Charles A. Adams, Jr., Daithi S. Heffernan, and William G. Cioffi
Wound healing and patients with altered or delayed healing cover the entire spectrum of surgical care. This chapter will review wounds, wound healing and closures, coverage options, and abnormalities in wound healing. It will focus on general principles and concepts rather than specific topics since the majority of these are dealt with in greater detail in other chapters. First, the biology and pathophysiology of wound healing will be explored in depth. Next, bites and stings, including emerging threats in the United States, will be detailed as our knowledge in these areas continues to advance.
Each year in the United States, millions of individuals sustain traumatic injuries but the overwhelming majority of these are simple and readily treated with minor interventions. In practical terms, satisfactory healing of wounds such as these would take place regardless of the treatments that they received. This chapter will focus on more severe wounds or those wounds that would not have a satisfactory outcome without special attention. The main principles in treating these wounds are preventing infection, retaining maximal function, and achieving acceptable cosmesis. The spectrum of health care providers who care for these wounds is extensive, including emergency medicine physicians, advanced practice nurses, family physicians, surgeons, and surgical subspecialists, but the treatment philosophy is the same. The nature and mechanism of the wound, its anatomic location, preexisting comorbidities, and the current clinical situation all dictate the approach to the wound but in general the simplest technique that fulfills the previously stated objections should be embraced. Fig. 47-1 provides a treatment algorithm for acute wounds that is applicable to a wide array of clinical scenarios and wounds.
FIGURE 47-1 Algorithm for the treatment of an acute wound. aAppropriate tetanus, rabies, and antibiotic prophylaxis. bIntermediate-risk wounds require more judgment. cSee Table 47-9.
Wound healing has always held an important status in medical care throughout recorded history. The Egyptians practiced advanced wound care as evidenced by the Edwin Smith and Ebers papyruses as did the ancient Greeks whose doctrine on the care of acute and chronic wounds in gladiators was described by Galen of Pergamum.1 The ancients observed that dead tissue and foreign bodies had to be removed in order for normal wound healing to progress and that cleanliness prevented infection. They recognized that organized collections of pus required drainage and that honey (a hypertonic, hygroscopic, and bactericidal fluid) could prevent infections while dirt and dung promoted them. However, the biology of this effect was a mystery to them.2 Later in the 1500s, the scholarly treatise on wounds by French surgeon Ambroise Pare established a truism that is still applicable today: “Do not put anything in a wound that you would not put in your own eye.” Despite the seminal contributions of Lister, Semmelweis, Ehrlich, Fleming, and Florey, it was not until the very end of the 20th century that our understanding of the biology of wound healing grew to the point that physicians are now able to manipulate wounds utilizing translational techniques taken from cellular and molecular biology.
Wounds are generally classified into one of the following two categories: acute and chronic. Acute wounds follow a systematic, organized series of stages that ultimately result in restoration of skin integrity. In contrast, chronic wounds follow many of the same steps but do not result in reestablishment of skin integrity. Generally, a wound that fails to fully heal by 3 months is said to be a chronic wound. However, such an arbitrary definition fails to consider the size or anatomic location of the wound or other impediments to healing. We will focus on the healing of acute, cutaneous wounds since they represent the vast majority of traumatic wounds.
NORMAL WOUND HEALING
Unlike humans, many lower life forms have the ability to regenerate after wounding. In humans only the liver and bone retain the ability to heal by regeneration. Excluding these two tissues, all other mammalian tissues heal through scar formation. The steps of scar formation or wound healing are classically divided into three distinct phases: inflammatory, proliferative, and remodeling (Table 47-1). These phases usually take place in a stepwise fashion, although, as we will discuss later, there are varying degrees of overlap and in certain wounds all phases may coexist simultaneously.
TABLE 47-1 Phases of Wound Healing
The inflammatory, or reactive, phase constitutes the first phase of wound healing and commences as soon as the injury occurs. All traumatic wounds lead to bleeding, disturbances in hemostasis, and an inflammatory reaction due to cellular destruction. The main goals of this stage are to stop bleeding, prevent infection, and remove devitalized tissue. Wounding invariably leads to disruption of blood vessels with ensuing bleeding that ranges from a slow ooze from capillaries to an exsanguinating hemorrhage if large arteries or veins are involved. In order to stop the bleeding, coagulation of blood must occur in a tightly regulated fashion so that clotting is confined to the site of injury but not at remote vascular locations. Blood vessel injury leads to the exposure of subendothelial, collagen, thrombin, and other procoagulant elements that bind and activate platelets. An important early response to vascular injury is contraction of the smooth muscle within the endothelium. Endothelin, a powerful vasoconstrictor, is released directly from the endothelium of the damaged vessel, an event occurring prior to the activation of platelets.3Prostaglandins from injured cells, as well as circulating catecholamines following the trauma, also contribute to this early vasoconstrictive response. Additional stimuli for vasoconstriction occur via platelet activation with the resultant release of bradykinin, fibrinopeptides, serotonin, and thromboxane A2.
Platelet activation leads to a chain reaction culminating in the formation of an aggregate of platelets known as the “platelet plug.” Subendothelial matrix collagen interacts with circulating platelets leading to subsequent platelet adhesion. This is achieved via a complex of the platelet glycoproteins VI, Ib–V–IX, and collagen-bound von Willebrand factor on exposed collagen, as is mediated by platelet integrins. Since platelets are the first major cell to respond to wounded tissue, activated platelets serve as the platform on which clotting factors interact to form an insoluble fibrin meshwork that is generated from soluble, circulating fibrinogen. This fibrin mesh is cross-linked and traps circulating erythrocytes and activates additional platelets resulting in a tight, hemostatic plug.4 Shortly after coagulation is initiated, the complement cascade is set also in motion that leads to the release of potent neutrophil chemotactic factors, such as C5a.5 Large wounds or massive trauma may lead to an overly robust activation of this complement cascade and is thought to contribute to the subsequent development of the systemic inflammatory response syndrome (SIRS).6 C5a is believed to play a key role in the apoptotic response that occurs in immune cells shortly following a traumatic event.7 Complement is also involved in the destruction of bacteria through formation of the membrane attack complex, as well as opsonizing bacteria that facilitates their phagocytosis.
Effective hemostasis leads to a relative lack of blood flow to the wound microenvironment. This, coupled with anaerobic metabolism by leukocytes, leads to a locally hypoxic, acidotic wound environment. Such settings are known to be a stimulus for leukocyte activation so that coagulation is quickly followed by inflammation, but there is some overlap in these processes.8 Activated platelets and endothelial cells release cytokines that attract neutrophils and macrophages to the area. If thrombin is present, endothelial cells exposed to leukotrienes C4 and D4 will release the potent proinflammatory phospholipid platelet-activating factor (PAF) that enables neutrophil adhesion.9 Excessive PAF activation and involvement may lead to chronic and poorly healing wounds.10 Accordingly, by the end of the first hour and for the first 2–3 days after wounding, the dominant cell type in the wound is the neutrophil. The main purpose of the neutrophil is destruction of bacteria through phagocytosis and the generation of reactive oxygen species through a process called “respiratory burst.” Respiratory burst results in the formation of many reactive oxygen species such as superoxide anion (SO2−), hydrogen peroxide, hydroxyl radicals, and hypochlorous acid. Neutrophils also debride the wound by elaborating activated proteases and elastases that break down devitalized tissues and cells. Unfortunately, the release of activated lysosomal enzymes along with reactive oxygen species leads to the indiscriminant collateral damage of otherwise healthy host cells as well.11 Ultimately, the action of neutrophils leads to the generation of pus that is simply a collection of dead neutrophils and bacteria along with tissue breakdown products. Once neutrophils have completed their job, they undergo apoptosis, or programmed cell death, and are eliminated by macrophages in a process that is remarkably free of inflammation.
Of all the cells involved in wound healing, none is as critical as the macrophage.12 Activation of platelets, endothelial, and other cells in the wound leads to the generation of inflammatory substances such as histamine, serotonin, prostaglandins, kinins, platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β), insulin-like growth factor-1 (IGF-1), fibronectin, fibrinogen, von Willebrand factor, thrombospondin, and thromboxanes. These substances have many varied effects including increasing capillary permeability by disrupting the integrity of the endothelium, both vasoconstriction and vasodilatation, and the recruitment of several other inflammatory cell types. Monocytes respond to chemotactic signals such as fibrin and fibrinopeptides and leave the blood vessels via diapedesis. This migration is facilitated by capillary leak and interstitial edema that results from the action of inflammatory substances such that by the end of 1.5 days postinjury the numbers of monocytes in the wound reaches its peak. The inflammatory milieu of the wound then stimulates the monocyte to become a macrophage and it is these macrophages in conjunction with resident tissue macrophages that orchestrate the entire wound healing process.
Macrophages release over 20 different growth factors and cytokines and can perform a wide range of functions so that they are truly the central cell in wound healing.13 Just like the neutrophil, macrophages contribute to clearing the wound of bacteria, although neutrophils remain the prime antibacterial cell in the wound. The phagocytic function of macrophages is not limited to bacteria alone since they also clear away apoptotic neutrophils and other cells via phagocytosis. Recent evidence is emerging pointing to a key role of invariant natural killer T cells in the proper functioning of macrophages for acute processes such as wound healing and bacterial clearance.14 Unlike neutrophils, phagocytosis is not the main function of the macrophage and this activity is typically manifested only in the very early stages of wound healing. As the wound is cleared of bacteria, the macrophages release growth factors that reinforce endothelial cell activation and are chemotactic signals for various cells. Activated endothelial cells display adhesion molecules so that additional inflammatory cells can bind to the activated endothelium and be recruited into the wound.15
Initially, leukocytes tether and roll on the exposed vascular endothelial cells, before they are activated to adhere firmly with the ultimate goal of migration into the extravascular space. Leukocyte tethering and rolling is primarily mediated via selectins. The later firm adhesion is mediated via the immunoglobulin (Ig) superfamily members, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and their integrin ligands, including lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18) and very late antigen-4 (VLA-4, CD49d/CD29). The three cell-surface molecules expressed by leukocytes (L-selectin), vascular endothelium (E- and P-selectins), and platelets (P-selectin) comprise the selectin family. Each selectin exhibits a characteristic time frame. L-selectin is constitutively expressed on most leukocytes, whereas ICAM-1 is constitutively expressed at low levels by endothelial cells. ICAM-1 can be rapidly upregulated during inflammation. P-selectin is rapidly mobilized to the surface of activated endothelium or platelets. E-selectin expression is induced within several hours after activation with inflammatory cytokines. The combination of endothelial cell activation and the release of chemotactic and growth factors leads to the next stage of wound healing, the migratory phase.
