing the 

whirlpool; it is called pulsed lavage. Pulsed lavage 

delivers an irrigating solution under pressure (4– 

15psi) that stimulates formation of granulation tissue. 

118 

Clean, nondraining wounds with healthy red 

granulation tissue should never be subjected to 

hydrotherapy. Even minimal water agitation can 

mechanically damage the fragile new cells. 

Ultrasound. Ultrasound is the result of electrical 

energy that is converted to sound waves at 

frequencies >20,000Hz. Sound waves are transmitted 

to the tissue through a hydrated medium 

sandwiched between the tissue and the transducer. 

The depth of penetration of the ultrasound energy 

depends on the frequency: the lower the frequency, 

the deeper the penetration. 

The therapeutic effects of ultrasound therapy stem 

from its thermal and nonthermal properties. The 

thermal component at a setting of 1–1.5W/cm 2 has 

been used to improve scar outcome. The 

nonthermal component at a setting of 0.3–1W/cm 2 

produces both cavitation (formation of gas bubbles) 

and streaming (a steady unidirectional force), which 

in the laboratory cause changes in cell membrane 

permeability, increase cellular recruitment, collagen 

synthesis, tensile strength, angiogenesis, wound contraction, 

fibrinolysis, and stimulate fibroblast and 

macrophage production. 119–122 Clinically, the results 

of ultrasound therapy on the healing of wounds are 

equivocal. 123–128 

Negative Pressure Therapy (V.A.C.). Vacuumassisted 

closure consists of using a subatmospheric 

pressure dressing to convert an open wound into a 

controlled closed wound. 129,130 The negative pressure 

relieves interstitial fluid and edema to improve 

tissue oxygenation; removes inflammatory mediators 

that suppress the normal progression of healing; 

130,131 speeds up formation of granulation tissue; 

and reduces bacterial counts in the wound. A V.A.C. 

dressing gives the surgeon time to transform a hostile 

wound into a manageable one. 

Hyperbaric Oxygen (HBO). Dividing cells in a 

wound require a minimum oxygen tension of 

30mmHg (normal range 30–50mmHg). Tissues in 

wounds that are not healing show oxygen values of 

5–20mmHg. When those wounds are placed in 

hyperbaric chambers at pressures of 2.4ATA, the 

tissue oxygen tension rises to 800–1100mmHg. 119 

Besides providing more oxygen to the wound site, 

HBO also increases expression of NO, which is 

crucial for wound healing. 132 Many reports attest to 

the benefit of HBO therapy in amputations, 133 

osteoradionecrosis, 134,135 surgical flaps, 136 and skin 

grafts, 136–138 but the results are not impressive in 

necrotizing soft-tissue infections. 

Hyperbaric oxygen administration increases tissue 

oxygenation considerably as long as the wound 

vessels are not obliterated, but cannot alter wound 

ischemia in the absence of satisfactory perfusion. 

In an ischemic rabbit ear model, HBO in combination 

with PDGF or TGF-β1 had a synergistic effect 

that totally reversed the healing impairment caused 

by ischemia. 139 In severely compromised wounds, 

Mathes, Feng, and Hunt 140 recommend surgical 

transplantation of a blood supply to bring O 2 

into 

the ischemic tissues and enhance the healing process. 

Electrostimulation. Electrostimulation is 

believed to accelerate the wound healing process 

by imitating the natural electrical current that occurs 

in skin when it is injured. 141–144 Electrical current 

applied to wounded tissue increases the migration 

of neutrophils and macrophages, 145–147 and promotes 

fibroblasts. 148–150 Electrostimulation results in a 109% 

increase in collagen 149 and 40% increase in tensile 

strength 151 and may also improve blood flow in a 

wound. 152,153 

Four types of electrostimulation are commonly 

used: direct current, low-frequency pulsed current, 

high-voltage pulsed current, and pulsed electromagnetic 

fields. 119 

Lasers. Low-energy laser management of open 

wounds has been used for over 35 years in Europe 

12


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

Weak biostimulation excites physiologic processes 

and results in increased cellular activity in wounded 

skin. 155,156 The mechanism is believed to be the 

stimulation of ascorbic acid uptake by cells, stimulation 

of photoreceptors in the mitochondria, changes 

in cellular ATP, and cell membrane stabilization. 157– 

159 

The common types of low-energy lasers used in 

wound management are the helium-neon laser and 

the gallium-arsenide (or infrared) lasers. 

Lasers accelerate healing of ischemic, hypoxic, 

and infected wounds, especially when combined 

with hyperbaric oxygen treatments. 160 Low-energy 

lasers promote epithelialization for wound closure 161 

and better tissue healing. 162–169 Laser biostimulation 

has different effects at different wavelengths, and 

optimal treatment requires several applications at 

various wavelengths. 

LED. The treatment area for a laser is limited; 

that is, large areas must be treated in a grid-like 

pattern. In contrast, light-emitting diodes (LED) produce 

multiple wavelengths (680, 730, and 880nm 

simultaneously 159 or 670, 720, and 880nm 170 in large, 

flat arrays to treat large wounds. NASA developed 

LED based on their research on wound healing in a 

weightless environment. Work done on space 

shuttle missions, on the international space station, 

and aboard submarines shows significant improvement 

in wound healing with LED therapy alone or 

in combination with hyperbaric oxygen treatment. 

Growth Factors. McGrath 2 defines growth factors 

as follows: “A polypeptide growth factor is an 

agent promoting cell proliferation. . . . These proteins 

also induce the migration of cells, and thus are 

not only mitogens but are also chemoattractants 

that recruit leukocytes and fibroblasts to the injured 

area.” Of particular importance to wound healing 

are the fibroblast growth factors (Table 2). 4 Their 

effect on the repair process is illustrated in Figure 6. 

Platelets contain growth factors that stimulate 

angiogenesis, fibroplasia, and collagen production. 

These are called platelet-derived wound healing 

factors (PDWHF). 171 A beta-chain recombinant 

c-sis homodimer of platelet-derived growth factor 

(rPDGF-β) appears to have immunologic properties 

similar to PDGF—ie, it stimulates fibroblast mitogenesis 

and chemotaxis of PMNs, MONOs, and fibroblasts. 

172 Both PDGF and rPDGF-β accelerate 

wound healing by augmenting the inflammatory 

response and the accumulation of granulation tissue. 

Table 2 

Growth Factor Signals at the Wound Site 

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

13


effects of cytokines on abnormal scars are being 

investigated. 185–187 

Transforming growth factor beta (TGF-β) has been 

linked clinically and experimentally to dermal proliferative 

disorders. Polo and colleagues 189 found 

an abnormal dose response by fibroblasts of proliferative 

scars to TGF-β2 stimulation. This response 

was not demonstrated by nonburn hypertrophic 

scars. 

The commercially available growth factor products 

and their uses are summarized in Table 3. 

Bioengineered Skin. Skin equivalents provide 

a living supply of growth factors and cytokines and a 

collagen matrix for a wound to build upon. The 

underlying principles and specific benefits of these 

products are discussed elsewhere in this overview. 

The bioengineered skin replacements currently on 

the market are shown in Table 4. 

Fig 6. Peptide growth factors released by the cells recruited 

into the injured area. (Reprinted with permission from McGrath 

MH: Peptide growth factors and wound healing. Clin Plast Surg 

17(3):421, 1990.) 

Brown and associates 173 studied epidermal growth 

factor (EGF) added to silver sulfadiazine in the healing 

of wounds. The cream mixture was applied to 

skin-graft donor sites of 12 patients. Complete healing 

was noted 1.5 days sooner in the experimental 

wounds than in the control wounds, which received 

silver sulfadiazine alone. In a separate study on 

chronic wounds, EGF applied topically b.i.d. resulted 

in complete healing in 8/9 wounds at a mean 34 

days. 

In vitro, EGF is a growth-promoting protein for 

skin fibroblasts and other cell types. In vivo, EGF 

stimulates epithelial proliferation in the skin, lung, 

cornea, trachea, and gastrointestinal tract. Epidermal 

growth factor affects keratinocyte proliferation 

mainly by increasing their rate of migration, which 

in turn increases the number of dividing cells, 

growth rate, culture lifetime, and the ability to begin 

new colonies. 174 Along with transforming growth 

factor alpha (TGF-α), other peptide growth factors, 

175–184 and cytokines, 185–187 EGF is “part of a 

complex program to orchestrate growth and differentiation 

of epidermal keratinocytes.” 174,188 The 

FETAL WOUND HEALING 

Tissue repair in the mammalian fetus is fundamentally 

different from normal postnatal healing. 

“In adult humans, injured tissue is repaired by collagen 

deposition, collagen remodeling, and eventual 

scar formation. [In contrast], fetal wound healing 

seems to be more of a regenerative process 

with minimal or no scar formation.” 190 

Siebert et al 191 examined healing fetal wounds 

histologically and biochemically and found that they 

contained a small amount of collagen identical to 

that found in the exudate from wounds in adults, ie, 

Type III collagen but no Type I. The fetal wound 

matrix was also rich in hyaluronic acid, which has 

been associated experimentally with decreased scarring 

postnatally. The authors propose a mechanism 

of hyaluronic acid-collagen-protein complex acting 

in fetal wound healing to check scar formation, and 

concluded that healing in fetuses involved a much 

more efficient process of matrix reorganization than 

that which takes place after birth. True regeneration 

apparently does not play a role in fetal healing, 

based on the few appendageal elements seen. 

Rowsell 192 suggests that the collagen present in 

fetal wounds is “structural” rather than “scar tissue” 

collagen. The amounts of collagen deposited in fetal 

and in adult wounds are not only markedly different, 

but the deposited collagen is also handled differently. 

The fetal pattern of wound healing “is 

14


Table 3 

Commercially Available Growth Factors, Indications and Benefits 

Table 4 

Bioengineered Skin Replacements 

characterized, at least in the early fetus, by the 

deposition of glycosaminoglycans at the wound site 

into which rapidly proliferating mesenchymal cells 

of all types migrate, differentiate, and mature.” 193 

The transition from fetal to adult patterns of wound 

healing for different tissues probably occurs at different 

times during gestation. 

In their review of scarless wound healing in the 

mammalian fetus, Mast and coworkers 190 state that 

“a striking difference between postnatal and fetal 

repair is the absence of acute inflammation in fetal 

wounds,” and offer several hypotheses to explain 

this phenomenon. Epithelialization occurs at a much 

faster rate in fetal wounds, but adult-like angiogenesis 

is absent. More important, the fetal wound 

matrix is markedly different from the adult’s in that 

it lacks collagen and instead contains predominantly 

hyaluronic acid. The fetal wound contains a persistent 

abundance of HA while collagen deposition is 

rapid, nonexcessive, and highly organized, so that 

the normal dermal structure is restored and scarring 

does not occur. The authors speculate about the 

applications of scarless fetal healing, namely for 

intrauterine repair and in the treatment of pathologic, 

postnatal processes. 

Whitby and Ferguson 193 studied the distribution 

of growth factors in healing fetal wounds in an 

attempt to identify the mechanism controlling the 

15


healing process in fetuses. They found plateletderived 

growth factor (PDGF) in fetal, neonatal, 

and adult wounds, but transforming growth factor 

beta and basic fibroblast growth factor (bFGF) were 

not detected in the fetal wounds. They conclude 

that it may be possible to manipulate the adult 

wound to produce more fetal-like, scarless wound 

healing by therapeutically altering the levels of 

growth substances and their inhibitors. This hope is 

shared by other groups 194–199 though it has not yet 

materialized in the clinical setting. Other growth 

factors are under study also. 200 

Tenascin (cytotactin) is a large, extracellular matrix 

glycoprotein synthesized by fibroblasts that is 

present during embryogenesis but only sparsely distributed 

in the connective tissue papillae of adults. 

The protein is re-expressed, however, in healing 

wounds, particularly close to the basement membranes 

at the wound edges beneath the proliferating 

and migrating epithelium, and later on during 

healing in the regenerating connective tissue area. 