The next phase of wound healing is the migratory phase. The initial “platelet plug and clot” need to be replaced with cells capable of achieving proper closure of the gap that was created from trauma, as well as to replenish the lost tissue. While the migratory phase is initiated early on in the wound healing process, its duration is highly variable and dependent on the size and nature of the wound that needs to be healed. The interaction of activated endothelial cells with circulating inflammatory cells leads to the margination of leukocytes. At this point, there is significant alteration in the cell–cell and cell–matrix adhesions to enable the progression from a laminin-V-and collagen-IV-rich basement membrane to provisional matrix substances.16 Migrating cells also assemble actin-rich lamellar protrusions that will enable crawling,17 and upregulate the expression of the proteolytic enzymes such as matrix metalloproteinases (MMPs). The migrating cells traverse the blood vessel wall through diapedesis and migrate along chemotactic gradients to the site of injury. Meanwhile, macrophages are progressing from bacterial phagocytosis to the coordination of the complex cell–cell interactions and are now the dominant cell type in the wound supplanting neutrophils and monocytes. The relatively hypoxic wound environment causes macrophages to release angiogenic growth factors, key among which is hypoxia-induced factor (HIF).18HIFs are transcriptional complexes that are regulated by protein degradation, thereby allowing a swift response. Using an HIF-knockout mouse, investigators have shown that HIF-alpha deficiency leads to a pattern of multiorgan dysfunction with significant anaerobic metabolism.19 A further key player in angiogenesis is PDGF that is released by activated platelets.20,21 Vascular endothelial growth factor (VEGF) stimulates angiogenesis in a strict dose-dependent fashion.22 Many other factors, such as angiopoietin-2/angiopoietin-1,23 PDGF, basic fibroblast growth factor (bFGF), and monocyte chemoattractant protein-1 (MCP-1),24 have been shown to be indispensable in increasing vascular permeability, endothelial growth, remodeling, cell proliferation, and vascular lumen formation. PDGF also stimulates fibroplasia by stimulating the normally present but quiescent fibroblasts to begin replicating by releasing them from their G0 arrest. Cytokines such as IGF-1 and epidermal growth factor (EGF) released from activated macrophages and platelets cause the fibroblasts to begin replicating. Additional fibroblasts from outside the wound environment arrive by traveling over the scaffold of the fibrin clot by binding to fibronectin within it. While angiogenesis and fibroblast proliferation occur simultaneously, it is obvious that like all cellular synthetic functions, fibroblast synthetic function is dependent on oxygen. Thus, in the healing wound, angiogenesis and fibroplasia are interconnected processes.25
Angiogenesis is dependent on the action of endothelial cells derived from the nearby uninjured portion of blood vessels.26 These endothelial cells first generate plasminogen activator to degrade the clot at the site of vessel injury so that they can migrate out into the extracellular matrix.25 This action is reliant on the activity of zinc-dependent MMPs that are required to dissolve the basement membrane and collagenases.26 Specifically, MMP-2 and MMP-9 have been shown to be prominent in the angiogenic response to hypoxia. Neutrophil granules are potent sources of MMP-9. Further neutrophils can release tissue inhibitors of matrix metalloproteinases (TIMP-1) pro-MMP-9 that can activate latent pro-MMP-9 in the wound environment.27 The newly “liberated” endothelial cells then migrate through the surrounding extracellular matrix by extending pseudopodia, just like leukocytes do, in response to chemotactic signals released by platelets and macrophages. The relatively hypoxic local wound environment leads to the formation of lactic acid through anaerobic metabolism, which has been shown to be a potent stimulus for macrophages to release endothelial cell growth factors.13 When tissue oxygen tension improves and the macrophages are no longer hypoxic, they stop elaborating endothelial cell growth factors in an elegant feedback loop controlling angiogenesis. Further, with restoration of oxygen to the wound, HIF-1alpha proteins are downregulated by the oxygen-dependent inhibitor, factor inhibiting HIF-1 (FIH-1).28 Thus, wound revascularization removes the stimulus for endothelial cell growth and migration and similarly to the preceding neutrophils, the endothelial cells also undergo apoptosis. The typical beefy red color of granulation tissue is a result of dense collections of capillaries formed through the process of angiogenesis.
While angiogenesis is occurring within the wound, reepithelialization is occurring at the margin of the wound. This process begins approximately 24 hours postinjury and is driven primarily by transforming growth factor alpha (TGF-α) that is released by platelets and macrophages. If a wound is sufficiently deep enough to destroy the stratum basale of the skin, keratinocytes from the wound edges or from deep skin appendages such as hair follicles, sweat glands, or sebaceous glands spared by the wounding insult serve as the source for reepithelialization. Interestingly, reepithelialization of the wound is almost entirely dependent on migration of keratinocytes, which occurs as sheets of cells move in from the wound periphery, rather than mitosis of keratinocytes within the wound. In order for keratinocytes to migrate they must detach themselves from their basement membrane by dissolving their anchoring desmosomes. Following this, they display integrins and migrate across the early wound matrix using fibronectin cross-linked with fibrin as adhesion sites exactly like the fibroblasts before them. As the keratinocytes migrate they elaborate MMPs, collagenases, plasminogen activator, and other proteases to dissolve debris as well as phagocytosize dead cells blocking their path.
As the sheet of migrating epithelial cells advances, new cells are formed at the wound margin by greatly upregulated mitosis to replenish the advancing cells. The rate of mitosis at the wound margin may be 17 times higher than that seen in normal tissue and remains the only focus of epithelial cell mitosis in the wound.29 The migration continues until keratinocytes encounter other cells that stop their advancement through contact inhibition, and downregulation of their fibronectin receptors that are necessary for their movement.25 Reepithelialization proceeds more rapidly if the basement membrane is intact, otherwise new basement membrane substances must be secreted.30 Keratinocytes will then reanchor themselves to the basement membrane and each other using desmosomes and hemidesmosomes and normal skin stratification is established by cell division of the basal layer of cells. Critical to this stability is the interaction between the hemidesmosomes, integrin-alpha6-beta4, and plectin.31
Thus, by the conclusion of the migratory phase, new blood vessels are being formed and fibroblasts are appearing in the wound and begin replicating so that fibroplasia may take place, while at the wound margin an advancing sheet of epithelial cells moves inward. Table 47-2 reviews some of the more important cytokines and growth factors involved in the regulation of wound healing.
TABLE 47-2 Cytokines and Growth Factors
The next phase of wound healing, the proliferative phase, is marked by the migration of multiple cell types including monocytes, lymphocytes, and endothelial cells into the wound along with the emergence of active fibroblasts. This phase usually commences around day 5 and is characterized by the dramatic increase in the number of cells and the production of collagen. The production of collagen may be detected as early as 10 hours after injury. However, collagen production reaches maximum velocity by day 7. Collagen synthesis continues at a vigorous pace until approximately day 21 when the wound approaches its peak of collagen content and collagen production plateaus. This is the physiologic basis for the practice of leaving retention sutures, used to reinforce tenuous laparotomy closures, in place until day 21.
Eventually, granulation tissue is formed as the fibrin–fibronectin network that comprises the blood clot along with the makeshift wound matrix of proteoglycans, glycosaminoglycans, and hyaluronic acid is replaced by a combination of collagen, new capillaries, and numerous inflammatory cells and fibroblasts. This process is largely accomplished by fibroblasts that interact with several adhesive ligands in the wound matrix such as laminin, tenascin, and fibronectin while they release hyaluronidases that degrade the provisional wound medium. This early wound continues to evolve as collagen is haphazardly laid down on the fibronectin and glycosaminoglycan scaffold. The amount of granulation tissue in the wound is dependent on the size and depth of wounds that are allowed to heal by secondary intention. Large wounds need to “fill in” with granulation tissue so that epithelial cells from the wound margin can migrate across and reepithelialize the wound. Alternatively, the development of a healthy bed of granulation tissue is the sign that a wound is ready to accept an autologous skin graft. It is the rich network of capillaries along with the relatively aqueous environment that supports the transplanted epithelium by bathing it in a flow of nutrient-containing fluid and oxygen. Full-thickness skin grafts are an important modality to mitigate the next step of wound healing that is contraction.
Wounds that are allowed to heal by secondary intention, and to a much lesser degree wounds closed primarily, undergo the phenomenon of wound contraction, which is a process whereby the wound edges and surrounding skin are pulled in toward the center of the wound. Contraction usually starts around 1 week after wounding, peaks in intensity around day 10, and may persist for weeks with a reported speed of nearly 0.75 mm per day. This process is a highly efficient way of reducing the surface size of the wound and decreases the amount of reepithelialization that needs to occur. Unfortunately, this process can be particularly debilitating if the wound overlies a joint, flexible part of the body or crucial orifice such as the eye or mouth. Significant loss of function due to the presence of a contracting wound is clinically called a “contracture.” Differences in the thickness of skin in various anatomic locations along with the laxity of the surrounding skin lead to variable degrees of contraction. Typically, the perineum and trunk experience the greatest degree of contraction while the extremities exhibit the least, while the head and neck exhibit an in-between amount of wound contraction. The exact mechanism of wound contraction is not well elucidated but appears to be dependent on modified fibroblasts that contain microfilaments and alpha smooth muscle actin and phenotypically resemble smooth muscle cells.32 The true phenotypic characteristics and capabilities of myofibroblasts are still poorly understood, but knowledge is growing as the role of the myofibroblast in pathological processes such as tumor dissemination is being better appreciated.33 Myofibroblasts are richly endowed with adhesion molecules in order to complex with a vast array of components making up the early wound environment. It is these attachments that allow them to bind and draw the wound edges together. As the wound contracts, other fibroblasts continue to synthesize collagen that effectively holds the wound together.
Nearly 20 different types of collagen have been identified and all share a common structural similarity known as the right-handed triple helix. Each type of collagen has unique structural properties that are attributed to specific breaks in the triple helix pattern. In general, collagen triple helices are composed of three alpha peptide chains that undergo extensive modification both in and outside the fibroblast. Collagen is the major component of all human tissues and is distinctive in that it contains large quantities of the unique amino acids hydroxyproline and hydroxylysine. The hydroxylation of specific prolines in the early peptide chain is extremely important because error at this stage of collagen synthesis leads to the creation of an unstable collagen that is quickly degraded in the extracellular environment. The hydroxylation of proline and lysine requires ascorbic acid (vitamin C), which is the mechanism whereby vitamin C deficiency leads to impaired wound healing, and even opening of previous healed wounds, as seen in the disease scurvy.
Regulation of collagen synthesis occurs at many levels, beginning with the transcription. Collagen transcription takes place on several different chromosomes from discontinuous genes resulting in a large precursor molecule that must be modified within the nucleus; thus, only limited amounts of messenger ribonucleic acid (RNA) are created. This highly modified mRNA then undergoes translation on ribosomes of the endoplasmic reticulum so that by the time the collagen molecule is ready to leave the Golgi apparatus, it has undergone significant glycosylation with glucose and galactose and has had “extension” peptides placed on its amino and carbon terminals to facilitate its orientation and handling. These procollagen monomers leave the cell where additional modification takes place extracellularly, resulting in highly cross-linked collagen fibers. The extracellular modification process is fairly unique to collagen, and it is during this juncture that the extension peptides are cleaved from the end of procollagen, which are then taken back into the cell and downregulate collagen expression. At the end of this stage of wound healing, sufficient collagen fibers have been synthesized and the wound is more appropriately called a scar.