This expression subsided later on during healing. 201 

Compared with adult wounds, tenascin is present 

earlier in fetal wounds, and may be responsible for 

initiating cell migration and the rapid epithelialization 

of fetal wounds. 202 Some investigators 201,202 

believe that tenascin could be a modulator of cell 

growth and movement and that it may influence 

the deposition and organization of other extracellular 

matrix glycoproteins during tissue repair. 

WOUND CARE 

Cleaning and Irrigation 

The general surgical principles of cleanliness and 

gentleness in managing wounds remain the mainstay 

of accepted medical practice. Next to debridement, 

cleaning the wound is the most important 

thing one can do to prepare the wound. It is not 

enough to simply soak the affected part; irrigation 

with at least 7psi of pressure is needed to flush out 

any bacteria in a wound. 203 High-pressure irrigation, 

however, may injure adjacent healthy tissue 

and cause lateral spread of the irrigating fluid, with 

resultant postoperative edema, therefore high-pressure 

irrigation should be reserved for highly contaminated 

wounds. 

Hollander looked at wound infection rates and 

cosmetic appearance of 1923 facial lacerations 1 

week after repair. 204 The infection rate was similar 

in 1090 lacerations that were irrigated (0.9%) vs 

833 that were not irrigated (1.4%), but there was a 

trend toward better early cosmetic appearance in 

the nonirrigated wounds. 

Wounds can be effectively cleansed with ordinary 

tap water. 205 Potent antibacterial agents like 

hydrogen peroxide, povidone-iodine, alcohol, etc. 

are unnecessary and will destroy healthy tissue. If 

they are used on a wound, they must be thoroughly 

rinsed out with sterile saline before the wound is 

sutured or bandaged. Most uncomplicated wounds 

can be irrigated with 50–100mL/cm of wound 

length, whereas contaminated wounds and wounds 

at high risk of becoming infected (marine wounds, 

farm injuries, and gunshot wounds) require 1–2L of 

irrigation. 

Debridement 

Adequate debridement is perhaps the most 

important step to produce a wound that will heal 

rapidly and without infection. Necrotic tissue is a 

safe haven for bacteria and the physical presence 

of the dead cells prevents the wound from contracting 

and healing. 

Scrubbing with a saline-soaked sponge is a very 

effective way of removing bacteria, proteinaceous 

coagulum and debris. 206 Scrubbing can also significantly 

damage healthy tissue and widen the area of 

injury. Scrubbing is best reserved for highly contaminated 

wounds with embedded particles—the 

so-called “road rash.” 

Nonselective debridement is also called 

mechanical debridement and may include any one 

or a combination of dry-to-dry, wet-to-dry, and/or 

wet-to-wet dressing changes; Dakin’s solution or 

hydrogen peroxide; and hydrotherapy or high-powered 

wound irrigation. Non-selective debridement 

is used for wounds with large amounts of necrotic 

tissue and debris. Once granulation tissue begins 

to develop, a more selective form of debridement 

should be used. 

Selective debridement can be sharp, enzymatic, 

autolytic, or biologic. Surgical debridement is the 

most effective, aggressive, and rapid means of 

removing large quantities of devitalized tissue. 

Clearly demarcated areas of living and dead tissues 

need to be appreciated or else too much viable 

tissue can be removed. 207 

16


Enzymatic debridement takes advantage of naturally 

occurring enzymes that will selectively digest 

devitalized tissue. Enzymatic debridement has the 

advantage of working continuously while the patient 

is at home or in the hospital. This form of debridement 

is slower and less aggressive than surgical 

debridement. Depending on the thickness of the 

eschar or fibrinous material to be debrided, crosshatching 

of the surface might speed the process by 

increasing the available surface area. The enzymes 

are typically applied daily and covered with gauze. 

They can be used for weeks and may need up to 1 

month of treatment for success. Silver sulfadiazine 

(Silvadene) should not be used concurrently because 

it will deactivate the enzyme. Some agents digest 

necrotic tissue from the bottom up (eg, collagenase) 

while others work from the top down (eg, 

papain–urea preparations) (Table 5). 208 

Autolytic debridement allows the body’s own 

enzymes and moisture to break down necrotic tissue. 

It acts in 7–10 days under semiocclusive and 

occlusive dressings, but not under gauze dressings. 209 

Transparent films, hydrocolloids, and calcium alginates 

may all be used to enhance autolytic debridement. 

Hydrogels hasten the autolytic process by 

quickly rehydrating necrotic tissue. Autolytic 

debridement is usually ineffective in malnourished 

patients. 

Biologic debridement with maggots was first 

introduced in the US in 1931 and was routinely 

used until the mid-1940s. With the advent of antibacterials 

maggot therapy became rare until the 

early 1990s, when it once again became popular. 

Up to 1000 sterile maggots of the green bottle fly, 

Lucilia (Phaenicia) sericata, are placed in the wound 

and left for 1–3 days. Maggot debridement can be 

used for any kind of purulent, sloughy wound on 

the skin, independent of the underlying diseases or 

the location on the body, and for ambulatory as 

well as for hospitalized patients. In addition to stimulating 

host healing through debridement and resultant 

cytokine release, the maggots secrete calcium 

salts and bactericidal peptides (defensins) 210 that provide 

an antimicrobial benefit. One of the major 

advantages of this type of debridement is that the 

maggots separate the necrotic tissue from the living 

tissue, making surgical debridement easier. Offensive 

odors and pain associated with the wound 

Table 5 

Enzymatic Debridement Agents 

17


decrease significantly, 211,212 and a complete debridement 

is achieved in most cases. 

WOUND CLOSURE 

INTRODUCTION 

Ancient Hindu medicine described the use of 

insect mandibles to approximate skin wounds. 213 

From these modest beginnings, increasingly sophisticated 

wound closure materials and techniques 

have evolved. 

Healing by primary intention is achieved by 

direct approximation of the wound margins and is 

preferable in most instances. However, when 

infection or excessive tension precludes primary 

closure, spontaneous contraction and epithelialization 

of open wounds (secondary intention) or 

delayed surgical closure (tertiary intention) may 

be necessary. 214,215 

PREOPERATIVE EVALUATION 

Hunt and Hopf 217 indicate the importance of 

simple, inexpensive, and readily available interventions 

in the perioperative setting. Their paper 

focuses on correcting for hyperglycemia and steroid 

use before surgery, preventing vasoconstriction 

by maintaining normothermia, and addressing 

malnutrition when present. 

Scars are generally less conspicuous if they can 

be made to follow a skin line. 218 The surgical incisions 

are planned so that the final scar lies parallel 

or adjacent to the relaxed skin tension lines 

(RSTL). 219–223 The RSTL in the face are the lines of 

facial expression. 223 In young, unlined persons, the 

RSTL can be visualized by pinching the skin in various 

directions. In older people the RSTL coincide 

with the nadir of wrinkles. 

Elective incisions for the removal of skin lesions 

should be planned as a long ellipse approximately 

four times longer than wide (Fig 7). If the ellipse is 

too short, the skin will bunch at the ends in a dogear. 

163 

PRINCIPLES 

Crikelair 216 listed the Halstedian fundamentals of 

surgical wound closure which apply to the management 

of any skin wound. 

• Place incisions to follow tension lines and natural 

folds in the skin. 

• Handle tissues gently and debride only as much 

as necessary to ensure an adequately clean bed. 

• Ensure complete hemostasis. 

• Eliminate tension at the skin edges. 

• Use fine sutures and remove them early. 

• Evert wound edges. 

• If possible, choose patients whose age is closer 

to 90 than to 9 years. 

• Allow time for scars to mature before repeat 

intervention. 

Fig 7. Elliptical excision. A, If the ellipse is too short, dog ears will 

form at the ends. B, Correct method. (Reprinted with permission 

from Grabb WC: Basic Techniques of Plastic Surgery. In: Grabb 

WC and Smith JW (eds), Plastic Surgery, 3rd Ed. Boston, Little 

Brown, 1979.) 

When the orientation of the RSTL cannot be 

determined, the lesion can be excised as a circle 

provided the margins are undermined in all directions. 

The natural skin tension will pull the wound 

into an elliptical configuration and one may then 

proceed with suturing. 218 

Semicircular lacerations, if sutured linearly, tend 

to yield a trapdoor deformity. Gahhos and 

18


Simmons 224 recommend immediate Z-plasty for the 

repair of curved lacerations. Borges 225 disagrees, 

arguing that (1) most lacerations go beyond the skin 

and therefore it is difficult to decide what may be 

viable tissue; (2) patients may not like a zigzag scar 

if they have not had an opportunity to compare it 

with the scar produced by linear closure; and (3) 

the risk of infection or hematoma after a traumatic 

laceration is greater than after elective scar revision. 

WOUND PREPARATION 

Local anesthesia in the face is induced with a 

dilute anesthetic solution injected at key points over 

the nerve to the wounded area using a 25-gauge or 

smaller needle. 226 The syringe should be small and 

the pressure on the plunger no more than needed 

for a slow but steady flow. 

Traumatic wounds must be rid of all devitalized 

tissue and foreign material. Only minimal debridement 

is recommended in the head and neck 

because of the ample blood supply of the area and 

the mutilating consequences of overly aggressive 

debridement. After sharp debridement the wound 

should be thoroughly cleansed with normal saline 

or with povidone iodine for antisepsis. 

If primary closure is contemplated, the wound 

edges are trimmed to make them perpendicular to 

the bed. The exception is in hair-bearing areas, 

where they should parallel the hair shafts. Every 

effort should be made to preserve key anatomic 

landmarks—the vermilion border, eyelid, eyebrow, 

nostril, and auricular helix—by precisely aligning 

the wound edges during closure. 

SURGICAL TECHNIQUES 

Meticulous surgical technique is required to 

obtain an inconspicuous scar. Critical elements 

include the obliteration of dead space, layered tissue 

closure, and eversion of skin margins. 

Deep dermal sutures align the skin edges and 

help decrease tension on the skin closure. Everting 

skin sutures are placed by encompassing a larger 

amount of deep dermis than epidermis in the closure 

(Fig 8). They are tied under the minimal tension 

necessary to oppose the skin margins. 

Nonabsorbable synthetic monofilament sutures 

(nylon, Prolene, Novafil) are minimally reactive and 

Fig 8. Technique of layered wound closure everting the skin 

edges. (Modified from Spicer TE: Techniques of facial lesion 

excision and closure. J Dermatol Surg Oncol 8:551, 1982.) 

thus preferred for skin closure when cosmesis is 

essential. Absorbable synthetic braided sutures 

(Vicryl, Dexon) are ideal for deep dermal closure, 

acting as transient but necessary skin splints. 

Absorbable natural sutures (catgut, chromic catgut) 

induce inflammation as they are degraded by 

phagocytosis. They are useful where suture removal 

is difficult and cosmesis is not critical (eg, in the oral 

cavity, nasal cavity, and non-facial wounds in children). 

227–233 

The simple interrupted suture is the most common 

skin closure method. Horizontal mattress sutures 

facilitate tissue eversion with the use of 50% fewer 

sutures, whereas vertical mattress sutures are useful 

in wounds under significant tension. Running 

sutures speed the closure of uncomplicated, linear 

wounds. Unlike interrupted sutures, they do not 

allow the differential adjustment of suture tension 

that is required in complex wounds. Subcuticular 

running sutures yield cosmetically pleasing results 

in wounds under mild tension. 234–238 

Tissue bonding with cyanoacrylate adhesives is 

becoming an increasingly popular method of wound 

closure in Canada and Europe. Mizrahi 239 reported 

the use of cyanoacrylate glue in more than 1500 

simple pediatric lacerations, with a 2.4% complication 

rate. Applebaum 240 cites the advantages of rapid 

19


and painless application at an average materials cost 

of $2.86 per patient. These products are not currently 

in mainstream use in the United States. 

A skin-stretching device has been developed 

recently by Hirschowitz. 241 Marketed in the U.S. 

as the Sure-Closure device, it uses the skin property 

of mechanical creep 242 to achieve primary 

closure of large wounds that would otherwise 

require grafts or flaps. Promising results have been 

demonstrated in the closure of fasciotomies, 

amputation stumps, and other wounds of the trunk 

and lower extremity. 

For difficult wound closure in the acute setting, 

Abramson and colleagues 243 describe a simple technique 

of intraoperative skin stretching with 18-gauge 

spinal needles placed parallel to the wound margins 

aided by a rib approximator. 

Markovchick 244 lists his recommendations for 

suture repair of soft-tissue injuries in an emergency 

department, including preferred anesthetic, suture 

material, surgical technique, wound dressing, and 

timing of suture removal (Table 6). 

POSTOPERATIVE CARE 

Immediately after completing the closure, antibiotic 

ointment is applied to the suture line without 

further occlusive covering. Most surgeons recommend 

that the wound be kept dry for the first 2 

days, after which gentle washing is encouraged. 

Borges, 245 however, questions the wisdom of keeping 

a wound dry, and instead recommends immediate 

application of a light dressing to prevent scab 

formation and to maintain a moist wound environment. 

In support of this practice Noe and Keller 246 

report no suture disruption, wound dehiscence, or 

infection in 100 patients who washed their wounds 

with soap and water twice a day beginning the 

morning after surgery. 

In the head and neck surgical sutures are 

removed in 3–5 days, while elsewhere they are 

left in place for 7–10 days. To remove it, the 

suture is cut close to the skin edge and its free 

end is pulled across the wound, not away from it. 

Crikelair 216 notes that the two most common 

causes of unsightly suture marks are delayed 

removal beyond 10 days and excessive tension 

of the closure. The size of the individual “bites”, 

type of needle, and suture material are not significant 

to the esthetic outcome. 

The eventual width of a scar is proportional to 

the force required for closure. Wray 247 suggests 

prolonged support of the wound edges with tape to 

effectively minimize scar width. Nonwoven 

microporous tape is superior in terms of breaking 

strength, extensibility, adhesive capacity, porosity, 

and resistance to infection. 248 

For a wound to heal as a good scar without 

hypertrophy, adhesion, or contracture, the processes 

of scar formation and remodeling must follow 

a precisely chartered, finely tuned course. 

Parsons 249 makes the following points regarding 

scar prognosis: 

• A scar usually looks its worst between 2 weeks 

and 2 months after injury. Scar revision should 

await scar maturation, which can take from 4 to 

24 months depending on the type of injury as 

well as on the patient’s age and genetic background. 

The only exception to this rule is when 

there is loss of function—eg, scars crossing concave 

surfaces or the flexor aspects of joints, which 

tend to contract into tethering bands that prevent 

full extension. 

• A scar becomes noticeable if it interrupts the 

homogeneous flow of tissue planes through color, 

contour, or texture differences—eg, hyperpigmented, 

depressed, or shiny scars. 

• The final appearance of a scar depends more on 

the type of injury than on the method of suture. 

Bruising and infection, traumatic tattooing, 

improper orientation of a laceration, tension, 

and beveling of edges on closure predict a poor 

outcome. 

• Differences among suture materials are of negligible 

importance to the result, but other technical 

factors of suture placement and removal do 

affect the final scar. 

• Immobilization is as important in soft-tissue healing 

as it is in bone fractures. Tension across the 

wound causes minute wound disruptions and 

subsequent excessive scarring. Adhesive strips 

across the suture line should be kept in place for 

1 or 2 weeks after the sutures are removed. 

20


Table 6 

Suture Repair of Soft-Tissue Injuries 

(Reprinted with permission from Markovchick V: Suture materials and mechanical after care. Emerg Med Clin North Am 10(4):673, 1992.) 

21


WOUND DRESSINGS 

There are more than 2000 wound dressing materials 

available commercially. See the Appendix 

for an overview of their respective properties, indications, 

advantages, and disadvantages. 

The red-yellow-black classification of wounds has 

removed the mystery in choosing a dressing. The 

RYB system is used for wound healing by secondary 

intention and is based on the balance of healthy 

granulation tissue and necrotic tissue (Table 7). 

When treating a wound with multiple colors, the 

worst problem should be treated first: black before 

yellow before red. 

Semipermeable Occlusive Dressings 

There is evidence that debridement, angiogenesis, 

dermal repair, and epithelialization are 

accelerated under occlusive dressings. The mechanisms 

involved include thermal insulation, changes 

in wound pH, PO 2 

and PCO 2 

, and maintenance of 

growth factors in the moist environment. 250 

Because occlusive dressings can cause skin maceration 

from excessive fluid accumulation, many 

popular modern dressings are semipermeable, 

allowing escape of moisture vapor and passage of 

gases but preventing entry of bacteria and liquid 

water. 250 Carver and Leigh 250 review the various 

types of commercially available occlusive dressings, 

Table 7 

Wound Management Protocol: The Red-Yellow-Black Classification 

22


including alginates, adhesive-coated films, hydrocolloids, 

hydrogels, foams, and absorptive powders 

and pastes. 

Katz et al 251 compared the effects of 6 commercially 

available semiocclusive dressings on the healing 

of contaminated surface wounds. All the materials 

tested were equally effective in increasing 

the rate of reepithelialization; all, however, produced 

microenvironments that were conducive 

to the growth of bacteria. Although occlusive dressings 

may provide a physical barrier to exogenous 

microorganisms, by themselves they are unable to 

prevent infection once pathogens are introduced, 

and may actually promote infection by encouraging 

bacterial proliferation, particularly with prolonged 

occlusion. 

Alginates are particularly well suited for use in 

wounds with heavy exudates. Upon contact with 

the wound exudate, the alginate is converted to 

a sodium salt, which results in a hydrophilic gel 

and an occlusive environment that promotes 

wound healing. The dressing must be changed 

when the gel-like substance begins to weep exudate. 

252 

Creams are opaque, soft solids or thick liquids 

intended for external application. Medications are 

dissolved or suspended in the emulsion base, a 

water–oil substance. Creams are usually applied to 

moist, weeping lesions and have a slight drying 

effect. Creams can be formulated to aid in drug 

penetration into or through the skin. Ointments 

are semisolid preparations that melt at body temperature 

and are used for their emollient properties. 

Their primary role in wound healing is to aid 

in rehydrating the skin and for topical application of 

drugs. 

Foam dressings consist of hydrophobic polyurethane 

sheets with a nonabsorbent, adhesive 

occlusive cover. Foam dressings are very absorbent 

and nonadherent to the wound. Because 

they absorb environmental water, reepithelialization 

does not occur as readily as under moisture-promoting 

dressings. 

Film dressings are transparent polyurethane membranes 

with water-resistant adhesives. They are 

highly elastic and conform easily to body contours. 

Film dressings are semipermeable to moisture and 

oxygen and impermeable to bacteria. The trapped 

moisture promotes autolytic debridement, but can 

also macerate the wound in the event of heavy 

exudate. Because the membrane is transparent, 

film dressings are best for visual monitoring of 

wounds. They do not hold up well in friction areas, 

and the adhesive can tear the skin in elderly 

patients. 253 

Gauze dressings are highly permeable to air and 

allow rapid moisture evaporation. They can stick to 

newly formed granulation tissue and damage it 

when dressing is removed, and dressing changes 

can be painful. In addition, both woven and nonwoven 

gauze will leave behind some lint and fibers 

which can harbor bacteria. 

Hydrocolloid dressings are completely impermeable 

and therefore should not be used for dressing 

wounds with anaerobic infections. These dressings 

adhere well, are comfortable for the patient, and 

are effective in absorbing minimal to moderate 

amounts of exudate. Hydrocolloid dressings are 

well suited for wounds over high-friction areas. 

Hydrogel dressings are simply starch and water 

polymers that are manufactured as gels, sheets, or 

impregnated gauze. They rehydrate a wound, and 

because of their high water content, they do not 

absorb large amounts of wound exudate. 

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

V.A.C. dressings provide a negative-pressure 

environment around the wound that helps remove 

interstitial fluid and edema and improve tissue oxygenation. 

They also remove inflammatory mediators 

that suppress the normal progression of wound 

healing. 130,131 Granulation tissue forms more rapidly 

and bacterial counts decrease to


ucts must be in the Ag + nonmetallic, ionic form to 

inhibit cell wall synthesis, ribosome activity, membrane 

transport, and transcription in bacteria. Silverimpregnated 

dressings provide broad-spectrum 

antimicrobial coverage and are effective against 

methicillin-resistant S. aureus and vancomycinresistant 

enterococci as well as against yeast and 

fungi. 254–256 

Oasis (Cook Surgical) is a unique wound dressing 

made from porcine small intestinal submucosa. Oasis 

is simple to use and appears to act as a scaffold for 

collagen to stimulate wound healing in chronic and 

possibly in acute wounds. 257 Oasis is relatively 

inexpensive, easy to handle, safe, and appears to 

have a sound scientific basis for its claim that it 

promotes healing. 258 

Apligraf 

For several years, Apligraf has been associated 

with improved healing over conventional therapy 

in skin ulcers from venous insufficiency or diabetic 

neuropathy. Apligraf is cultured human skin delivered 

“fresh” on a culture medium to be placed on 

a patient’s ulcer. Apligraf is bilayered living skin— 

epidermis and dermis—that contains no Langerhans 

cells, melanocytes, macrophages, lymphocytes, 

hair, or blood vessels. Cytokines have been identified 

in it, including interleukin, platelet-derived 

growth factor, tumor necrosis factor, vascular 

endothelial growth factor, and fibroblast growth factor. 

It is derived from human foreskin that has 

undergone extensive viral and genetic processing. 

259,260 

Treatment with Apligraf is expensive, but when 

all factors are taken into consideration (the actual 

cost of the bandage plus all health care resources 

such as office visits, home visits, laboratory tests, 

treatment failures and complications, and subsequent 

hospitalizations), Apligraf therapy is less costly 

than traditional therapies for chronic ulcers. 261 

Dermagraft 

Dermagraft is a human fibroblast-derived dermal 

substitute that consists of neonatal dermal fibroblasts 

cultured in vitro on bioabsorbable mesh to produce 

a living, metabolically active tissue containing the 

normal dermal matrix proteins and cytokines. 262 To 

date there are no trials comparing the efficacy of 

Dermagraft vs. Apligraf, although multiple studies 

attest to a higher percentage of healed diabetic 

foot ulcers treated with Dermagraft compared with 

controls. 262–266 

HYPERTROPHIC SCARS 

AND KELOIDS 

INTRODUCTION 

“A preferred scar is one that has matured rapidly 

without contracture or increase in width, and 

without forming more collagen than is necessary for 

its strength.” 

van den Helder and Hage (1994) 267 

While most modern societies perceive prominent 

scars as disfiguring, some primitive societies 

continue to use scarification for ornamental purposes. 

268 The existence of surface scarring was probably 

recognized centuries before Jean-Louis Alibert 

described the cheloide. 269 However, the wide variety 

of current theories and proposed treatments for 

these abnormal scars demonstrates how inadequate 

our understanding remains. 

Gross Morphology 

Hypertrophic scars are characteristically elevated 

above the skin surface but limited to the initial 

boundaries of the injury. The severity of the initial 

tissue injury determines the extent of scar. Hypertrophic 

scars may occur at any age or site and tend 

to regress spontaneously. They are more common 

than keloids and are generally more responsive to 

treatment. 270–273 Hypertrophic scars may regress with 

time and occur earlier after injury (usually within 4 

weeks). 

Keloids are distinguished clinically from hypertrophic 

scars by their extension beyond the original 

wound and lack of regression. They may develop 

from either superficial or deep injuries, are better 

correlated with young age and dark skin color, and 

are frequently resistant to treatment. 270–273 Most 

keloids form within 1 year of wounding, although 

some may begin to grow years after the initial 

injury. 271 Symptoms associated with keloid forma- 

24


tion include pain, pruritus, hyperpigmentation, disfigurement, 

and decreased self-esteem (especially 

in teenagers). Persistent pruritus is associated with 

keloid formation. 274 Areas of the head and neck 

that are spared include the eyelids and the mucous 

membranes. 274 

Rudolph 275 described a third type of abnormal 

scar, the widespread scar, which apparently results 

not from excessive collagen deposition but rather 

from a mishap occurring during the third phase of 

healing as a consequence of continued tension and 

mobility of the wound. The typical widespread 

scar is flat, wide, and often depressed. 

ETIOLOGY AND PATHOGENESIS 

The underlying mechanism of abnormal scars is 

an excessive accumulation of collagen from increased 

collagen synthesis or decreased collagen degradation. 