Although it seems contradictory, it is true that collagen must be degraded at the same time it is created in order for normal wound healing to occur. When the rate of collagen synthesis is balanced by an equal rate of collagen degradation, the wound is said to have reached the remodeling or maturational phase. This phase of wound healing may last for several months or even years for large wounds that heal by second intention. The tensile strength of the wound increases over time as the disorganized type III collagen that was laid down initially is degraded by MMPs and slowly replaced by type I collagen. The activity of the MMPs is itself regulated by TIMPs so that a balance between synthesis, deposition, and degradation of extracellular matrix is maintained.34 Progression from laying down collagen haphazardly to the organized structure seen at the end of the remodeling phase requires a careful balance within the wound environment. This balance may be quite delicate as evidenced by the role of arginine. Therapeutic supplementation with arginine has been proposed as a safe method of providing the necessary proline and polyamines to improve wound healing; however, excess arginine has been associated with poor collagen matrix formation, impaired collagen remodeling and cross-linking, and altered wound tensile strength. It is believed that this occurs via excess nitric oxide production rather than ornithine and an imbalance in the pace of collagen remodeling.35
As type I collagen is laid down and oriented parallel to lines of stress, the tensile strength of the wound increases. This increase is most rapid during the first 6 weeks, and then slows down but may persist for over a year or more. The tensile strength of the wound approaches 50% of normal skin by 3 months after injury and plateaus out about 80% by the end of remodeling, although this process continues on at an extremely slow rate for several more years. The increase in tensile strength is attributed to collagen cross-linking since the collagen content of the wound does not change beyond the third week. The scar that was originally red or purple in color due to the tremendous amount of capillaries it contains gradually turns white as these are readsorbed and replaced with type I collagen. The final result of the repair is an inelastic, avascular, brittle scar that is devoid of skin appendages such as hair follicles and sweat glands and never recovers more than 80% of the tensile strength of unwounded skin.
CLINICAL MANAGEMENT OF WOUNDS
Types of Wound Closure
Wound closure falls into one of the following four general categories: primary, secondary, delayed primary, and tissue transfer. In primary closure, the cutaneous defect is approximated through the use of sutures, staples, adhesive dressings, or topical sealants and the previously described phases of wound healing occur albeit on a limited scale. These wounds are typically closed in layers along tissue planes and derive their strength from collagen-rich layers such as dermis or fascia. The duration of healing and the final cosmetic result are closely linked to the amount of devitalized tissue, bacteria, and blood left in the wound at the time of closure. Meticulous debridement of the wound along with scrupulous hemostasis minimizes the inflammatory phase of wound healing and allows the wound to progress rapidly to the migratory and proliferative phases of the healing process and promotes earlier wound closure with improved cosmesis as well. The decision to close a wound primarily is based on the judgment by the clinician that the wound is at minimal risk for wound infection or that subsequent wound infection after primary closure is less detrimental than open management of the wound.
Wounds that are felt to be at excessive risk for infection are best left open to heal by secondary intention. Spontaneous or secondary intention closure occurs when the wound edges are not reapproximated and the wound must undergo contracture, granulation, and reepithelialization in order to close. Open wounds are much less likely to become infected, but they are not immune to wound infection. The presence of increased bacteria and tissue debris leads to a longer, more intense inflammatory phase that results in more scarring and decreased cosmesis. Failure of healing by secondary intention leads to a chronic wound and in large part is due to a fundamental shift in the type and quality of wound inflammation. Chronic wounds, which are practically defined as a wound that has failed to close within 3 months, exhibit much higher levels of collagenases and MMPs, yet have reached a point of stasis and do not ultimately heal.
In delayed primary closure, a wound is left open for a few days and is treated much the same as a wound that is healing by second intention. The difference is that after a certain time the wound is then closed primarily. The main reason that a wound is handled in this fashion is that there is too much bacterial contamination, tissue trauma, or foreign bodies to allow a primary closure and the wound is left open so that wound care and dressing changes can remove these impediments to infection-free healing.36 There tends to be more inflammation in wounds that are managed by delayed primary closure than in those managed by primary closure, but eventually these wounds exhibit the same tensile strength and cosmesis as wounds that were initially closed primarily and with lower infection rates.36 Some authors have advocated delayed primary closure, rather than closure by secondary intention, for gunshot wounds. However, this needs to be applied on a case-by-case basis.37
Open wounds and those with extensive soft tissue loss that are technically difficult to close are best treated by application of a skin graft or tissue transfer. In general, the simplest technique that will result in a closed wound should be employed so that a flap should not be done when a skin graft would suffice, and a free flap should be avoided if a rotational flap will be satisfactory. The timing of grafting or flapping is somewhat controversial and is best determined by the overall physiologic condition of the patient. Vascular anastomoses and exposed blood vessels are special cases and need to be covered as soon as possible to prevent catastrophic “blowouts.” In patients with an open abdomen it is highly desirable to get coverage of intestinal anastomoses with omentum, absorbable mesh, or the abdominal wall since uncovered they have a tendency to break down leading to devastating “enteroatmospheric fistulas.”38 Split-thickness skin grafts are usually applied 5 days after injury but this is based more on tradition than physiology.
Wound Management Decision Making
The way a wound is treated is dependent on several decisions and sound clinical judgment. The first determination in whether to close a wound or leave it open is related to the time since injury. In general, wounds that have been open for more than 6–8 hours should be left open, otherwise primary closure is advantageous. Obviously, there are many exceptions to this “rule” since open wounds on the face or scalp tend to do well even when closed more than 8 hours after wounding. This observation is due to the relatively low levels of commensal bacterial colonization coupled with an outstanding blood supply in these locations. On the other end of the spectrum, a 4-hour-old wound in an ischemic extremity in a diabetic is best left open since neither bacterial flora nor blood supply favors infection-free healing.
The next consideration in establishing a treatment plan for the wound is based on the mechanism of wounding. High-velocity gunshot wounds, crush injuries, close-range shotgun wounds, and high-energy open fractures are all characterized by extensive soft tissue destruction and are frequently complicated by wound infection.39 Heavily contaminated wounds such as human bites, farming-related accidents, and wounds with gross contamination, especially soil, are at exceedingly high risk for subsequent wound infection and are best managed open. These contaminated wounds are at risk for tetanus and the patient should receive tetanus prophylaxis. Tetanus prophylaxis is detailed in Table 47-3, while Table 47-4 reviews the characteristics of a wound that is tetanus prone. Guidelines have been published detailing the indications and considerations for tetanus and other vaccines following traumatic injuries.40
TABLE 47-3 Tetanus Prophylaxis
TABLE 47-4 Wound Characteristics Relating to Likelihood of Tetanus
In addition to local wound factors, systemic conditions can also increase the incidence of wound infection. Hemorrhagic shock has been identified as a strong risk factor for wound infection.41,42 This phenomenon is likely multifactorial since trauma and hemorrhage affects blood flow on both the global and tissue levels and causes immune,43 hemtapoeitic,44 and myelopoeitic45 bone marrow dysfunction. Diabetes,46 connective tissue disorders,47advanced cancers,48 immunosuppressed states, atherosclerosis, hypothermia, malnutrition,49 COPD, corticosteroid therapy, and a multitude of other systemic disease processes all negatively impact wound healing and need to be considered in the wound treatment plan. Thus, the decision to close a wound is based on a series of assessments of the mechanism of injury, anatomic location, degree of contamination, and physiologic and medical condition of the patient.
In addition to the factors predisposing to wound infection discussed above, additional variables leading to wound infections have been identified. These threats to infection-free healing are listed in Table 47-5. Devitalized tissue is a common finding in high-velocity gunshot and high-energy wounds and represents a major risk factor for wound infection. Such tissue acts as a culture medium for bacteria, is poorly penetrated by immune cells and antibiotics, and incites an increased inflammatory response. Debridement is an effective way of removing this source of infection and inflammation and is an integral part of wound care.50
TABLE 47-5 Threats to Infection-Free Wound Healing
Meticulous hemostasis is often cited as a key component to normal wound healing; however, the rationale behind this statement is frequently omitted. Iron is an essential component for bacterial replication,51so it is tightly regulated in vivo by sequestration in macrophages as well as by hepcidin, an iron-binding protein released by the liver in response to inflammation.52 Wound hematomas lead to increased infections by overwhelming the body’s ability to restrict iron and inhibit bacterial growth, and thus render a wound susceptible to infection by smaller bacterial numbers. In a similar fashion, foreign body contamination also leaves a wound more susceptible to smaller bacterial burdens by reducing granulocyte phagocytosis. If adequate hemostasis cannot be obtained due to coagulopathy or extensive injury or if debridement is inadequate, it is best to postpone primary closure until these conditions are corrected. Such wounds can be managed as open wounds and then treated by delayed primary closure at the bedside or taken to the operating room for further debridement and eventual closure.
Operative Versus Nonoperative Wound Management
Similar to the decision process regarding closure of a wound, the setting of wound care is equally important. In general, large complex contaminated wounds containing foreign bodies or devitalized tissue are best managed in the operating room. The anatomic location of the wound can be critical as well since perineal, facial, and severe hand injuries can have serious consequences if initially mismanaged. Noncompliant patients and those with hazardous communicable diseases are best treated in the operating room for safety reasons for the patient and clinician alike. Although a wound may be impressive, it is frequently the associated injury that is most threatening to the patient. A 2-cm neck wound is not impressive; however, it may lead to a disastrous sequence of events if it overlies the carotid artery. In general, attempting to manage a major wound without adequate light, exposure, anesthesia, equipment, or patient cooperation leads to missed injuries, retained foreign bodies, inadequate debridement, wound hematomas, and soft tissue infections or worse. Table 47-6 summarizes some conditions mandating operative management of a wound.
TABLE 47-6 Conditions Requiring Management in Operating Room
Once the decision is made to proceed to the operating room, the next step is to consider patient positioning and skin preparation. In general, the patient should be positioned in such a way so that access to other body cavities and surfaces is maintained. The lateral decubitus position offers excellent access to a hemithorax but does so at the expense of access to the contralateral chest and abdomen. Extremities are best fully prepped and free draped to maximize exposure and operative options.
After positioning, the patient’s skin is prepared with an antiseptic. As part of this preparation, body hair may need to be removed to facilitate wound exploration and exposure and to prevent hair from becoming trapped in the wound and functioning as a foreign body leading to increased wound infections. Shaving hair should be avoided since it has been shown to lead to higher wound infection rates when compared with depilatories or clippers.53 While depilatories may be useful in elective surgery, they have little role in the management of urgent traumatic wounds; thus, surgical clippers with disposable heads should be readily available in the emergency department and operating room. Hair should be removed in an atraumatic fashion so as not to cause additional injury. Loose foreign bodies and debris should be removed as well. Eyebrows should not be removed since in a minority of patients their regrowth can be inadequate.54
The most common skin antiseptics are povidone–iodine solution (Betadine®) and chlorhexidine gluconate solution (Hibiclens®). Both agents are rapidly bactericidal; however, emerging evidence shows that chlorhexidine is a superior prep agent since it has more residual activity and is associated with lower rates of infection.55–57 A 2% chlorhexidine in 70% alcohol solution has been shown to be the most efficacious form of chlorhexidine and is now available commercially (ChloraPrep®).58 Both povidone–iodine and chlorhexidine are toxic to normal tissue, so they should only be used as preparatory agents rather than topical wound treatments.59 Ambroise Pare admonished against putting anything into a wound that would not be tolerated in one’s eye, but this is especially true for chlorhexidine since it causes direct corneal injury.60,61 Povidone–iodine or hexachlorophene solution (PHisoHex®) should be used for prepping the face to avoid corneal damage and possible blindness.62
One of the hallmarks of operative management of heavily contaminated wounds centers on the use of high-pressure pulse lavage systems. In the past, it was felt irrigation had to be performed at high pressure in order to effectively remove microparticulate contaminants and bacteria.63 Lavage of contaminated wounds with a bulb syringe or low-pressure systems was thought to be ineffective. While commercially available high-pressure irrigating systems are undoubtedly effective, their destructive effects on already injured tissues are frequently overlooked. In addition to the increased devitalization of the wound, high-pressure irrigation can also have detrimental effects on immune function and wound healing.64 Emerging evidence suggests that in addition to local trauma, high-pressure irrigation may not be as effective in removing contamination as gentler methods and may in fact drive bacteria deeper into tissues.65 Sharp debridement, curettage, suction, and irrigation of all nonvariable and grossly infected tissues should be undertaken until the wound is left with only clean, healthy, and well-perfused tissues. Outside of the operating room, one of the simplest irrigation systems can be made by punching several holes in the top of a 0.5-L bottle of saline utilizing an 18-gauge needle. Alternatively, a syringe and angiocatheter can be fashioned into an effective irrigator as demonstrated in Fig. 47-2.