276,277 A number of genetic and environmental 

factors have been implicated in the pathogenesis of 

hypertrophic scars and keloids (Fig 9). 

Fig 9. Factors implicated in the pathogenesis of hypertrophic 

scarring. (Reprinted with permission from Thomas DW et al: The 

pathogenesis of hypertrophic/keloid scarring. Int J Oral Maxillofac 

Surg 23:232, 1994.) 

The most common triggering mechanism for 

keloid formation is earlobe piercing, although 

localized skin trauma, vaccination, hormonal excess, 

increased skin tension, genetic factors, and other 

minor factors have also been implicated. 278 Virtually 

all abnormal scars are associated with trauma, 

including surgery, lacerations, tattoos, burns, injections, 

bites, vaccinations, and occasionally blunt 

impact. 271 Skin tension is frequently implicated, 

especially in hypertrophic scar formation. Areas of 

high skin tension, such as the anterior chest, shoulders, 

and upper back are commonly involved. 279,280 

Brody and colleagues 281 point out that hypertrophic 

scars may result from compressive forces across the 

scar rather than excessive tension, as hypertrophic 

scar contractures occur only on the flexor surfaces 

of joints. Other local etiologic factors include wound 

infection or anoxia, prolonged inflammatory 

response, and a wound orientation different from 

the relaxed skin tension lines. 

Tissue hypoxia has been implicated in keloidal 

scar formation. 282 The mechanism by which 

hypoxia may lead to keloidal scar formation is 

unclear. Vascular endothelial growth factor (VEGF) 

is released from fibroblasts in response to hypoxia. 

Gira et al 283 found that VEGF production was 

abundant in keloids and the source of the VEGF 

was the overlying epidermis. In contrast, 

Steinbrech et al 284 found no difference in levels 

of VEGF between keloidal fibroblasts and normal 

dermal fibroblasts. 

There is a theory that keloidal scars are caused 

by an immune reaction to sebum. 285 Proponents 

suggest random damage to pilosebaceous structures 

in the skin. 286 This theory is supported by the following 

observations: keloids are more common in 

adolescence; they rarely occur on the palms and 

soles; spontaneous keloids occur in skin areas with 

sebaceous activity; and one scar may be keloidal 

whereas an adjacent scar may be normal. 

Keloids can be considered a mesenchymal neoplasm. 

Keloid fibroblast have been shown to contain 

the oncogene gli-1 and express the protein 

Gli-1, 287 and in this regard are similar to basal cell 

carcinomas. This oncogene is not expressed in 

fibroblasts from normal tissue and non-hypertrophic 

scars (no reports in the literature whether it is 

expressed in fibroblasts of hypertrophic scars). 

A detailed review of keloids, their etiology, pathogenesis, 

and treatment by Shaffer et al 288 is highly 

recommended. A brief discussion of the differences 

between keloids and hypertrophic scars is 

presented. 

EPIDEMIOLOGY 

Keloids are far more common in blacks than in 

other races, whereas other abnormal scars do not 

exhibit an ethnic predilection. Even though they 

25


can occur at any age, keloids are prevalent in patients 

between 10 and 30 years of age, 289 while young 

children 290 and older adults 291 are rarely 

affected. 294 There are many reports of keloids 

being more frequent in women, but this may just 

be a reflection of which sex seeks correction. 292 

A study of rural Africans reveals a similar incidence 

of keloids in men and women. 293 Although 

keloids can occur in persons of all races, darkly 

pigmented skin is affected 15X more often than 

lighter skin. 295,296 

Keloids show racial and familial heritability, indicating 

a genetic component. A predisposition to 

keloid formation is inherited as an autosomal dominant 

297 or autosomal recessive trait. 298 Keloids tend 

to have accelerated growth during puberty or pregnancy 

and to resolve after menopause. 299,300 

HISTOLOGY 

Microscopic analysis reveals large collagen 

bundles in keloidal scars but not in hypertrophic 

scars. 301,302 Collagen bundles are “crisp” in 

hypertrophic scars and more “glazed” in keloidal 

scars. 303 Keloidal scars may have few macrophages 

but abundant eosinophils, mast cells, plasma 

cells, and lymphocytes. 301 Keloidal scars are associated 

with a mucopolysaccharide ground substance 

and hypertrophic scars have only scant 

amounts. 301 

Hypertrophic scars have nodules containing 

cells and collagen within the mid-to-deep part of 

the scar. 304 Within these nodules are smooth 

muscle actin-staining myofibroblasts which are 

absent from normal dermis, normal scars, and 

88% of keloids. On electron microscopy, Ehrlich 

et al 304 found an amorphous substance around 

keloidal fibroblasts that separate them from the 

collagen bundles. This substance was not seen in 

hypertrophic scars. 

BIOCHEMICAL AND METABOLIC ACTIVITY 

The increased metabolic activity of hypertrophic 

scars and keloids is reflected in elevated 

glycolytic enzyme activity, fibronectin deposition, 

and collagen MRNA expression. 305–307 Unlike normal 

wounds, fibroplasia in these abnormal scars 

continues well beyond the third post-injury week 

without resolution. 271 The scars remain immature, 

with an abnormally high content of Type III 

collagen and a disorganized pattern of collagen 

deposition. 308 The scars are initially hypoxic but 

later exhibit increased blood flow that is three to 

four times greater than that of normal scars. 309 

Although hypertrophic scars and keloids are histologically 

indistinguishable by light microscopy, 279 

Ehrlich et al 304 have recently demonstrated a number 

of electron microscopic and immunochemical 

differences. Keloids contain thick collagen 

fibers with increased epidermal hyaluron content, 

310 whereas hypertrophic scars exhibit nodular 

structures with fine collagen fibers and 

increased levels of alpha-SM actin 216,220,221,223,311 

(Table 8). 

Ueda et al 312 found that keloidal scars have 

higher levels of adenosine triphosphate (ATP) and 

fibroblasts than hypertrophic scars. Nakaoka et al 313 

found a higher density of fibroblasts in both keloidal 

scars and hypertrophic scars, but keloidal scars 

had a higher expression of proliferating cell nuclear 

antigen, which may help explain the tendency of 

keloidal scars to grow beyond the boundary of the 

original wound. 

Immunologic alterations have been demonstrated 

in abnormal scars, including irregular immunoglobulin 

and complement levels, 314,315 increased mast 

cells and TGF-β, 316,317 and decreased TNF and 

interleukin-1. 318,319 

Antinuclear antibodies against fibroblasts and 

epithelial and endothelial cells have been found in 

patients with keloidal scars but not in those with 

hypertrophic scars. 320 

Lower rates of apoptosis have been observed in 

keloidal fibroblasts. 321 It has been suggested that 

keloidal fibroblasts resist physiological cell death, 

continuing to proliferate and produce collagen. 322 

Keloidal fibroblasts have increased levels of PAI- 

1 and low levels of urokinase. 323 This may lead to 

reduced collagen removal and contribute to scar 

formation. 288 

TREATMENT 

Prevention is the best therapy for keloids. Preventive 

measures include avoiding nonessential 

cosmetic surgery, closing wounds with minimal tension 

following skin creases, and using cuticular, 

monofilament, synthetic permanent sutures in an 

effort to decrease tissue reaction. 274 One should 

26


Table 8 

Biochemical Alterations in Abnormal Scars 

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

1997, Ch 1.) 

also avoid Z-plasties or any wound-lengthening techniques 

and any incisions that cross joints. 

No universally effective treatment for keloids 

exists. A “shotgun approach” to treatment is most 

often used, and specific modalities are chosen on a 

patient-to-patient basis. 278 For example, although 

injected triamcinolone is considered to be efficacious 

as a first-line therapy, silicone gel sheeting 

may be more useful in children and others who 

cannot tolerate the pain of other therapies. 324 

Lindsey and Davis 325 reported a 15% overall recurrence 

rate in 202 patients with head and neck 

keloids treated with excision, intralesional steroids, 

silicone sheeting, and radiation therapy. All patients 

had more than 2-years of follow-up. 

The following is a list of current treatment options 

for keloids: 278 

Excision and closure by direct approximation, local 

flap, homograft, or keloid skin suturing 

Cryosurgery 

Laser excision — argon, CO 2 

, or Nd:YAG laser 

Radiation therapy — as primary treatment or surgical 

adjuvant 

Steroids — intralesional injection, topical ointment, 

or as a surgical adjuvant 

Pressure therapy 

Retinoic acid (topical) 

Verapamil (intralesional injection) 

5-fluorouracil (intralesional injection) 

Penicillamine 

Colchicine 

Thiopeta 

Hyaluronidase 

Vitamin E (oral) 

Silicone sheet or gel 

Interferon — IFN-α-2b or IFN-γ 

Excision Alone. Excision alone has not been 

successful in eliminating keloids. Recurrence rates 

range from 45% to 93%. 296,326 Apfelberg et al 327 

proposed using the keloid epidermis as an autograft 

after keloid excision to avoid donor site morbidity, 

decrease the amount of tension on the closure, and 

to lessen the cosmetic deformity. Weimar and 

Ceilley 328 used the autograft technique with 

27


adjunctive pressure therapy and steroid injections. 

Adams and Gloster 329 recommend excision and 

suprakeloid flap closure (Fig 10) with postoperative 

radiation therapy for the successful treatment of an 

earlobe keloid. 

Fig 11. Core excision of a dumbbell keloid of the ear having both 

a posterior and anterior component. (Reprinted with permission 

from Porter JP: Treatment of the keloid: What is new? Otolaryngol 

Clin North Am 35:207, 2002.) 

Fig 10. Keloid of the earlobe: dissection from the epidermis and 

closure with suprakeloid flap. The excision is followed by 

radiotherapy to the site to prevent recurrence. (Reprinted with 

permission from Adams BB, Gloster HM: Surgical pearl: excision 

with suprekeloid flap and radiation therapy for keloids. J Am Acad 

Dermatol. 47:307, 2002.) 

Surgical Excision and Steroids. Treatment of 

an earlobe keloid consists of a single intralesional 

injection of triamcinalone acetonide, 40mg/mL, 

through a 27-gauge needle. It should be very 

difficult to inject the medication; if it injects freely, 

then the needle is incorrectly positioned. Approximately 

0.3mL of steroid is injected into the lesion. 

If the response is significant, the injection is repeated 

after 1 month. If there is no response at 1 

month, the keloid is excised by the core technique 

278 (Fig 11). Approximately 5mg of triamcinalone 

acetonide, 10 mg/mL, is deposited in the 

wound at the time of excision. The wound is closed 

anteriorly and is allowed to granulate posteriorly. 

After reepithelialization has occurred, the patient 

is instructed to begin use of silicone gel twice 

daily. Monthly steroid injections of the 40mg/mL 

concentration are performed for 2–3 months to 

prevent recurrence. 

Core excision of a dumbbell keloid on the earlobe 

with adjuvant steroids shows excellent cure 

rates. The anterior wound is closed primarily and 

the posterior wound is allowed to granulate. 

Salasche 330 reports successful treatment of 6 patients 

without recurrence at the 1-year follow-up period. 

Adjuvant therapy has become the standard of care 

to effect improved outcomes. 

Laser Excision. Lasers are believed to wound in 

such a way so as to minimize scar contraction. Both 

carbon dioxide and argon lasers showed early promise 

in keloid excision, but long-term studies revealed 

recurrence rates of up to 92% when used as a 

single treatment modality. 294,296,331–333 The most 

promising form of laser therapy seems to be the 

585nm flashlamp-pumped pulsed-dye laser (PDL), 

which has been effective in reducing pruritus, 

erythema, and the height of keloids, with improvement 

in 57% to 83% of cases. 331–335 The best results 

are obtained when laser excision is combined with 

adjunctive therapy. 

Steroids. Intralesional steroids are used often 

for the initial treatment of keloids, but more commonly 

they are the adjuvant treatment of choice 

perioperatively. Steroids suppress the inflammatory 

phase of wound healing, decrease collagen 

production by the fibroblast, and control fibroblast 

proliferation. Triamcinolone acetonide, 

40mg/mL, is the usual agent, and is administered 

preoperatively, intraoperatively, and/or postoperatively. 

No single regimen has proved to be 

most effective. 

28


Table 9 

Reports of X-ray Therapy for Keloids 

(Reprinted with permission from Norris JEC: Superficial X-ray therapy in keloid management: a retrospective study of 24 cases and literature 

review. Plast Reconstr Surg 95:1051, 1995.) 

Adverse reactions to the use of intralesional steroids 

may include local depigmentation or 

hypopigmentation, epidermal atrophy, telangiectasia, 

and skin necrosis. Systemic side effects and 

Cushing’s syndrome are rare and associated with 

improper dosages. Ketchum and colleagues 336 

injected up to 120mg triamcinolone intralesionally 

at the time of excision, and noted 88% regression 

to varying degrees and disappearance of pruritus 

within 3–5 days. Complications included atrophy, 

depigmentation, and recurrence. Currently most 

practitioners do not administer such high doses; 

rather, monthly doses of ~12mg are recommended. 

337 

Radiation Therapy. Radiation therapy has been 

used for treating keloids since 1906. 296 Used alone, 

radiation therapy is associated with a wide range of 

cure rates (15%–94%). 326 

Radiotherapy is best used in conjunction with 

surgical excision. When the lesions are first excised 

and subsequently radiated, the response rates 

increase to 33%–100%. 326 More recent studies show 

even better response rates (64%–98%). 326 In large 

keloids resistant to treatment, radiotherapy offers a 

reduction in recurrence rate, from 50%–80% with 

surgery alone, to ~25% with combined surgery 

and early postoperative radiotherapy (Table 9). 338,339 

Success seems to depend on the number of rads 

delivered to the surgical site and start of RT immediately 

postoperatively. Preoperative irradiation 

does not offer any advantage. The usual dosage is 

15–20Gy administered over 5 or 6 treatment sessions. 

Possible complications include scar hyperpigmentation 

and, rarely, malignant degeneration. 

340 

Controversy abounds regarding the safety of 

delivering radiation to a benign tumor, 341 fueled by 

anecdotal reports of malignant tumors developing 

after RT of a keloid. Although the recommended 

dose for the treatment of keloids is low, long-term 

follow-up is needed to put this issue to rest. 

Pressure Therapy. Pressure therapy is effective 

in the treatment of hypertrophic scars and 

keloids, especially after burn injury. 342 This therapeutic 

strategy is used in combination with other 

treatment modalities (eg, silicone gels or sheets). 

The applied pressure should be 24–30mmHg to 

avoid excessive compression of peripheral blood 

vessels. Maximum benefit is achieved from wear- 

29


ing the pressure appliance for 18–24h/d for at least 

4–6 months. 296,343,344 

Pressure is thought to decrease tissue metabolism 

and increase collagenase activity within the 

wound. 272 Pressure techniques include various compression 

wraps and custom garments for large areas, 

or the use of large clip-on earrings after excision of 

earlobe keloids. 345 Pressure therapy requires 

patience and perseverance, as continuous application 

of pressure is required for several months to 

obtain a satisfactory result. 

Several authors report good response rates of 

90%–100% in patients treated with keloid excision 

followed by pressure therapy, 296,343,344 especially 

when the keloid was located on the earlobe. 

Intralesional verapamil combined with 6 months of 

pressure therapy after keloid excision resulted in a 

55% cure rate in one series. 346 

Interferon. Interferons interfere with the ability 

of fibroblasts to synthesize collagen. Specifically, 

IFN-α-2b normalizes the collagen and glycosaminoglycan 

of the keloid. 347 Complications of IFN-α- 

2b injection include flu-like symptoms of headache, 

fever, and myalgias. In a retrospective study, Berman 

and Flores 347 found lower recurrence rates with 

postexcisional IFN-α-2b (18.7%) than with either 

excision alone (51.1%) or postexcisional triamcinalone 

injections (58.4%). Conejo-Mir et al 348 

report 0% recurrence at 3 years with the combination 

of CO 2 

laser excision and IFN-α-2b injections 

for keloids of the earlobe. 

Interferon-γ is believed to work similarly to IFN-α- 

2b. There have been several anecdotal reports regarding 

the benefits of IFN-γ in treating the keloid. 

Pittet et al 349 reported improvement of hypertrophic 

scars in 7 patients who were given human recombinant 

gamma-interferon in twice-weekly intralesional 

injections for 4 weeks. Granstein 350 and Larrabee 351 

have also reported modest success with gammainterferon 

in a small number of patients. 

A small pilot study by Broker et al 352 followed 

the course of patients with two keloids, one of 

which was treated with IFN-γ injections and the 

other with placebo injections after excision. Only 

7 patients were enrolled in the study and 3 

dropped out by the 1-year follow-up examination. 

Both experimental and control groups had uniformly 

poor results, with an approximate 75% 

recurrence. 

Other researchers have used antitransforming 

growth factor-beta (anti-TGF-β) to decrease scarring 

in experimental animals. 317 Tredget 353 

describes antagonizing the proliferative effects of 

TGF-β2 and histamine with interferon-α-2b. 

Imiquimod is an immune response modifier that 

stimulates innate and cell-mediated immune pathways, 

enhancing the body’s natural ability to heal. 354 

Imiquimod also induces the local synthesis and 

release of cytokines, including IFN[alpha], 

IFN[gamma], tumor necrosis factor-[alpha], and 

interleukins-1, -6, -8, and -12 when topically 

applied. 355 A number of recent case reports and 

clinical studies document success with imiquimod 

under conditions where interferons are also successful. 

Nightly application of topical imiquimod 

5% cream for 8 weeks after surgical excision of 13 

keloids from 12 patients resulted in no recurrence 

of keloidal growth at 24 weeks. 356 

Silicone Gel Sheeting. The mechanism of action 

of silicone gel sheeting is not known. Histologic 

examination reveals no evidence of silicone leakage 

into the tissues. Hydrocolloid dressings are 

occlusive and facilitate scar hydration, and are considered 

to be safe in the treatment of wounds in the 

initial stages of healing. 357 

Depending on the series, between 80% and 100% 

of patients show significant improvement of their 

hypertrophic scars with silicone gel. 358–360 In patients 

with keloids, however, silicone gel is successful only 

35% of the time. 360 Silicone gel sheeting may reduce 

recurrence rates after excision of keloids. It is a benign 

intervention that does not cause any problems and 

may be useful as an adjunctive measure. In human 

trials, topical silicone gel was used to treat 22 keloids 

in 18 patients, with a significant response rate of 

86%. 361 Possible drawbacks to silicone gel include 

patient noncompliance (especially children) and 

occasional rashes, skin breakdown, or difficulty 

obtaining adherence to the scar. 362 

The review by Shaffer et al 288 summarizes and 

compares all keloid treatments in the literature. 

SURGICAL TREATMENT 

Keloids that are resistant to corticosteroid injection, 

pressure therapy, or other topical therapy 

should be considered for surgical excision. Surgery 

alone is associated with recurrence rates of 50%– 

30


80% and is therefore indicated only in compliant 

patients who are willing to undergo adjuvant therapy 

postoperatively to try to avoid a recurrence. 363 

Hypertrophic scars, although more responsive to 

appropriate surgery, also frequently require adjuvant 

treatment. 

Guidelines for the surgical management of 

abnormal scars are as follows: 

• combination therapy—eg, surgery and corticosteroids—is 

more effective in preventing recurrence 

than any single modality 

• for small scars, surgical excision and corticosteroids 

are appropriate therapy 

• for moderately large scars, pressure therapy should 

be added to the surgery-steroid combination 

• for very large, treatment-resistant scars, the best 

results are reported with a combination of surgery 

and postoperative radiotherapy 

• pressure and irradiation are useful surgical adjuvants 

but are ineffective in the treatment of 

established lesions 

• skin grafts should be harvested from areas where 

pressure can be easily applied 

Z-plasty 

A Z-plasty entails creation of triangular transposition 

flaps which are used to lengthen a contracted 

scar or to reorient a scar parallel to the RSTLs (Fig 

12). Although a single large Z-plasty often gives 

more length, multiple small Z-plasties may better 

camouflage the scar. 

The goals of excisional scar revision are to redirect 

the scar, divide it into smaller segments, and 

make it level with the adjacent skin. The location 

and size of the scar will also influence the choice of 

revision procedure. 364 

Fusiform Excision 

Fusiform excision is the most commonly used 

technique of scar revision because of its simplicity 

and because it does not add to scar length. Ideally 

an ellipse at least four times as long as it is wide 

should be removed to prevent dog-ears. Fusiform 

excision is indicated for short, linear, minimally 

wide but unsatisfactory scars that approximate the 

RSTLs. The technique is much less effective in 

addressing depressed scars or wide hypertrophic 

scars resulting from primary wound closure. 365 

Bowen and Charnock 366 recently described a 

double-blade scalpel for excising long, linear scars, 

and reported excellent results in 27 widespread 

abdominal scars. 

Fig 12. Z-plasty angles and their theoretical gain in length. (After 

Grabb WC: Basic Techniques of Plastic Surgery. In: Grabb WC, 

Smith JW (eds), Plastic Surgery, 3rd Ed. Boston, Little Brown, 1979.) 

The three limbs of the Z must be of equal length. 

Increasing the angles between the limbs will gain 

length at the expense of increased tension. The 

usual Z-plasty angle is 60° and the resulting scar will 

31


be 75% longer than the original minus 25%–45% 

lost to skin elasticity. 218,367,368 Z-plasty scar revision 

is indicated in the following circumstances: 369 

• antitension-line (ATL) scars of the eyelids, lips, 

nasolabial folds, and nonfacial areas 

• scars on the forehead, temples, nose, cheeks, 

and chin running at less than 35° of inclination 

to the RSTLs 

• severe trapdoor and depressed scars 

• small linear scars not amenable to fusiform excision 

• most areas of multiple scarring 

W-plasty 

Unlike Z-plasties, a W-plasty breaks up the 

straight-line configuration of a scar without adding 

length to its axis (Fig 13). Since it requires excision 

of additional tissue, it should not be used in scars 

under significant tension. W-plasty scar revision is 

indicated for the following conditions: 220,370 

• ATL scars of the forehead, eyebrows, temples, 

cheeks, nose, and chin 

• bowstring scars 

• small but broad, depressed scars 

Y-V-plasty 

A series of Y incisions can be made on the same 

plane across a scar to break up the scar cord and 

lengthen it. 371 The tongue at the top of the Y stem 

can be advanced to form a V without raising the 

dermis (Fig 14). This ensures a good blood supply. 

Running Y-V plasties are indicated in the management 

of some contracted burns scars and may be 

used in conjunction with W-plasties to break up a 

linear scar. 

Fig 13. W-plasty. A, W-plasty for repair of a straight scar. 

Triangles become smaller at the end of the scar, and the length 

of the limbs of the flap is tapered to avoid puckering. B, On 

a curved scar, the angles of the inner aspect of the curve should 

be more acute than the angles of the outer aspect of the curve. 

(After Borges AF: W-plasty. Ann Plast Surg 3:153, 1979; 

reprinted with permission from McCarthy JG: Introduction to 

Plastic Surgery. In: McCarthy JG (ed), Plastic Surgery. Philadelphia, 

WB Saunders, 1990. Vol 1, Ch 1, pp 1-68.) 

Serial Excision 

Staged excision is appropriate for wide scars 

that cannot be excised completely without tension. 

Although largely supplanted by tissue 

expansion, serial excision remains simpler and 

more cost-effective. 234 

Fig 14. The running Y-V-plasty. (Reprinted with permission from 

Olbrisch RR: Running Y-V plasty. Ann Plast Surg 26:52, 1991.) 

32


Tissue Expansion 

Full-thickness unscarred skin can be recruited 

from areas adjacent to large hypertrophic scars and 

burn scar contractures by placement and gradual 

inflation of expanders. In a second stage, the scar is 

excised and the expanded skin is used to resurface 

the tissue deficit. 372 Tonnard et al 373 described a 

technique for scar-length reduction by circumferential 

adjacent tissue recruitment using two semicircular 

expanders. 