FIGURE 47-2 Technique for high-pressure syringe irrigation of a wound.
Operative treatment of a wound gains the added benefit of effective analgesia and anesthesia administered by an additional clinician, the anesthesiologist. For wounds cared for in other venues, local anesthesia plays a crucial role, and is typically administered by the clinician caring for the wound. Local anesthesia facilitates excision of devitalized tissue and removal of foreign bodies, and enhances patient comfort and cooperation during closure of the wound. Most local anesthetics work by binding neural cell membrane sodium channels to block depolarization and conduction of noxious stimuli. These drugs are weak polar bases that are structurally composed of an aromatic, hydrophobic ring, a hydrophilic tertiary amino group, and an intermediary chain. It is the presence of an ester or amide linkage in the intermediary chain that is used to broadly classify the local anesthetics.66 Ester local anesthetics are rapidly metabolized by plasma pseudocholinesterases and the resultant hydrophilic metabolites are renally excreted. In contrast, amide anesthetics are metabolized by the liver, so their clearance is a much slower process and the potential for adverse effects is greater due to accumulation of the drug or impaired clearance secondary to hepatic dysfunction.67
The lipid solubility of a local anesthetic is proportional to the drug’s potency while its protein binding helps regulate its duration of action. The duration of action of local anesthetics may be enhanced by the addition of dilute concentrations of epinephrine in order to cause vasoconstriction and impair the clearance of the drug from the tissues. The addition of epinephrine to the local anesthetic increases the maximum dose since vasoconstriction reduces systemic absorption. Obviously, local anesthetics containing epinephrine should not be injected into tissues perfused by end arterioles such as the fingers, toes, nose, penis, or ear since vasoconstriction may result in tissue necrosis. Although some recent literature has challenged this dogma, it is still prudent to avoid this complication altogether.68,69 Inadvertent intravascular injection is another potential pitfall when using these agents; thus, the syringe should be aspirated slightly to exclude this possibility prior to injecting the drug. Lastly, there is some concern that the injection of epinephrine into a contaminated wound may result in an increased incidence of wound infection.70
Injections of local anesthetics are inherently painful; however, several simple techniques can be utilized in order to minimize patient discomfort. Small-gauge needles, as fine as 30 gauge, should be utilized and the drug administered by a technique of slow infiltration. Beginning the process through the existing break in the dermis rather than injecting into intact skin can also lessen pain. Intradermal injections should only be administered when needed and only after attempts of subdermal administration fail. Perhaps the most effective method for reducing the pain associated with local anesthetics can be achieved through the addition of sodium bicarbonate to buffer the pH of the anesthetic (49–52).71–74 What remains puzzling is why this well-described and efficacious technique is so underutilized in medicine today.75
Shortly after Carl Koller popularized the local anesthetic properties of cocaine in 1884, clinicians began noting serious unintended side effects.76 While cardiac toxicity is most pronounced with cocaine, it is seen with all local anesthetics and is related to their effect on sodium channels in excitable membranes. Like the cardiovascular system, the central nervous system (CNS) also contains excitable cell membranes and is the other major site of local anesthesia toxicity. Increasing concentrations of local anesthetics lead to blockade of the inhibitory pathways in the amygdala and result in excess neural stimulation.77 Local anesthetic CNS toxicity is initially manifested as muscle twitching, tinnitus, and agitation that can progress to seizures, coma, and death as levels continue to rise. The cardiovascular system is relatively more resistant than the CNS to local anesthetic toxicity but arrhythmias and cardiovascular collapse are the most feared complications of local anesthetic use. Unfortunately, as the potency of a local anesthetic increases, so does its potential for cardiac depression and arrhythmias.78 This observation is borne out by the fact that the potent anesthetic bupivacaine exerts a greater degree of cardiac toxicity than the weaker related amide anesthetic lidocaine (see Table 47-7 for a review of the symptoms of local anesthesia toxicity).
TABLE 47-7 Symptoms of Local Anesthetic Overdose
Lidocaine and bupivacaine are the two most commonly used local anesthetics in the United States. Both are amide-type anesthetics and are available in combination with dilute concentrations of epinephrine (1:100,000 to 1:400,000) that lessens systemic absorption of the anesthetic due to vasoconstriction. As a result, the maximum dosage for lidocaine for infiltrative anesthesia goes from 4.5 mg/kg for plain lidocaine to 7 mg/kg when it is combined with epinephrine. The best way to avoid local anesthetic toxicity is to be cognizant of the total dose being administered. Bupivacaine is far more potent, as well as toxic, than lidocaine due to its lipophilicity. It also has a much longer onset of action than lidocaine; thus, lidocaine is the most commonly used local anesthetic in clinical medicine. Lidocaine is occasionally administered in combination with bupivacaine in order to capitalize on lidocaine’s short onset of action coupled with the high potency and long half-life of bupivacaine (please refer to Table 47-8 for a summary of both agents).
TABLE 47-8 Local Anesthesia
For large areas where the dose of anesthetic required to achieve anesthesia would be prohibitive or areas that are technically difficult to infiltrate, a regional block may be an excellent way to achieve anesthesia.79 Local blocks can be more efficacious than infiltrative anesthesia with less pain and a smaller volume of anesthetic used. Knowledge of the neural anatomy relevant to the sensory innervation of the region to be blocked is critical and allows complete anesthesia of the region of interest. Two of the most commonly employed peripheral blocks are the median and ulnar nerve blocks that are reviewed in Figs. 47-3 and 47-4, respectively. Fig. 47-5 illustrates the ubiquitous digital block that is an extremely helpful technique utilized in the management of trauma to the fingers.
FIGURE 47-3 Technique of median nerve block anesthesia.
FIGURE 47-4 Technique of ulnar nerve block anesthesia.
FIGURE 47-5 (A) Method of executing a digital block. (B) Position of skin wheals and level of cross-section.
Antibiotic Usage for Acute Wounds
For over 50 years, it has been known that administering an antibiotic well in advance of bacterial inoculation is a highly effective method of reducing wound infection; however, when dealing with traumatic wounds, this is simply not possible. Since traumatic wounds are always contaminated with bacteria prior to their clinical presentation, the use of antibiotics for acute wounds is considered empiric rather than prophylactic. Accordingly, there is little role for empiric antibiotics in the management of open wounds except for a few special circumstances. Although controversial, most clinicians would agree to the use of antibiotics in the following situations:
1. Open fractures or open joints. An open fracture, defined as communication of a fracture site with the outside environment through an associated wound in the skin, can have devastating long-term consequences if nonunion or osteomyelitis sets in. Similarly, bacterial destruction of the articular surfaces of a joint can also lead to significant morbidity. Accordingly, these wounds are best treated with antibiotics; however, in this capacity the antibiotics are an adjunct to basic wound and fracture care consisting of surgical debridement, joint irrigation, and fracture fixation.80–83
2. Heavily contaminated extensive soft tissue wounds. Similar to traumatic orthopedic injuries, antibiotics serve an adjunctive role in the management of heavily contaminated soft tissue injuries. However, the mechanism of injury and degree of contamination remain far more predictive of subsequent wound infection than the choice of antibiotic.84 Data are lacking about the duration of antibiotic usage in such wounds, but in general the shorter the course, the better.
3. Delayed presentation. Traumatic wounds that present in a significantly delayed fashion are well along on the continuum from contaminated to infected and likely would benefit from antimicrobial therapy.
4. Host factors. Patients with profound immunosuppression, indwelling foreign bodies such as mechanical heart valves, and those unable to tolerate transient bacteremias are all likely to derive benefit from antibiotic therapy in the management of an acute wound. This decision is not based on evidence-based recommendations but rather on clinical judgment since trials of efficacy in these populations will never be undertaken for ethical reasons.
Rather than delve into the seemingly infinite number of wound gels, foams, and dressings individually, we will approach the topic of wound dressing in a similar fashion to the chapter as a whole: focusing on general ideas and concepts rather than specifics. This decision is in fact a necessity since despite the tremendous number of wound products available, there is a paucity of large, randomized prospective controlled trials comparing various dressings with each other.85 For over 100 years, the benefits of keeping a wound moist have been known86; however, it was not until the seminal article by Winter in 1962 showing that an occlusive dressing led to 40% faster healing than wounds left open to air did the concept of “wet” wound healing take hold.87 Unfortunately, for many clinicians the choice of wound dressings is based on tradition and experience rather than data88 and one of the most painful, labor-intensive dressing remains the most commonly used: the wet to dry gauze dressing. This dressing is composed of saline-moistened gauze in close contact with the wound covered by several layers of dry gauze. By the time this dressing is changed, it typically dries out and sticks to the wound so that when it is removed it debrides the wound of necrotic tissue, secretions, and bacteria while causing significant pain and occasional bleeding.
One particularly useful type of dressing is a modification of the technique used on split-thickness skin graft donor sites to treat asphalt abrasions or “road rash.” Road rash is a common finding after motorcycle or bicycle collisions, ejection from automobiles, or in pedestrians struck by automobiles. These wounds are typically contaminated with small stones, dirt, and other road substances and can present a serious challenge to the treating physician. For patients with small wounds, a combination of a topical viscous lidocaine solution with systemic analgesics can facilitate scrubbing and debridement; however, extensive wounds are best managed in the operating room. After adequate anesthesia, the wound can be scrubbed clean of all foreign bodies using a presurgical scrub brush. Failure to fully debride the wound will lead to “tattooing” or retention of foreign bodies in the healing wound causing discoloration. Following debridement, the wound can be treated like a donor site; hemostasis is achieved through the application of epinephrine-soaked lap sponges followed by a petrolatum-impregnated dressing that will adhere to the wound. This dressing can then be trimmed as reepithelialization takes place underneath it, much like the donor site of a split-thickness skin graft.
Wound dressings can be roughly broken down into several groups, including gauzes, semipermeable occlusive film dressings, foam dressings, alginates, and hydrocolloids, all of which are reviewed in Table 47-9. In general, the perfect dressing does not exist, but if it did, it would have the following properties:
1. Encourage a moist but not macerated wound environment. As discussed earlier, moist wound healing is far superior to dry wound healing; however, a major concern surrounds avoiding skin maceration. Macerated skin can serve as a portal of entry for skin bacteria and may lead to infection.
2. Avoid the presence of toxic substances. Previously we have learned that povidone–iodine, chlorhexidine, acetic acid solutions, and dilute sodium hypochlorite solutions (Dakin’s) all exhibit some degree of fibroblast or keratinocytes toxicity and should be avoided.
3. Avoid leaving foreign bodies in the wound. Foreign bodies are undesirable because they retard phagocytosis and delay wound healing.89
4. Prevent bacterial contamination. The dressing must not be penetrable to the outside environment and bacteria.
5. Maintain optimal temperature and pH. Wound healing proceeds faster at physiologic temperature and pH.90
6. Require less frequent dressing changes. Many of the newer hydrocolloid, alginate, and foam dressings are very expensive. It is surmised that they may be cost-effective if the need for them to be changed is infrequent since skilled labor cost is one of the most expensive aspects of modern medical care. Regrettably, studies are still lacking.