Skin Stretching 

The Sure-Closure device is discussed in the 

Wound Closure section. The device has been proposed 

to excise and primarily close large scars on 

the trunk and extremities. 241 

Miscellaneous 

Dermabrasion. Dermabrasion removes the epidermis 

and partial-thickness dermis and smoothes 

surface irregularities. It is most effective for mildly 

elevated or depressed scars, particularly acne scars. 

Dermabrasion is often used as an adjunct to scar 

excision. 374,375 

Scalpel Sculpturing. Snow et al 376 reported using 

a #15 scalpel blade to microshave and feather the 

skin edges as an alternative to dermabrasion. Other 

authors have used razor blades to contour small, 

mildly elevated scars. 377 

Cryosurgery. The first prospective study of 

cryosurgery for abnormal scars was recently reported 

by Zouboulis et al. 378 Good-to-excellent responses 

were seen in 57 of 93 White patients treated with 

nitrous oxide once a month for at least 3 months. 

Significant pain occurred in 32% of patients and 

lesional pigmentary changes were seen in 11%. 

Laser. Lasers have been applied to the management 

of abnormal scars because of their ability to 

remove lesions precisely with minimal injury to 

normal adjacent tissue. The Nd:YAG, CO 2 

, and 

argon lasers have been used with modest success. 

379,380 Dierickx et al 381 reported 80% improvement 

in 26 patients with erythematous or pigmented 

scars after treatment with the flashlamp-pumped 

pulsed dye laser. Alster and Nanni 382 report symptomatic 

improvement of hypertrophic burn scars 

after treatment with the 585nm pulsed dye laser, 

namely improved scar pliability and texture and 

decreased erythema. 

EXOTIC WOUNDS 

This section will address some of the more exotic 

wounds, including 

Extravasation injuries 

Radiation burns 

High-pressure injuries 

Chemical burns 

Ballistics and high-velocity missile wounds 

Aquatic animal wounds 

Bites — snakes, spiders, centipedes 

Stings — scorpions and caterpillars 

EXTRAVASATION INJURIES 

Leakage of solution from a vein into the surrounding 

tissue spaces during intravenous administration 

may lead to severe local tissue injury. Adult 

patients undergoing chemotherapy have a 4.7% 

risk of extravasation. 383 In children the risk is 11% 

to 58%. 384 Usually extravasation is recognized early, 

remains localized, and heals spontaneously. The 

injury can be classified as necrotic, irritant, or vesicant. 

The most common agents involved are 

osmotically active chemicals (eg, total parenteral 

nutrition), cationic solutions (eg, potassium ion [K + ], 

calcium ion [Ca 2+ ]), and cytotoxic drugs. 385 

Certain groups of patients are prone to extravasation 

injury: Babies in special care units are at 

greater risk because of their immature skin and 

their frequent need for antibiotics or intravenous 

electrolyte and nutritional support. Elderly patients 

may be unable to report the pain from extravasation 

injury and the general fragility of their skin and 

veins make them more susceptible to injury. 386 

Cancer patients often have fragile veins that are 

difficult to cannulate. Patients who are unable to 

communicate or have a decreased level of consciousness 

may have extravasation injuries that go 

unnoticed. 

33


The sequelae of extravasation are often more 

serious than the original injury and are often 

underestimated. Common sites of injury are the 

dorsum of the hand and the antecubital fossa, where 

there is little soft-tissue coverage. 385 Extravasation 

may result in large wounds that require debridement 

and coverage with a split skin graft or local 

flap, and when next to a major artery in the forearm 

or leg, extravasation may lead to amputation. 

Severe damage to the underlying nerves and tendons 

can also happen. Chemotherapeutic agents 

may produce an insidious injury because they spread 

to the surrounding tissue and produce indolent 

ulcers that resemble radiation necrosis. 385 

The extent of damage after extravasation injury 

depends on the toxicity of the drug, the site of 

extravasation, the amount that has leaked out, and 

the general nutrition of the patient. The clinical 

presentation varies. There may be a loss of blood 

return at the cannula site, which may be accompanied 

by pain (a burning sensation). Persistent pain 

suggests a more severe injury. 387 Erythema may be 

present, accompanied by swelling of the surrounding 

area and local blistering, suggesting at least a 

partial-thickness injury, which may also be associated 

with mottling and darkening of the skin. Early, 

firm induration and pain are good indicators of eventual 

ulceration, which may lead to eschar beneath 

which is the ulcer cavity. 

A wide array of treatments has been proposed, 

ranging from no intervention to early aggressive 

excision. 388–390 If the extravasated drug is an antibiotic 

or hypertonic solution, application of ice to the 

area, elevation, and monitoring the patient for 48 

hours are usually sufficient. 391 Scuderi and Onesti 392 

recommend local injection of copious amounts of 

saline and topical application of corticosteroids if 

only a few hours have elapsed since injury. 

Extravasated high osmolarity contrast medium 

(such as is commonly used for contrast CT scans) is 

treated with 4–6 small incisions around the area 

of extravasation. A blunt-ended liposuction cannula 

with side holes is inserted in the incisions and 

used to aspirate extravasated material and subcutaneous 

fat. Saline is then injected through the 

same cannula, up to 200mL. After extensive irrigation, 

the saline is aspirated using the liposuction 

device. 393 

Khan and Holmes 394 list five mechanisms of 

extravasation necrosis: 

1) direct cellular toxicity (chemotherapeutic agents, 

pentathol) 

2) osmotically active substances with an osmolality 

greater than that of serum (parenteral nutrition, 

contrast dye) 

3) ischemic necrosis from vasopressors and cationic 

solutions (epinephrine, dopamine) 

4) mechanical compression 

5) bacterial colonization 

The authors devised a kit and protocol for the 

rapid treatment of extravasations caused by cytotoxic 

drugs. 394 The kit contains hydrocortisone 

cream, injectable hyaluronidase and lidocaine, 

sodium chloride infusion, and a number of syringes 

and needles. The aim is to flush out as much of the 

cytotoxic agent as possible. 

When preventive measures and drug therapy 

are insufficient to avert tissue necrosis, or if the 

injury is extensive or more than a few hours old, 

early surgery is indicated. Gault 386 reviewed a series 

of 96 patients with extravasation injuries seen at 

two London hospitals during a 6-year period. Of 

the 44 patients treated by either saline flushout 

(37), liposuction (1), or both (6), 86% healed without 

soft-tissue loss. Examination of the flushout fluid 

confirmed the presence of the extravasated material. 

Early treatment was associated with a good 

outcome. Patients who were referred late suffered 

skin necrosis and significant scarring around tendons, 

nerves, and joints, and many required extensive 

reconstruction. 

Most authors now recommend early detection 

and excision of all affected tissue following 

Adriamycin extravasation. 395–398 The excision may 

be guided by fluorescence microscopy; 396,397 

delayed closure is indicated. 

RADIATION INJURY 

The morphologic and functional changes that 

occur in noncancerous tissue as a direct result of 

ionizing radiation can range from mild to extremely 

debilitating or life-threatening. Ionizing radiation 

causes damage to tissue by means of energy transference. 

Free radicals are formed and cause intracellular 

and molecular damage. The primary targets 

of ionizing radiation are cellular and nuclear membranes 

and DNA. The susceptibility of an individual 

34


cell to radiation damage is directly proportional to 

its mitotic rate. The most sensitive cells are those 

which divide rapidly, such as cells of the skin, bone 

marrow, and gastrointestinal tract. In addition to 

sensitivity of the exposed cell, morbidity from 

radiation depends on the dose received, time over 

which the dose is received, volume of tissue irradiated, 

and type of radiation. 399 Cellular changes 

resulting from low-dose radiation are probably due 

to an apoptotic mechanism, whereas changes 

related to high-dose radiation are probably due to 

direct cellular necrosis. 

The direct effects of radiation can be immediate, 

acute (days to weeks), or delayed (months to 

years). Acute effects result from necrosis of the rapidly 

proliferating cell lines. A transient, faint erythema 

may appear during the first week of treatment due 

to dilation of capillaries and may be associated with 

an increase in vascular permeability. Radiation 

inhibits mitotic activity in the germinal cells of the 

epidermis, hair follicles, and sebaceous glands. Epilation 

and dryness of the skin occur. By the third or 

fourth week of radiation, typical erythema is localized 

to the radiation field and the skin is noticeably 

red, edematous, warm, and tender. Larger vessels 

may be obstructed by fibrin thrombi, edema is 

prominent, and there may be small foci of hemorrhage. 

400 Cellular exudate is rare. If the total radiation 

dose to the skin does not exceed 30Gy, the 

erythema phase is followed during the fourth or 

fifth week by a dry desquamation phase characterized 

by pruritus, scaling, and an increase in melanin 

pigmentation in the basal layer. Within 2 months 

the inflammatory exudate and edema have subsided, 

leaving an area of brown pigmentation. 

If the total radiation dose to the skin is >40Gy, 

the erythema phase is followed by a moist desquamation 

phase. This stage usually begins in the fourth 

week and is often accompanied by considerable 

discomfort. Bullous formation occurs above the basal 

layer and sometimes just below the epidermis. Eventually 

the roofs of the bullae are shed and the entire 

epidermis may be lost in portions of the irradiated 

area. Edema and fibrinous exudate persist. In the 

absence of infection, reepithelization of the 

denuded skin usually begins within 10 days. Ulcers 

may appear 2 weeks or more after radiation exposure. 

These ulcers are a result of direct necrosis of 

the epidermis; they usually heal but tend to 

recur. 399,401 

Approximately 1 year after radiation treatment 

the epidermis is thin, dry, and semitranslucent, with 

vessels easily seen. Hair follicles and sebaceous 

glands are usually absent. Some sweat glands may 

also have been destroyed. In time, increasing fibrosis 

of the skin is present. Much of the collagen and 

subcutaneous adipose tissue are replaced by atypical 

fibroblasts and dense fibrous tissue that may 

cause induration of the skin and may limit movement. 

In radiation injury of soft tissue, fibrinous 

exudate accumulates under the epidermis. Characteristic 

features of delayed radiation lesions are 

eccentric myointimal proliferation of the small 

arteries and arterioles as well as telangiectasia. These 

changes may progress to thrombosis or complete 

obstruction. Delayed ulcers are more common than 

acute ulcers and result from ischemic changes in 

small arteries and arterioles; they heal slowly and 

may persist for several years. Irradiated skin in the 

chronic stage is thin, hypovascularized, extremely 

painful, and easily injured by any slight trauma or 

infection. 399,401 

Skin reactions to radiation should be treated early 

to prevent complications later. Keeping the skin 

moist and pliable to prevent fissures and cracks and 

free of infection is extremely important. Mendelsohn 

et al 402 has compiled a list of products to treat 

radiation-induced skin changes (Table 10). If an 

ulcer develops, the normal wound care protocols 

should be initiated. In severe cases, wide 

debridement and a skin graft or flap coverage may 

be necessary. 

Treatment with hyperbaric oxygen accelerates 

healing in some patients, 403,404 but its effectiveness 

in soft-tissue necrosis from radiation injury is 

unproven. Experimental therapies include topical 

TGF-β1, 405 granulocyte-macrophage colonystimulating 

factor (GM-CSF), 406 orgotein (a Cu/Zn 

chelate with superoxide dismutase), 407 topical vitamin 

C, 408,409 topical corticosteroids, 410 glucorticoids, 

411 NSAIDs, 412 aloe vera gel, 413,414 heliumneon 

laser treatments, 415 and oral pentoxifylline 

treatment. 416 

HIGH-PRESSURE INJECTION INJURIES 

High-pressure injection devices such as are used 

for painting, cleaning, degreasing, etc. can produce 

pressures of 600–12,000psi. 417,418 The substance 

enters the skin through a seemingly insignificant 

35


Table 10 

Skin Care Products Used for Different Radiation Skin Reactions 

(Adapted from Mendelsohn FA, Divino CM, Reis ED, Kerstein MD: Wound care after radiation therapy. Adv Skin Wound Care, 15:216, 2002.) 

wound and rapidly spreads through the tissues along 

fascial planes. In the hand, the injected material 

can course volar to the tendon sheath and extend 

into the forearm. The tendon sheath is rarely 

breached. The degree of injury varies with the 

injection pressure and type of injected material. 

With high injection pressures and large amounts of 

caustic substances, tissue damage can be so extensive 

that salvage may not be possible. Amputation 

rates after high-pressure injection injuries range up 

to 48% in the literature. 419 

Water, low volume vaccines, and air generally 

cause no serious damage. 420,421 In these cases medical 

treatment with wide spectrum antibiotics and 

tetanus prophylaxis are usually all that is needed. 422 

Other times the pressure itself is responsible for the 

initial damage; a compartment syndrome may be 

induced immediately by the amount of material 

injected and later by the inflammation elicited. 423 

Digital injection injuries do worse than palmar 

injuries because of the limited space available for 

expansion. 423,424 

An immediate progressive toxic effect has been 

shown to take place in cases of paint and paint 

thinners, 425 and a foreign body reaction occurs if 

the material is not removed, leading to fibrosis and 

draining sinuses. 424 

The nature of the injected material is probably 

the most important factor in the subsequent injury. 

Injected paint wounds have a worse outcome than 

those injected with oil or grease. Spirit-based paints 

cause damage by disintegration of cell membranes, 

whereas oil-based paints cause an intense inflammatory 

response. Latex paints in a water base are 

the least noxious. 419 

Not surprisingly, delayed and conservative treatment 

of high pressure injection injuries is associated 

with very poor results and frequent amputation. 

424,426,427 The proper management of these 

lesions is primarily surgical, with immediate removal 

of the foreign material, debridement, cleansing of 

necrotic areas, and insertion of a drain. X-ray evaluation 

should precede the surgical treatment, both 

to detect fractures and to guide the decompression. 

Angiograms are also useful to show any areas 

that are not being perfused. Medical treatment 

includes tetanus and antimicrobial prophylaxis and 

antibiotic administration. A postoperative physical 

rehabilitation program will help reduce the degree 

of functional impairment. 426 

36


CHEMICAL BURNS 

The proper treatment of chemical burns is tailored 

to the wounding agent, as follows. 

Black Liquor 

Black liquor is a warm alkaline solution (pH 11– 

13) that is used to convert wood chips to pulp. 428 It 

consists of a mixture of sodium bicarbonate (10%), 

sodium hydroxide (60%), sodium sulfide (4%), sodium 

thiosulfate (5%), and sodium sulfate (4%) at a 

temperature of 85–95°C. Surgical treatment begins 

with irrigation with tap water. Silver sulfadiazine 

cream and sodium chloride solution occlusive dressings 

are applied twice daily. Debridement and skin 

grafting procedures may be necessary. 428 

Cement 

Cement burns are either alkaline or heat related. 

Wet cement is roughly 64% calcium oxide and 

21% silicon oxide and has a pH of ~12.5. Abrasions 

by the coarse cement allow the alkali to enter 

the skin and cause increased tissue destruction. The 

most frequently affected areas are the knees, calves, 

and feet. Because the initial contact is typically 

painless, the injury progresses from prolonged contact 

with the skin. 429,430 In time there is reddish 

discoloration of the contact areas, followed by a 

gradual change to a deep purple-blue color and this 

may go on to painful burns, blistering, and ulceration. 

429,431 Treatment consists of removing the agent 

with a cloth followed by washing the affected area 

with soap and copious amounts of running water. 431 

Chromic Acid 

Chromic acid is an industrial chemical used for 

electroplating in alloy and dye production. Chromic 

acid burns produce coagulative necrosis and 

may lead to systemic toxicities, including gastrointestinal 

hemorrhage, vomiting, diarrhea, renal or 

hepatic failure, CNS disorders, anemia, and 

coagulopathies. An exchange transfusion may be 

required to remove hexavalent chromium bound 

to hemoglobin from the circulation. Circulating 

chromium may also be removed by peritoneal 

dialysis or by hemodialysis the day after the burn 

occurs. 432,433 

Treatment initially involves water irrigation or 

use of phosphate buffer or 5% thiosulfate soaks, 

which convert hexavalent chromic ion into a less 

toxic trivalent form. Topical use of 10% calcium 

ethylenediamine tetraacetic acid (EDTA) ointment; 

5–10% sodium citrate; lactate- or tartrate-soaked 

dressings; or cream containing ascorbic acid, sodium 

pyrosulfate, ammonium chloride, tartaric acid, and 

glucose is recommended to prevent further absorption. 

Dimercaprol, ascorbic acid, or sodium calcium 

edetate are often used as systemic treatment. 

432,433 

If the burn is 2% TBSA, immediate wide excision reduces systemic 

chromium absorption, and should be followed 

by split-skin grafts. Peritoneal dialysis in the first 24 

hours prevents parenchymal chromium uptake. 

Formic Acid 

Formic acid or formate is used industrially as a 

descaling agent, as a rubber processor, and as a 

textile tanning substance. The main concern in 

cases of formic acid burn is systemic acidosis, which 

impairs the elimination of formic acid because of 

increased reabsorption in the proximal tubule. 434 

Patients often present with hypotension, intravascular 

hemolysis (because of cytotoxic formate 

effects), hematuria, hemoglobinuria, kidney failure, 

CNS depression, and evidence of other organ damage. 

434 

Treatment is similar to that of other acid burns. 

All clothing is removed and the patient is thoroughly 

washed with water. Internally, the formate is 

removed or neutralized with intravenous hydration 

and aggressive bicarbonate therapy. Folic acid can 

be administered to accelerate formate breakdown. 

Dialysis may be necessary. 

Hydrofluoric Acid (HF) 

HF is used to frost, etch, and polish glass and 

ceramics; to remove sand from metal castings; to 

clean stone and marble; and to treat textiles. HF is 

also prevalent in the manufacture of fertilizers, pesticides, 

solvents, dyes, plastics, refrigerants, highoctane 

fluids, rust removers, aluminum brighteners, 

and heavy-duty cleaners. 435,436 Although an 

acid, HF causes injury similar to an alkali because it 

37


reaches deeply into tissue. Because of its ability to 

penetrate lipid membranes, HF breaches cell membranes 

and binds calcium and magnesium ions within 

the cell. The initial corrosive burn causes little damage 

compared with the secondary damage produced 

by the fluoride ions. The F ions produce 

extensive liquefaction of soft tissues and decalcification 

and corrosion of bone. Most exposures 

involve dilute HF on small spots. Exposure of concentrated 

HF to even small areas (~2%) of the body 

often has a fatal outcome. 435,436 

The clinical presentation is of blanched tissue 

with surrounding erythema and immediate severe 

pain. Edema and blistering occur within 1–2 hours, 

then gray areas followed by necrosis and deep 

ulceration within 6–24 hours and possible tenosynovitis 

and osteolysis. Even burns from dilute HF, 

if left untreated, will progress to similar destruction. 

436 In addition to the obvious burn, systemic 

effects of hypocalcemia and hyponatremia must also 

be addressed. Cardiac arrhythmia often results from 

hypocalcemia, and free fluoride ions may cause 

respiratory arrest and ventricular arrhythmia. 436 

Treatment consists of copious irrigation for about 

20 minutes to clean the wound of any unreacted 

chemicals and to dilute the chemical that is in contact 

with the skin. Washing is extremely important 

in HF burns because the toxic properties derive 

from complex ions that are not present at concentrations 

of


etration progresses, white phosphorus continues to 

be oxidized until it is removed by debridement or 

consumed by oxidation. 439 

White phosphorus is difficult to remove and often 

becomes embedded in the skin. Immediate treatment 

consists of prompt removal of all clothing in 

contact with the agent. The skin is then washed 

with cool water to end oxidation of the white phosphorus. 

Greasy dressings should be avoided because 

they contribute to tissue permeability. The phosphorus 

is then neutralized with a dilute solution of 

copper sulfate (1%–5%) briefly applied to the wound 

(because of the danger of copper toxicity). Bicarbonate 

may be used to neutralize the pH of the 

wound. 439 

BULLET WOUNDS 

Santucci and Chang 440 reviewed the tissue effects 

of different bullet types, as follows: 

Jacketed bullets travel faster than 2000ft/sec 

and are used primarily in assault rifles. They are 

more likely to wound than to kill. Hollow-point 

bullets are designed so that the tip flattens and 

expands on impact, to 2–3X the original diameter. 

They cause more tissue damage and a larger permanent 

wound cavity. These bullets are prohibited 

by the Geneva Convention for military use but are 

sold legally to U.S. civilians. Exploding bullets are 

designed to detonate on impact, but do not explode 

reliably. Surgeons must be careful when handling 

these bullets, which should always be grasped with 

forceps. PTFE (cop killer) bullets have a steel or 

tungsten core coated with PTFE and are intended 

to penetrate Kevlar vests. Similarly, armor piercing 

rounds have a hardened steel or tungsten core 

designed to penetrate light military armor of trucks 

and other vehicles. Black talon bullets have a 

reverse-tapered hollow point designed to open into 

petal-like blades that cut tissue as it spins into the 

wound. These bullets should always be grasped 

with forceps or hemostats because the razor-sharp 

blades will easily cut the surgeon’s fingers. Frangible 

bullets, eg, the Glaser Safety Slugs, use a 

lightweight cup of jacketed lead filled with small 

lead shots. When the bullet hits its target, the cup 

collapses and empties its shot contents into tissue, 

causing massive destruction at a relatively superficial 

level. A large caliber round at close range 

causes severe, widespread tissue damage. 

Shotshells are meant to turn handguns and small 

rifles into minishotguns. Shotgun injuries are devastating 

at close range. Air bursting ammunition 

will be fired from US Army M-16 rifles in the near 

future. When fired, high explosive, air bursting 

ammunition will detonate at a prescribed distance 

to send shrapnel to multiple targets. The projected 

increase in wounding power is 4-fold over standard 

rifle rounds. 

The authors 440 dispelled some misconceptions 

about high velocity projectiles, primarily that ballistic 

wounds require massive debridement. Their 

extensive review of the literature led them to the 

following conclusions: 

1) It is not true that high velocity weapons always 

cause more tissue damage than low velocity 

weapons. In fact, the fastest bullets are just as 

likely to keep traveling past the victim after leaving 

the body and impart little wounding energy 

onto the target. 

2) It is not a good idea to debride the bullet path 

up to 30X the diameter of the bullet; this may 

actually harm the patient. Overdebridement is 

to be avoided. 

3) The current recommendation is to debride 

obviously detached and nonviable tissue, then 

reexamine the wound after 2 days for additional 

debridement if necessary. 

WOUNDS BY AQUATIC ANIMALS 

The treatment of wounds inflicted by some marine 

vertebrates, from stingrays to sea snakes, is summarized 

in Table 11. 

Marine wounds easily become infected, and as 

such most wounds should be left to heal secondarily. 

Special culture media are required for isolation 

of certain marine organisms. Infected wounds 

should also be cultured for routine aerobes and 

anaerobes. Management of marine acquired infections 

should include therapy against Vibrio spp. Any 

patient with a marine acquired wound who develops 

rapidly progressive cellulitis or myositis should 

be suspected of having Vibrio parahemolyticus or 

Vibrio vulnificus infection. 441 

Soft-tissue infections are common after alligator 

and crocodile bites, and broad-spectrum antibiotics 

should be administered prophylactically. A variety 

of gram-negative aerobes including Aeromonas 

39


Table 11 

Emergency Treatment of Wounds Caused by Marine Organisms 

(Reprinted with permission from McGoldrick J, Marx JA: Marine envenomations. Part 1: Vertebrates. J Emerg Med 9:497, 1991.) 

hydrophila, Acinetobacter, Citrobacter, Enterobacter, 

Yersinia, Proteus, and Pseudomonas; anaerobes 

such as Bacteroides, Clostridium, Fusobacterium, 

and Peptococcus; and fungi such as Candida, 

Aspergillus, and Torulopsis have been cultured from 

the mouths of alligators. 442 The same principles of 

diagnosis and treatment apply for alligators bites as 

for shark attacks, including the administration of 

tetanus toxoid vaccine. 