7. Cause less patient discomfort.
8. Serve as a vehicle to deliver wound care adjuncts. Topical silver,91 anti-infectives,92 and growth factors93 have all been delivered by some of the newer surgical dressings.
TABLE 47-9 Wound Dressing Materials
Subatmospheric Sponge Dressings
One of the biggest advances in wound management of the last decade has centered on the use of the “vac sponge.” Vacuum-assisted closure of difficult wounds as initially described by Argenta and Morykwas94 consists of an open-cell foam sponge, connected to a controlled vacuum device. The sponge is covered by a thin, adhesive occlusive dressing so that the wound environment remains subatmospheric. Kinetic Concepts, Inc (KCI, San Antonio, Texas) has patented Argenta’s system (V.A.C.® system) and offers a vast array of vacuum dressing products and wound therapies such as ionic silver-impregnated sponges, irrigating vacuum systems, and polyvinyl alcohol sponges for use in tunnels and on top of skin grafts. The applications of this technology continue to grow and now several versions are commercially available.
Subatmospheric dressings have to a large part simplified wound care, wound closures and reconstructions, and skin grafting as well. These dressings have been shown to speed up the development of granulation tissue95 and often allow a simple skin graft to be placed instead of a complex plastic surgery flap procedure. The reason why these dressings speed up the healing process is poorly understood and may be related to reducing wound edema, increasing blood flow,95 increasing cellular proliferation,96 or removing inhibitor substances from the wound milieu. Additional benefits of these types of dressings include keeping the wound environment moist and drawing the edges of the wound closer together that presumably combined with the natural process of wound contraction leads to faster closure times and reduced wound size. In a recent systematic review of the use of negative pressure dressings, there was no clinically significant advantage when used in chronic wounds, but was associated with more wound healing, and in a faster time.97
Early reports reported that an infected wound was a contraindication to the use of a V.A.C. system; however, a significant body of literature is building on the role of such a device with infected wounds.98Overall, while authors do not report any major complications, in general the V.A.C. system should be changed, and the wound reviewed by the clinician, more frequently than if the wound was not infected. Some centers advocate changing the V.A.C. as often as every 8 hours. Further, the system may be impregnated with silver in an effort to reduce the bioburden and to minimize the development of a biolayer. The use of silver has been demonstrated to have broad-spectrum antibacterial and antifungal properties. Silver has many mechanisms of action including inhibition of cellular respirations, denaturing nucleic acids, and altering cellular membrane permeability.99 However, the optimal dose of silver in any dressing is yet to be elucidated, with some authors expressing concern for the effect of silver on surrounding normal tissue viability.100
While negative pressure wound therapy represents a major advance in the wound care armamentarium for both acute and chronic wounds, it is not a panacea for all wounds. Failure to fully debride a necrotic wound before placing the sponge can lead to ongoing necrosis, infection, and clinical deterioration. The currently recognized contraindications to negative pressure wound therapy include wounds with necrotic tissue, malignancy within the wound, exposed arteries, veins, or vascular grafts, untreated osteomyelitis, and fistulas between epithelial surfaces. Wound ischemia and severe malnutrition are relative contraindications. Some physicians have reported success treating fistulas, and while this is an off-label use, it is rapidly becoming standard therapy.101
BITES AND STINGS
Human bites may be the most common bites seen in many urban emergency rooms. The main clinical problem in human bites relates to soft tissue infection since human saliva contains up to 1011 bacteria/mL, and plaque on teeth has even greater numbers of bacteria. Common infecting organisms include Streptococcus viridans, Staphylococcus spp., Eikenella corrodens, Bacteroides spp., and microaerophilic streptococci. The most common serious infections develop when there has been penetration of the joint capsule, which typically occurs when a clenched fist strikes the tooth of the person being assaulted (“fight bite”). These wounds usually involve the metacarpophalangeal (MCP) or the proximal interphalangeal (PIP) joints. These are usually benign-appearing wounds and are frequently missed unless the examiner is aware of the potential problems of joint penetration. Such wounds may not be directly over the MCP joint unless the hand is examined with the fist clenched. These wounds should be seen in consultation with a hand surgeon and are usually best treated with intraoperative irrigation, intravenous antibiotics, and elevation of the hand and arm but should not be treated on an outpatient basis. In general, human bites should not be closed, with the exception of wounds on the face.
Antibiotic prophylaxis for human bites consists of ampicillin plus a beta-lactamase inhibitor (intravenous ampicillin/sulbactam or amoxicillin/clavulanate). Alternative agents include cefoxitin or ampicillin alone or in combination with clindamycin. Although the incidence is unknown, hepatitis and infection with human immunodeficiency virus (HIV) are potentially transmissible by human bites. As with other exposures, the risk of infection depends on the size of the inoculums and the virulence of the viral agent. HIV exists in relatively low concentrations in human saliva and is relatively fastidious, presumably making its transmission difficult. Hepatitis B and C require a much smaller inoculum, and their transmission in a human bite is theoretically a greater risk. If the individual responsible for the bite is known or available for evaluation, serologic testing for HIV and hepatitis B and C is recommended. If the individual responsible for the bite is unavailable for testing, the administration of gamma globulin and hepatitis B vaccination should be considered in nonimmunized patients. Tetanus immunization should be given if indicated40(see Table 47-4).
Cat bites, like human bites, tend to be heavily contaminated. Cats tend to leave deep, small punctures that may penetrate all the way to bone. Commonly isolated organisms include Pasteurella multocida and Staphylococcus spp. Ampicillin plus a beta-lactamase inhibitor provides reasonable empiric coverage and tetanus and rabies prophylaxis should be given if indicated (Tables 47-3, 47-4, 47-10, and 47-12).
TABLE 47-10 Treatment Recommendations and Estimates of the Risk of Rabies, According to Type of Exposure and Geographic Area
Dog bite wounds are another common clinical problem. Wound concerns center around injury to soft tissue since large dogs can generate tremendous force with their muscles of mastication. Soft tissue infections following dog bites are not as common as after cat and human bites, but they do occur. The bite wound should be copiously irrigated, and empiric preventive antibiotics are generally recommended. Facial dog bite wounds are usually closed, while wounds in other locations are managed with delayed primary closure or healing by secondary intention. Common infecting organisms include P. multocida, S. viridans, Bacteroides spp., Fusobacterium, and Capnocytophaga. As in the case of human and cat bite wounds, ampicillin plus a beta-lactamase inhibitor provides reasonable empiric coverage for dog bite wounds. Tetanus and rabies prophylaxis should be administered if indicated (see Tables 47-3, 47-4, 47-10, and 47-12).40
A number of different strains of highly neurotropic viruses cause clinical rabies infection. Most of these viruses belong to a single serotype in the genus Lyssavirus, family Rhabdoviridae. The virion contains a single-stranded, nonsegmented, negative-sense RNA genome, which encodes for five structural proteins.102 Guidelines for the administration of rabies vaccine as well as for tetanus among others vaccines following traumatic injuries have been published by the Surgical Infection Society of North America.40
Susceptibility to rabies infection varies according to species, although most wild mammals can become infected with the virus. Foxes, coyotes, wolves, and jackals are most susceptible; skunks, raccoons, bats, bobcats, mongooses, and monkeys are intermediate; and opossums are surprisingly resistant.102
In the United States, rabies is found in terrestrial animals in 10 distinct geographic areas. In each of these areas, one species is the predominant reservoir, with one of the distinct antigenic variants predominating. Bats account for an additional eight variants, accounting for sporadic outbreaks throughout the United States. The majority of the cases of rabies encephalitis acquired in the United States probably originate from exposure to bats. The epidemiology of human rabies reflects the geographic distribution of animals, emphasizing the fact that rabies is primarily a disease of nonhuman mammals. Vaccination programs for domestic animals in the United States have been responsible for a dramatic decline in rabies acquired from domestic dog and cat bites (Tables 47-10 and 47-11). Internationally, the majority of human rabies is still acquired from dog bites, where canine rabies is still endemic.102
TABLE 47-11 Human Rabies Cases in the United States by Exposure Category, 1946–1995a
In humans, the established disease is almost always fatal. The diagnosis is relatively straightforward when a history of an animal bite is obtained; however, the history of a probable bite is inconsistently reported. Clinical symptoms of human rabies include pain at the bite site, dysphagia, pharyngeal spasms, paralysis, hydrophobia, and seizures. Distinguishing rabies from other causes of viral encephalitis or tetanus can be difficult. An effective vaccine is available for preventing the onset of clinical rabies. The dismal prognosis of rabies encephalitis emphasizes the importance of appropriate use of the vaccine and Ig preparations to prevent infection.
The risk of acquiring rabies depends on the probability of rabies infection in the animal and the amount of inoculum delivered into the wound, with the greatest risk from a bite. All animal wounds should be irrigated and cleansed with soap or a detergent. This has been shown to protect 90% of experimental animals from infection following inoculation of rabies virus into a wound.
Because public health officials monitor the incidence of rabies in populations of domestic and wild animals, a treating physician should be familiar with the local incidence of rabies in his or her region. Several historical clues may be of benefit in determining the likelihood that the animal was rabid. If the bite was unprovoked or the animal was behaving erratically prior to the bite, the chance of rabies inoculation is increased. Bites from most wild carnivores, skunks, raccoons, and bats should be considered as rabid, while bites from immunized animals should be considered low risk. Healthy dogs and cats in nonendemic areas are low risk. Tables 47-10 and 47-12 summarize recommendations regarding the risk of transmission of rabies and treatment. If there is any question concerning prophylaxis, public health officials should be promptly consulted.
TABLE 47-12 Schedule of Prophylaxis Recommended in the United States After Possible Exposure to Rabies
Snakebite is a challenging but rare problem that is more common in the Southern United States and Mexico than elsewhere in North America. Like most other traumatic illnesses, it is more common in men than it is in women. Approximately 50% of patients are bitten during recreational activity or while working outdoors, while the remaining half are bitten by pet snakes or snakes being handled for some other reason. Snakebites are responsible for an average of only 12 deaths per year in the United States with rattlesnakes causing the majority of severe envenomations. Venomous snakes indigenous to the continental United States are either crotalids, which include rattlesnakes, copperheads, and cottonmouths, or elapids, of which coral snakes are the only indigenous species in the United States (Table 47-13reviews the common Crotalidae of North America).
TABLE 47-13 Crotalidae of North America
Since no evidence-based recommendations can be made for the treatment of snakebite, treatment recommendations are based on clinical series, animal studies, and common sense. While the clinical data are conflicting, the experimental animal data are clear. In this chapter, a treatment regimen for snakebite is proposed, pertinent controversies are discussed, and a rationale for the treatment scheme is presented (Fig. 47-6).
FIGURE 47-6 Algorithm for the treatment of snakebite, only in a setting in which anaphylaxis can be treated.