Wounds from stinging animals should be soaked 

in hot water as soon as possible to inactivate any 

heat-labile components of the venom and perhaps 

to help reverse local toxin-induced vasospasm and 

tissue ischemia. 441,443,444 This should be continued 

for 30–90 minutes or until the pain is relieved. If 

pain is not controlled with the hot water soak, a 

regional nerve block or local infiltration with 

bupivacaine can be performed. 441 Delayed primary 

wound closure may be performed later. 

BITES 

Snakes 

Venomous snakes are responsible for 8000 of 

the 45,000 snake bites reported in the U.S. annually, 

445 yet fewer than 15 cases per year are fatal. 446 

In other parts of the world, however, approximately 

30,000 fatal snake bites are sustained annually. 447 

These figures underscore the importance of prompt 

and appropriate treatment of snake bites. 

A regional poison-control center (which in the 

U.S. may be reached through the national hotline, 

800-222-1222) should be contacted for assistance 

in treating patients who have been bitten by a snake. 

These centers are staffed by persons who have been 

trained in all types of poisoning and maintain a list 

of consulting physicians throughout the country who 

are experienced in the management and treatment 

of bites from venomous snakes. 

Pit Vipers 

The vast majority of venomous snake bites in 

North America are by pit vipers (Crotalidae). Pit 

vipers are distinguished by a heat-sensing pit located 

between the eye and the nostril, and are most common 

in the southern U.S. This family of snakes 

includes the cottonmouth, copperhead, and rattlesnakes. 

Pit viper venom contains at least 26 enzymes 

and 69 enzymatic peptides capable of producing 

extensive local tissue necrosis. 448 Systemic envenomation 

increases capillary permeability, which may 

induce coagulopathy, shock, and acute renal failure. 

449 

Proper patient assessment should include identification 

of the species of snake, its size, the presence 

or absence of discrete fang marks, and any 

evidence of local or systemic toxicity. The eastern 

and western diamondback rattlesnakes account for 

most fatalities. Deaths typically occur in children, 

in the elderly, and in people who are either not 

40


given antivenom or receive too little of it or too 

late. 446 

The current treatment for snake bite is summarized 

by Seiler et al 448 as follows (Table 12): 

• Incision and suction. This technique is only 

effective if perfomed within 45 minutes of the 

bite, and thus is of limited value in the emergency 

department. A linear incision should be 

made through skin only, across the fang marks 

and slightly beyond. 450 Suction is applied with a 

Sawyer venom extractor. 

• Loose tourniquet. A loosely applied tourniquet will 

reduce venom dissemination from the affected 

limb by 50%. The tourniquet should be applied 1 

hour after the snake bite only if a significant delay 

in hospital transport time is anticipated. Tourniquets 

that are too tight will exacerbate tissue loss 

from the injured extremity. 448 

• Antibiotics and tetanus prophylaxis. Both measures 

are appropriate. Rattlesnake fangs may harbor 

gram negative organisms, and clostridial 

infections have been reported. 451,452 

• Surgical debridement. Wound debridement is 

indicated for the removal of all necrotic tissue. 

Because most of the injected venom remains in 

the subcutaneous tissue for a few hours, some 

authors recommend aggressive early local excision 

to remove the contaminated tissues. 452,453 

Others advocate a more conservative approach. 

454,455 

• Compartment pressure release. Severe 

envenomations by rattlesnakes may be associated 

with increased compartment pressure. 

The clinical diagnosis requires objective evidence 

of elevated compartment pressure to 

>30mmHg. The bite site should be elevated 

and the patient given an additional 4–6 vials of 

FabAV in 1h. 446 The extra antivenom should 

effectively neutralize the venom components 

and reduce compartment pressure. Fasciotomies 

are controversial and may actually prolong the 

recovery. 

• Antivenom. Indications for the use of antivenom 

have not been strictly defined. Most authors 

reserve antivenom administration for confirmed 

cases of envenomation by a medium to large 

snake, particularly a rattlesnake; for patients with 

signs and symptoms of systemic envenomation; 

and for children under age 12. 454,456–458 

After rattlesnake bites, signs of worsening local 

injury (pain, swelling, and ecchymosis), coagulopathy, 

or systemic effects (hypotension and altered 

mental status) dictate administration of antivenom. 

FabAV is a lyophilized antivenom. Each 

dose must be reconstituted and then diluted to a 

volume of 250mL in a crystalloid fluid before being 

administered. The initial dose is given by slow 

infusion for the first 10min, and the infusion of 

the rest of the dose is completed over the course 

of 1h. The dose of antivenomn is correlated with 

the clinical severity of envenomation. In most 

reported cases, 8–12 vials are sufficient to establish 

initial control. 459 Skin testing is unreliable in 

predicting the development of immediate (anaphylaxis) 

or delayed (serum sickness) hypersensitivity 

reactions to antivenom. Because the complications 

of antivenom administration can be lifethreatening, 

it should be used selectively and 

judiciously. 460,461 

Other types of therapy for crotalid bites include 

hyperbaric oxygen, cryotherapy, corticosteroids, and 

electroshock. None of these has proved efficacy. 448 

Coral Snakes 

Only one other snake indigenous to North 

America poses any serious threat to man, and 

that is the coral snake. Unlike pit vipers, coral 

snakes possess a potent neurotoxic venom consisting 

chiefly of acetylcholinesterase. Coral-snake 

envenomations produce little or no pain but may 

result in tremors, marked salivation, and changes 

in mental status, including drowsiness and 

euphoria. The neurologic manifestations are usually 

cranial-nerve palsies such as ptosis, dysarthria, 

dysphagia, dyspnea, and respiratory paralysis. 

The onset of neurotoxic effects may be delayed 

up to 12h. 446 Once manifestations appear, it may 

not be possible to prevent further effects or reverse 

the changes that have already occurred. Although 

local tissue destruction is minimal, envenomation 

may cause respiratory paralysis and immediate death 

(Table 12). Subacute deaths are usually due to 

aspiration pneumonia. 462 

41


Spiders 

Although all spiders are venomous, only a handful 

of spiders are dangerous to man from among the 

more than 100,000 species worldwide. Two North 

American species, the black widow and the brown 

recluse, are capable of penetrating the skin and 

injecting sufficient venom to inflict serious injury. 

Black Widow 

The black widow spider (Latrodectus mactans) 

is widely distributed throughout the continental 

United States. Although both sexes carry venom, 

only the female spider is large enough to cause 

significant envenomation in man. 463 The venom is 

a potent neurotoxin that causes an irreversible blockade 

of nerve conduction. The initial sharp pain at 

the envenomation site is often accompanied by 

two small red marks—the fang punctures. Within 

20 to 30 minutes of the bite, neurologic signs and 

symptoms begin to manifest, including first localized 

and then generalized muscle cramps, abdominal 

pain, restlessness, perspiration, and occasionally 

convulsions or shock. If the patient is not treated, 

milder symptoms may linger for days or weeks. 464 

Pennell et al 465 recommend the following therapeutic 

regimen (Table 12): 

• Calcium gluconate. A 10mL dose of a 10% solution 

of calcium gluconate is administered intravenously 

over 15–20 minutes. If this is effective 

in controlling pain, the diagnosis of black widow 

envenomation is confirmed. 

• Muscle relaxants. One ampule of methocarbamol 

(Robaxin) or 5–10mg of diazepam 

(Valium) may be given. 

• Black widow antivenin. A single 2.5mL vial of 

Lyovac is administered intravenously in severely 

envenomated patients. 

At greatest risk of an adverse outcome from black 

widow bites are young children, the elderly, and 

people who have underlying medical problems. 

These patients should be monitored closely and 

treated aggressively. 466 

Brown Recluse 

The brown recluse spider (Loxosceles reclusa) is 

common throughout the southern United States. 

Although nondescript in appearance, the spider may 

be distinguished by its long slender legs, fiddle-like 

markings on its dorsal thorax, and shiny brown 

exoskeleton. 467 The bite usually goes unnoticed at 

first. Within several hours, however, increasing pain 

is accompanied by erythema and blistering at the 

puncture site, which frequently has a pale halo. 

Over the next few days, a central ulceration may 

spread to adjacent skin, resulting in extensive tissue 

destruction and occasional limb loss. 

Systemic envenomation is uncommon but may 

cause hemolytic anemia, thrombocytopenia, and 

disseminated intravascular coagulation. Five of the 

six reported deaths from brown recluse bites have 

been in children. 468,469 

Treatment remains controversial. Dapsone, an 

anti-leprosy drug, has been advocated for the prevention 

of tissue necrosis. Oral administration of 

dapsone (100–200mg q.d. x 10–25d) inhibits neutrophil 

migration. Patients must be selected carefully 

and monitored closely, since dapsone may 

induce a dose-dependent hemolytic anemia or 

agranulocytosis. 467,470 Surgical excision may result 

in significant scarring and soft-tissue defects and 

does not appear to inhibit the spread of venom. 

Conservative surgical debridement limited to 

infected or obviously necrotic tissues is appropriate 

(Table 12). 

Centipedes 

Like spiders, centipedes are venomous, and any 

centipede with large-enough fangs to penetrate 

human skin has the ability to envenomate humans. 

Centipede envenomation usually results in burning 

pain, local swelling, lymphangitis, and lymphadenopathy. 

Symptoms may persist for weeks and then 

disappear, only to recur. Systemic reactions in the 

United States are rare. Treatment is symptomatic, 

and infiltration of the bitten area with lidocaine or 

other anesthetic agent promptly relieves pain. Tetanus 

prophylaxis should be provided. 471 

STINGS 

Scorpions 

In 2002 there were 15,687 calls to U.S. poison 

control centers related to scorpion stings. Of these, 

485 (3%) required medical attention, 2 resulted in 

42


Table 12 

Symptoms and Treatment of Patients after Snake and Spider Bites 

death, and 8 had major complications. 472 Worldwide 

there are an estimated 5000 deaths from scorpion 

stings every year. 

Scorpions have a stinger at the end of their tail 

through which they introduce venom that immobilizes 

their prey. The size of a scorpion does not 

correlate with its aggressiveness or the potency of 

its venom. Scorpions can control the amount of 

venom released per sting depending on the victim’s 

size, and can sting repeatedly and rapidly when 

faced with large prey. In the United States and 

Mexico, the small Centruroides scorpions account 

for the majority of severe human envenomations. 473 

Scorpion venom varies among species, but 

generally is a mixture of single-chain polypeptides 

containing neurotoxins that block ion channels, 

particularly sodium and potassium. A pronounced 

acetylcholine and catecholamine release triggers 

secondary effects. The most notable aspect of a 

scorpion sting is significant pain at the puncture site 

with little redness and edema. Typical adults experience 

local pain and some paresthesias extending 

along the affected limb that can last for several hours, 

but have minimal systemic effects. Systemic 

envenomation is the cause of most deaths in children 

and the elderly. Initially there is a transient 

excess cholinergic tone at the neuromuscular junction 

resulting in salivation, lacrimation, urinary 

incontinence, defecation, gastroenteritis, and emesis 

(SLUDGE syndrome). The subsequent norepinephrine 

release causes tachycardia, hypertension, 

hyperpyrexia, myocardial depression, and pulmonary 

edema that can be fatal. The pain, paresthesias, 

and tachycardia can persist for 2 weeks. 473 

Caterpillars 

Caterpillars are the larval stages of moths and 

butterflies. There are approximately 50 species of 

caterpillar in the United States that can cause 

envenomation, with symptoms that range from a 

painful sting to dermatitis and conjunctivitis. The 

puss caterpillar, Megalopyge opercularis, is one of 

the more toxic species, sometimes resulting in epidemics 

of envenomation. It is common in the southeastern 

United States and its body has toxincontaining 

spines. A person who brushes against 

this caterpillar experiences an intense burning sensation 

at the contact site, followed shortly by redness, 

swelling, and proximally radiating pain. 

Vesicles usually appear, and pain and pruritus can 

last for days. 474 The swelling can be impressive 

and involve an entire limb. Some patients go into 

shock or have seizures. 475 

Treatment consists of local wound care and cleansing, 

immobilization and elevation of the affected 

extremity and tetanus prophylaxis. Any embedded 

broken-off spines are removed with adhesive tape. 

Diphenhydramine may be necessary for the relief 

of pruritus. Early application of ice may provide 

pain relief, but morphine or meperidine may be 

necessary in more severe cases. 475 

43


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