Identification of the Snake
Because the majority of snakebites in the United States are nonvenomous, an attempt should be made to identify the snake. This is possible by history as well as direct observation, particularly if the victim brings the snake to the emergency department for this to occur. If at all possible, the snake should be identified by someone knowledgeable in herpetology and no identification should be attempted by hospital personnel unless the snake is dead or completely contained. For patients who are snake handlers or those bitten by pet snakes, the patients themselves will be the best resource to identify the type of snake. Fig. 47-7 summarizes the physical characteristics of crotalid snakes. The three important genera of Crotalidae in the United States are Crotalus and Sistrurus (rattlesnakes) and Agkistrodon (copperheads and water moccasins; Table 47-13). These snakes are characterized by a broad triangular head, relatively thick body, elliptical pupils, and facial pits. All but one species of rattlesnakes have rattles, which distinguishes them from copperheads and water moccasins. The only other snakes of clinical importance in the continental United States are the coral snakes. The two species of these that are common to the United States are Micrurus fulvius fulvius (Eastern coral snake) and the Micrurus fulvius tenere (the Texas coral snake). The Sonoran coral snake (Micrurus euryxanthus) is present in a small area of Southern Arizona, but is mostly indigenous to Mexico. These snakes are brightly colored, with red, yellow, white, and black rings. They are relatively small bodied and have small nontriangular heads without facial pits. Their rings encircle the body and the mouth area is black. Their characteristic coloring pattern of a red band adjacent to a yellow one distinguishes coral snakes from other snakes that are brightly colored but nonvenomous, which is the justification for the idiom, “Red on yellow, kill a fellow, red on black, venom lack.” Coral snakes belong to the family Elapidae, or elapid, which includes cobras, kraits, mambas, and the poisonous snakes of Australia. Coral snakes tend to be secretive, burrowing, and nonaggressive, accounting for the low incidence of bites by these animals. They do not have large fangs, and when they do bite, they tend to chew on the offending animal or part.
FIGURE 47-7 Characteristics of poisonous and nonpoisonous snakes.
An assessment for envenomation must be made in cases of bites by poisonous snakes. If there are no fang marks, envenomation is not possible and even with the presence of fang marks, approximately 20–25% of patients will not have been envenomated. It is estimated that another 50% have minimal to mild envenomation, which would not be a threat to life or limb. Agkistrodon (moccasin and copperhead) bites tend to be less severe than rattlesnake bites and rarely require antivenin or invasive treatment. With rattlesnake bites, it is usually easy to assess whether envenomation has occurred. Crotalid venoms are a mixture of enzymes, polypeptides, and glycosylated peptides that have broad biologic actions; however, one of the common features of these venoms is local tissue destruction. This locally destructive action is an accurate marker of the degree of envenomation. A great deal of pain, edema, and frequently discoloration or formation of bullae is associated with envenomation. Recent data appear to point to the presence of metalloproteinases in crotalid venom as a major source of local and systemic adverse effects.103
Given the relatively rare nature of severe envenomation, there is little in the literature pertaining to scoring the severity of the injury. One group has proposed and validated a Snakebite Severity Score (SSS).104This takes into account not only the potential for the dose of the envenomation but also the variability in response between patients. The scoring system reviews both the local wound of the bite and any possible systemic (pulmonary, GI, cardiovascular) symptoms, and was useful in determining the level and type of care needed.
Since the signs and symptoms of envenomation have a rapid onset, it is probable that if by the time the patient arrives there is no edema or pain, a significant envenomation has not occurred, or the patient was bitten by a moccasin or copperhead. These points are emphasized because no treatment advocated for a rattlesnake bite is free of risk (most actually have a relatively high risk) and because, in the absence of envenomation or with mild exposure only, supportive care alone will suffice. This point is one that makes evaluation of the snakebite literature difficult. If the clinical series in question includes a large number of Agkistrodon bites or patients with mild envenomations, the outcome will almost always be favorable, regardless of the treatment applied. The real concern in the treatment of snakebite relates to the patient with a severe envenomation associated with extensive destruction of local tissue or systemic signs of toxicity. The outcome for this type of patient is harder to assess from clinical series involving humans.
First aid is defined as the care delivered to the patient prior to arrival in the hospital. “First do no harm” should be loudly emphasized for first aid in the treatment of snakebites. A large number of first aid measures have been proposed for the treatment of venomous snakebites, and many, if not most, have carried a high risk of harm to the patient. The atmosphere at the scene of a snakebite is usually characterized as chaotic at best, punctuated by poorly trained first aid providers. This combination sets the stage for a therapeutic disaster if overly aggressive therapy is initiated at the scene of the bite. The most common potentially harmful treatments include incision and suction, electrical shock therapy, use of tourniquets, and limb immersion in ice.
Incision and suction have been shown experimentally to remove subcutaneously injected venom from animals; however, unless this is done very soon after envenomation, the yield of extracted venom is low.105 The risk of incision and suction is significant when one considers that the person making the incision is probably doing it for the first time, the patient is in pain and unanesthetized, and there is probably no knowledge of anatomy by either person involved in the procedure. It should also be remembered that 25% of the victims of snakebite will have no envenomation or a trivial one. For these reasons, incision and suction has fallen into disfavor as a first aid measure.
In a series of letters to the editor of the Lancet, a group of physicians practicing medicine in Ecuador advocated the use of electrical shock therapy for snakebite. They presented a series of 34 patients who were treated with electrical current using a modification of a stun gun.106 A stun gun is a personal protective device that delivers an extremely high voltage with very little current, which when used on attackers, temporarily disables them. The Ecuadorean investigators used this device on a group of patients with snakebite, probably from Bothrops atrox. All of the patients were said to have fared well, with immediate improvement. Follow-up in this series was not described, and there were no controls. This report led to the widespread use and indeed to the marketing of the stun gun for use in human snakebite. This treatment is typical of snakebite therapy throughout history. A theoretical treatment plan, usually with the potential for great pain or harm, is proposed, implemented, and adopted without any degree of scrutiny. Several controlled animal studies have now shown electrical shock therapy to be ineffective in the treatment of snakebite.
Ice therapy for snakebite has been advocated on the basis of decreasing the optimal temperature range for the enzyme component of the venom, and thus decreasing local tissue damage.107 This topic has been hotly debated without any clear resolution; however, the weight of the evidence would suggest that ice therapy is not efficacious. It has the potential for harm in cases of snakebite, and its use is discouraged. While putting a topical ice pack on the wound carries no risk, it is immersion of the extremity containing a bite or adding salt to the ice that has been associated with problems.
The use of a tourniquet has also been a debated issue in first aid for snakebite. A loosely applied venous tourniquet may decrease systemic absorption of the venom and delay the onset of symptoms; however, it certainly does not help the affected extremity and, if applied too tightly or if excessively tightened by the formation of edema, it carries the potential for causing great harm. Data from Australia suggest a treatment that would seem to be logical and safer that involves the application of a compression bandage and immobilization of the bitten extremity, instead of a tourniquet. With a compression bandage alone there is a great delay in the systemic absorption of venom.108 A splint and elastic bandage wrap or an inflatable air splint could also be used for this purpose. These measures have much less associated risk than placing a tourniquet on the involved extremity.
In summary, immobilization, neutral positioning, and a compression dressing of some sort are recommended as first aid in cases of snakebite, followed by rapid transport of the patient to a hospital. If a skilled surgeon is present and there is a significant and obvious envenomation, immediate incision and suction or local excision of the bite wound may be considered.109
The care of the patient in the hospital is no less controversial than is first aid for snakebite.110 The principal debates center around: (a) the use of antivenin therapy, (b) aggressive debridement and fasciotomy, and, more recently, (c) observation with supportive care alone. For severe bites, antivenin use is favored along with the aggressive use of supportive care. Fasciotomy is reserved only in the treatment of compartment syndrome. The use of antivenin for mild or even moderate envenomations is not appropriate since the patient will almost certainly do well without any therapy. Immediate surgical debridement for the purpose of removal of venom and nonviable muscle is also not recommended. Experimentally, this approach does not remove the venom, and it is impossible to determine if muscle tissue is viable on the basis of the usual clinical criteria.111 Supportive care alone is not recommended for severe envenomations, although patients with all but the most massive envenomations could probably survive with aggressive modern intensive care and replacement of blood factors.112 In the case of rattlesnake bites there is a relatively effective treatment that limits the amount of tissue damage and systemic action of the venom if administered early. The problem is not efficacy but safety. Antivenin therapy carries a definite risk of anaphylaxis and serum sickness; however, the risk of its use is outweighed by the potential benefits in victims with life- or limb-threatening bites.
A polyvalent equine antivenin (Wyeth-Ayerst Laboratories, Marietta, Pennsylvania) and an ovine Crotalidae polyvalent immune Fab antivenin, consisting of cleaved Fab antibody fragments (CroFab; Protherics, Inc, Nashville, Tennessee), are currently commercially available for the treatment of crotalid envenomations. These products are manufactured by immunizing animals to crotalid venoms and then pooling the globulin fraction containing the antibodies. The ovine Fab product, CroFab, undergoes further modification by cleavage of the Fab antibody fragments and purification with affinity chromatography. Experimentally, antivenin has been shown to be effective in preventing death following the injection of rattlesnake venom. In an animal model, it also preserves muscle function and minimizes the systemic side effects of the venom.
Like all antibody therapies, the equine antivenin is most effective if given immediately before envenomation; however, it is also effective when given after envenomation.111 It has also been shown to be effective if given up to 4 hours after envenomation, although there is little evidence to support its use beyond 4 hours. There have been anecdotal reports of clinical responses when it is given later than this, however, and it is recommended for use in life-threatening envenomations for up to 24 hours following a crotalid bite. Nevertheless, it must be emphasized that if antivenin therapy is going to be used, it should be used as soon as possible after envenomation.
Although widely used clinically, there are significant problems with the unmodified polyvalent equine antivenin. It is a foreign, impure horse serum protein fraction and has been associated with severe and even life-threatening anaphylactic reactions. The exact incidence of such reactions is unclear, ranging from 1% to as high as 39%. The antivenin infusion should be started at a very slow rate and stopped with any signs of an allergic reaction. The antivenin may also cause a dose-dependent, delayed-type serum sickness, which is much less severe than an anaphylactic response, although probably more common with massive infusions of antivenin. These side effects have fueled a debate over use of the antivenin. CroFab is an attempt to make the immunotherapy safer by purification of Ig and cleavage of the Fc fragment to produce Fab fragments.113 An increasing body of evidence supports the safety and efficacy of the Fab product, although additional postmarketing clinical data will ultimately be required.114 The Fab fragment has not been directly compared with other antivenin products. CroFab appears to be different than the older equine antivenin in that it probably requires repeat dosing in the immediate period after administration.113,114
In addition to being given as early as possible and in doses large enough to effect a difference, antivenin should not be administered in any setting in which anaphylaxis cannot be treated (i.e., in the field) and should initially be infused very slowly, with the infusion stopped with signs of hypersensitivity as noted earlier. The dose of antivenin to be given is empiric and based on the physician’s assessment of the amount of venom injected. The dose is the same in children as in adults, again being based on the amount of venom to be neutralized rather than on the weight of the patient. A minimum of 6–10 vials of CroFab is used for severe bites, although this amount is increased as needed. Various schemes have been devised for assessing the dose of antivenin based on the severity of envenomation. As the antivenin should not be used for mild or uncomplicated, moderate envenomations, these classification schemes are not clinically useful. Skin testing prior to antivenin administration should probably be eliminated and replaced by a very small, very slow intravenous injection of the antivenin, with constant monitoring for signs of anaphylaxis. The manufacturer recommends skin testing, but there have been anaphylactic reactions to the skin test, and the presence or absence of a wheal does not always predict anaphylaxis. The treatment of anaphylaxis is reviewed in Table 47-14.
TABLE 47-14 Treatment for Anaphylaxis
An ongoing debate during the past several decades has concerned the role of surgery in treating a rattlesnake bite. The theoretical rationale for surgical intervention is based on several observations. Crotalid venoms have very powerful, locally destructive effects. Part of the venom can be removed by incision and suction when this follows immediately after injection of the venom but intramuscular injection of the venom produces extensive edema that can lead to a compartment syndrome. These three observations lead to the conclusion that a rattlesnake bite is a local problem that should be amenable to local therapy (i.e., excision of the venom, dead muscle, and relief of a compartment syndrome). Excellent results have been claimed in clinical series in which this approach has been used.115 Unfortunately, no controlled trials have been conducted, and there are large series in which excellent results have been reported without operative intervention.116,117
An animal study performed in rabbits using an intracompartmental injection of western diamondback rattlesnake (Crotalus atrox) venom has yielded interesting results.111 In this study, animals were randomized to undergo fasciotomy with debridement alone, fasciotomy with antivenin alone, fasciotomy with debridement plus antivenin, or to have no treatment. Antivenin therapy prevented loss of muscle and improved survival, while surgery alone did not. It was also clear that muscle that would have survived was removed in the group that had the combination of antivenin plus surgery, since late muscle function was significantly worse in this group than it was in that treated with antivenin alone. The authors concluded, therefore, that although the theory of local treatment of rattlesnake bite was attractive, it was not supported by the data. The issue of fasciotomy alone was not addressed in this study. Based on these unanswered questions, fasciotomy should be done infrequently, and should be reserved for the usual indication of compartment syndrome, which would only occur if there is an intramuscular or intracompartmental envenomation.112 Although rare, this does occur, being more common over the anterior leg, fingers, and the hand. If there is a tight compartment with evidence of compartment syndrome, a fasciotomy should be performed.112 No debridement should be done acutely, as injured muscle may be salvaged with immunotherapy.
Supportive care should consist of fluid resuscitation, tetanus prophylaxis, appropriate monitoring, and the correction of coagulopathy. The bacteriology of rattlesnake mouths has been studied. Commonly present organisms include Pseudomonas spp., Enterobacteriaceae, Staphylococcus spp., and Clostridia.118,119 An extended-spectrum penicillin with a beta-lactamase inhibitor would provide reasonable empiric coverage; however, the weight of evidence supports not using empiric antibiotics.120,121 Coagulopathy due to fibrinolysis is a common complication of envenomation and should be corrected with fresh frozen plasma and cryoprecipitate. The patient’s prothrombin time/international normalized ratio, partial thromboplastin time, fibrinogen concentration, and platelet count should all be monitored, with replacement therapy based on these values and evidence of clinical bleeding.122
Coral Snake Envenomation
The symptoms of coral snake envenomation include local pain at the bite site, but the venom has primarily systemic effects consisting of respiratory depression and changes in CNS function.123 Antivenin and supportive care are the mainstays of treatment for coral snake envenomations. A commercially available antivenin exists for subspecies of Micrurus fulvius (the Eastern and Texas coral snake). This product probably has little cross-reactivity with the venom of M. euryxanthus (the Sonoran coral snake). Patients with fang marks or fang scratches should be admitted for observation. Any signs or symptoms should be treated with between three and five vials of antivenin. It is probably not wise to wait for full-blown systemic symptoms to develop before initiating treatment. If signs of respiratory distress develop, the patient should be treated supportively with intubation and mechanical ventilation as needed.
BITES AND STINGS BY MARINE ANIMALS
Marine invertebrates, Cnidaria, are a heterogeneous group of phylogenetically primitive animals that are responsible for a large number of sea-water envenomations.124 The phylum is divided into four major groups including Scyphozoa (true jellyfish), Hydrozoa (Portuguese Man o’ War and hydras), Anthozoa (corals and anemones), and Cubozoa (box jellyfish and sea wasps). All of these animals have specialized organelles known as nematocysts for poisoning and capturing prey. Most nematocysts cannot penetrate human skin and cause only a painful superficial skin reaction; however, full-thickness penetration can lead to serious illness and even death. Common manifestations of jellyfish stings include local pain and eruption, edema, urticaria, anaphylaxis, and, rarely, cardiorespiratory arrest. The principles in the management of such stings are to minimize the number of nematocysts being discharged and minimize the harmful effects of discharged nematocysts. Any adherent tentacles should be carefully removed. Unexploded nematocysts should be deactivated with a sodium bicarbonate slurry, papain (meat tenderizer), or a vinegar soak. The management of systemic side effects is largely supportive. Hypotension is treated with fluids and inotropic agents if necessary, while pain should be controlled with systemic narcotics. Calcium gluconate may improve the muscle spasms sometimes seen in cases of stings by marine invertebrates.
Most venomous fish are slow swimmers that are relatively nonmigratory and are not typically found in North American waters. Stingrays are the most clinically significant with regard to causing stings and envenomation. Typically this occurs when the stingray is stepped on by a swimmer. The wounds are a combination of laceration and puncture. Treatment consists of irrigation and soaking of the wound in warm water. Much of the venom may be removed by simple mechanical irrigation. Tetanus prophylaxis should be given; however, no antivenin exists for stingray envenomation.125
Travelers to tropical waters and aquarium workers may encounter other venomous creatures such as the blue-ringed octopus (Haplochlaena spp.), stonefish (Synanceia spp.), lionfish (Pterois volitans), and cone shells that posses potent venoms, some of which can be fatal to humans. Only an antivenin to stonefish toxin has been created, which is helpful in ameliorating the excruciating, narcotic-resistant pain associated with this venom.125 This antivenin may have some usefulness in the treatment of lionfish stings, which may be of particular interest to aquarium workers.126
There has been a recent alarming increase in the number of reported piranha attacks within the United States. Piranhas belong to the subfamily Serrasalminae, and only four genera (Pristobrycon, Pygocentrus, Pygopristis, and Serrasalmus) are considered true piranhas. The characteristic feature that is most harmful to humans and other animals is the extremely sharp nature of their teeth. President Roosevelt, on a visit to Brazil, was afforded an opportunity to see their destructive nature up close. In his 1914 book Through the Brazilian Wilderness, he described these fish as “the most ferocious fish in the world … more formidable than sharks or barracudas.” Traditionally, these fish have lived in the warm waters of South and Central America, with most reports of attacks emerging from Brazil. Reports have recently emerged of piranha located in lakes within the United States, with evidence of such fish as far north as Lake Winnebago in Wisconsin. It is speculated that this fish may have been dumped into the cold lake by illegal exotic fish traders to avoid getting caught. Rather than dying in the cold lake waters, it is theorized that they found an area of water that was just warm enough year-round to sustain the fish.
The red-bellied piranhas (Pygocentrus nattereri) have established a fearsome reputation in the Amazon forests for attacking their victims in large groups. However, the reported medical literature differs from lay press anecdotal descriptions, in that the medical literature often relates victims sustaining only one or two bites. It is believed that these bites relate to the fish defending its brood.127 Further, many of the victims relate prior open wounds that may have attracted the fish to the swimmer in the first place. There are no reports of envenomation associated with these piranha bites, and if encountered, these wounds should be treated akin to any other dirty laceration, with good local wound care and antibiotics reserved for infected or heavily contaminated wounds.
The chance of being bitten by a shark is exceedingly rare but these wounds do occur in all coastal areas of the world.128 The principles described in Section “Clinical Management of Wounds” should be employed for the management of complex shark bite wounds. These wounds should be considered tetanus prone and preventive antibiotics are generally recommended, especially against Vibrio spp. and Aeromonasspp., in the management of these wounds.128
Insect and Bug Bites
Insect bites are usually more of a nuisance than a serious medical problem, and most are not seen by a physician. Allergic reactions are the most common serious problem following insect bites. Because of their widespread distribution and proximity to humans, bees and wasps kill more people per year through fatal anaphylactic reactions to their venoms than do all other venomous animals combined.
Fire ants were imported to Mobile, Alabama, in the early part of the 20th century. The black fire ant (Solenopsis richteri) was the first species to be imported from Uruguay and Argentina and has a limited range along the Mississippi–Alabama border. The red fire ant (Solenopsis invicta), which originates from Brazil and Northern Argentina, has had tremendous success in colonization and now has a range extending over most of the Southeastern United States.129 Its adaptability and aggressiveness have been remarkable. S. invicta tends to give multiple bites that are usually limited, but near-fatal cases of multiple bites have been reported. The bites of the imported fire ant have a typical appearance consisting of an initial vesicle, followed by the development of a sterile pustule. The venom of the fire ant is unique among that of venomous animals. It consists of 95% nonprotein alkaloid, in contrast to most other venoms, of which protein is a major component. Allergy to a fire ant bite is relatively common, with anaphylaxis being the most common major reported problem. Treatment consists of immediately scrubbing the wounds with soap and water, since much of the venom may be removed by cleansing and mechanical action.
All spiders have a venom apparatus for killing other insects or spiders, although most pose no danger to humans. Of the two common species dangerous to humans in the continental United States, bites by the brown recluse spider (Loxosceles reclusa) are the most clinically significant. This is a brown spider with three pairs of eyes (dyads), one anterior and two lateral, with a violin-shaped carapace on its body, although this may be absent or difficult to discern.130 Usually, there is minimal pain following a brown recluse bite, which often makes exact identification of the location of the bite difficult. In serious bites, a hemorrhagic blister develops with progression to a dark black necrotic area that may extend over several centimeters. Systemic symptoms may be present, but these are usually mild, and respond well to supportive care. Initial reports131 that early treatment with dapsone prevented ulceration or hastened healing have been largely superseded by evidence showing that adverse effects of dapsone are common and its efficacy is doubtful.130,132
Bites by the black widow (Lactrodectus macrotans) spider are characterized by a systemic toxic reaction. Only the female black widow spider, identified by her large size and shiny black body with a red hourglass on the underside of her abdomen, contains sufficient venom to envenomate a human.133 Symptoms of envenomation are usually rapid, beginning within 1 hour of biting, and include pain, muscle rigidity, altered mental status, and seizures. Death rates from severe bites have been reported to be as high as 5%. Treatment is supportive, although an equine antivenin is available for use in severe cases. Muscle rigidity has been effectively treated with dantrolene,134 as well as calcium and methocarbamol.135
Bee and Wasp Stings
Bee and wasp stings are very common throughout the world but most victims never seek medical attention and recover uneventfully. The most serious problem in cases of bee and wasp stings relates to the development of an immediate hypersensitivity reaction. As noted earlier, due to the large number of bees in the United States and their close proximity to humans, anaphylactic reactions from bee stings are responsible for more deaths than all other venomous animal bites and stings, including rattlesnake bites. Honeybees were not indigenous to the Americas, but were imported to the continent in the 1600s (the European honeybee). While exceedingly popular in the media, the Africanized honeybee (“killer bees”) is still a member of the same species as the European honeybee (Apis mellifera). Africanized honeybees are a population that has evolved under different environmental conditions, and has significantly different behavior than the common honeybee.
African honeybees were imported to Brazil in 1956 with the hope of creating bees that would be more suited to a tropical environment. Unfortunately, they escaped and bred with the local European honeybees and have been slowly migrating northward ever since. The first Africanized honeybee colony in the United States was discovered in South Texas in 1990. Africanized honeybees tend to be aggressive, and persons stung by them are more likely to sustain multiple stings, although the stings themselves are no different than those of other honeybees. Bees sting with double-barbed lancets, which tend to anchor the bee to the victim’s skin. When the bee dislodges itself, it usually leaves its stinging apparatus behind, thus killing the bee. The exuded venom sac of the bee should be scraped with a knife, instead of squeezing the skin to get the poison sac out, in order to avoid injecting the venom remaining in the sac. Application of an ice pack to the local area tends to alleviate the associated pain. The treatment of anaphylaxis from bee stings and other bites and stings is outlined in Table 47-14. Patients who have a known sensitivity to bee or wasp stings should carry an emergency kit for the injection of epinephrine (EpiPen®, Dey, Inc, Napa, California) and should wear a medical identification bracelet identifying their hypersensitivity.
1. Atta H. Edwin Smith surgical papyrus: the oldest known surgical treatise. Am Surg. 1999;65:1190–1192.
2. Namias N. Honey in the management of infections. Surg Infect. 2003; 4:219–226.
3. Armstead W. Endothelins and the role of endothelin antagonists in the management of posttraumatic vasospasm. Curr Pharm Des. 2004; 10(18):2185–2192.
4. Santoro M, Gaudino G. Cellular and molecular facets of keratinocytes reepithelization during wound healing. Exp Cell Res. 2005;304:274–286.
5. Amara U, Rittirsch D, Flierl M, et al. Interaction between the coagulation and complement system. Adv Exp Med Biol. 2008;632:71–79.
6. Levi M, van der Poll T, Buller H. Bidirectional relation between inflammation and coagulation. Circulation. 2004;109(22):2698–2704.
7. Wesche D, Lomas-Neira J, Perl M, et al. Leukocyte apoptosis and its significance in sepsis and shock. J Leukoc Biol. 2005;78(2):325–337.
8. Jensen J, Hunt T, Scheuenstuhl H, et al. Effect of lactate, pyruvate and pH on secretion of angiogenesis and mitogenesis factors by macrophages. Lab Invest. 1986;54:574–578.
9. Ayala A, Chaudry I. Platelet activating factor and its role in trauma, shock and sepsis. New Horiz. 1996;4(2):265–275.
10. Stafforini D, McIntyre T, Zimmerman G, et al. Platelet-activating factor, a pleiotrophic mediator of physiological and pathological processes. Crit Rev Clin Lab Sci. 2003;40(6):643–672.
11. Szpaderska A, DiPietro L. Inflammation in surgical wound healing: friend or foe? Surgery. 2005;137:571–573.
12. Leibovich S, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975;78:71–100.
13. DiPietro L. Wound healing: the role of the macrophage and other immune cells. Shock. 1995;4:233–240.
14. Emoto M, Yoshida T, Fukuda T, et al. Alpha-galactosylceramide promotes killing of Listeria monocytogenes within the macrophage phagosome through invariant NKT cell activation. Infect Immun. 2010;78:2667–2676.
15. Springer T. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol. 1995;57:827–872.
16. Nguyen B, Gil S, Carter W. Deposition of laminin 5 by keratinocytes regulate integrin adhesion and signaling. J Biol Chem. 2000;275:3 1896–31907.
17. Mitchison T, Cramer L. Actin-based cell motility and cell locomotion. Cell. 1996;84:371–379.
18. Chen L, Alexander E, Shibasaki F. Hypoxia and angiogenesis: regulation of hypoxia-inducible factors via novel binding factors. Exp Mol Med. 2009;41(12):849–857.
19. Scortegagna M, Ding K, Oktay Y, et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1–/– mice. Nat Genet. 2003;35(4):331–340.
20. Trabold O, Wagner S, Wicke C, et al. Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing. Wound Repair Regen. 2003;11:504–509.
21. Thakral K, Goodson W, Hunt T, et al. Stimulation of wound blood vessel growth by wound macrophages. J Surg Res. 1979;26:430–436.
22. Ferrara N, Gerber H, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–676.
23. Li L, Barlow K, Metheny-Barlow L. Angiopoietins and Tie2 in health and disease. Pediatr Endocrinol Rev. 2005;3:399–408.
24. Deshmane S, Kremlev S, Amini S, et al. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009;29(6): 313–326.
25. Stadelmann W, Digenis A, Tobin G. Physiology and healing of chronic cutaneous wounds. Am J Surg. 1998;176(2A suppl):26S–38S.
26. Bauer S, Bauer R, Liu Z, et al. Vascular endothelial growth factor-C promotes vasculogenesis, angiogenesis and collagen constriction in three dimensional collagen gels. J Vasc Surg. 2005;41:699–707.
27. Heissig B, Nishida C, Tashiro Y, et al. Role of neutrophil-derived matrix metalloproteinase-9 in tissue regeneration. Histol Histopathol. 2010; 25(6):765–770.
28. Koivunen P, Hirsila M, Gunzler V, et al. Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J Biol Chem. 2004;279(11): 9899–9904.
29. Deodhar A, Rana R. Surgical physiology of wound healing: a review. J Postgrad Med. 1997;43:52–56.
30. Marinkovich M, Keene D, Rimberg C, et al. Cellular origin of the dermal–epidermal basement membrane. Dev Dyn. 1993;197(4):255–267.
31. Margadant C, Frijns E, Wilhelmsen K, et al. Regulation of hemidesmosome disassembly by growth factor receptors. Curr Opin Cell Biol. 2008;20(5):589–596.
32. Gabbiani G. Evolution and clinical implications of the myofibroblast concept. Cardiovasc Res. 1998;38:545–548.
33. Eyden B. The myofibroblast: phenotypic characterization as a prerequisite to understanding its function in translational medicine. J Cell Mol Med. 2008;12(1):22–37.
34. Bullard K, Lund L, Mudgett J, et al. Impaired wound contraction in stromelysin-1 deficient mice. Ann Surg. 1999;230:260–265.
35. Heffernan D, Dudley B, McNeil P, et al. Local arginine supplementation results in sustained wound nitric oxide production and reductions in vascular endothelial growth factor expression and granulation tissue formation. J Surg Res. 2006;133(1):46–54.
36. Lowry K, Curtis G. Delayed suture in the management of wounds: analysis of 721 traumatic wounds illustrating the influence of time interval in wound repair. Am J Surg. 1950;80:280–287.
37. Graham A. Delayed primary closure in the management of gunshot wounds. J Wound Care. 1999;8(3):145–148.
38. Miller R, Morris J, Diaz J, et al. Complications after 344 damage control open celiotomies. J Trauma. 2005;59:1365–1374.
39. Grande C. Mechanism and patterns of injury: the key to anticipation in trauma management. Crit Care Clin. 1990;6:25–35.
40. Howdieshell T, Heffernan D, DiPiro J. Surgical infection society guidelines for vaccination after traumatic injury. Surg Infect. 2006;7(3): 275–303.
41. Livingston D, Malangoni M. An experimental study of the susceptibility to infection after hemorrhagic shock. Surg Gynecol Obstet. 1989;168(2): 138–142.
42. Angele M, Knoferl M, Schwacha M. Hemorrhage decreases macrophage inflammatory protein 2 and interleukin-6 release: a possible mechanism for increased wound infection. Ann Surg. 1999;229:651–656.
43. Angele M, Chaudry I. Surgical trauma and immunosuppression: pathophysiology and immunomodulatory approaches. Langenbecks Arch Surg. 2005;390:333–341.
44. Livingston D, Gentile P, Malangoni M. Bone marrow failure after hemorrhagic shock. Circ Shock. 1990;30:255–263.
45. Livingston D, Anjaria D, Wu J. Bone marrow failure following severe injury in humans. Ann Surg. 2003;238:748–753.
46. Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366:1736–1743.
47. Busti A, Hooper J, Amaya C, et al. Effects of perioperative antiinflammatory and immunomodulating therapy on surgical wound healing. Pharmacotherapy. 2005;25:1566–1591.
48. Biuck M, Houglum K, Chojkier M. Tumor necrosis factor-alpha inhibits collagen alpha-1 gene expression and wound healing in a murine model of cachexia. Am J Pathol. 1996;149:195–204.
49. Harris C, Fraser C. Malnutrition in the institutionalized elderly: the effects of wound healing. Ostomy Wound Manag. 2004;50:54–63.
50. Fowler E, van Rijswijk L. Using wound debridement to help achieve the goals of care. Ostomy Wound Manag. 1995;41(7A suppl):23S–36S.
51. Schaible U, Kaufmann S. Iron and microbial infection. Nat Rev Microbiol. 2004;2:946–953.
52. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102:783–788.
53. Alexander J, Fischer J, Boyajian M, et al. The influence of hair removal methods on wound infections. Arch Surg. 1983;118:347–352.
54. Fezza J, Klippenstein K, Wesley R. Cilia regrowth of shaven eyebrows. Arch Facial Plast Surg. 1999;1:223–224.
55. Chaiyakunapruk N, Veenstra D, Lipsky B, et al. Chlorhexidine compared with povidone–iodine solution for vascular catheter-site care: a meta-analysis. Ann Intern Med. 2002;136:792–811.
56. Bibbo C, Patel D, Gehrmann R, et al. Chlorhexidine provides superior skin decontamination in foot and ankle surgery: a prospective randomized study. Clin Orthop Relat Res. 2005;438:204–208.
57. Kinirons B, Mimoz O, Lafendi L, et al. Chlorhexidine versus povidone iodine in preventing colonization of continuous epidural catheters in children: a randomized, controlled trial. Anesthesiology. 2001;94:239–244.
58. Adams D, Quayum M, Worthington T, et al. Evaluation of a 2% chlorhexidine gluconate in 70% isopropyl alcohol skin disinfectant. J Hosp Infect. 2005;61:287–290.
59. Wilson J, Mills J, Prather I, et al. A toxicity index of skin and wound cleansers used on in vitro fibroblasts and keratinocytes. Adv Skin Wound Care. 2005;18:373–378.
60. Varley G, Meisler D, Benes S, et al. Hibiclens keratinopathy: a clinicopathologic case report. Cornea. 1990;9:341–346.
61. Murthy S, Hawksworth N, Cree I. Progressive ulcerative keratitis related to the use of topical chlorhexidine gluconate (0.02%). Cornea. 2002; 21:237–239.
62. McRae S, Brown B, Edelhauser H. The corneal toxicity of presurgical skin antiseptics. Am J Ophthalmol. 1984;97:221–232.
63. Gross A, Cutright D, Bhaskar S. Effectiveness of pulsating water lavage in the treatment of contaminated crushed wounds. Am J Surg. 1972;124: 373–377.
64. Wheeler C, Rhodenheaver G, Thacker J, et al. Side effects of high pressure irrigation. Surg Gynecol Obstet. 1976;143:775–778.
65. Draeger R, Dahners L. Traumatic wound debridement: a comparison of irrigation methods. J Orthop Trauma. 2006;20:83–88.
66. Tetzlaff J. The pharmacology of local anesthetics. Anesthesiol Clin North America. 2000;18:217–233.
67. McLure H, Rubin A. Review of local anesthetic agents. Minerva Anestesiol. 2005;71:59–74.
68. Krunic A, Wang L, Soltani K, et al. Digital anesthesia with epinephrine: an old myth revisited. J Am Acad Dermatol. 2004;51:755–759.
69. Wilhelmi B, Blackwell S, Miller J, et al. Epinephrine in digital blocks: revisited. Ann Plast Surg. 1998;41:410–414.
70. Stratford A, Zoutman D, Davidson J. Effect of lidocaine and epinephrine on Staphylococcus aureus in a guinea pig model of surgical wound infection. Plast Reconstr Surg. 2002;110:1275–1279.
71. Bartfield J, Crisafulli K, Raccio-Robak N, et al. The effects of warming and buffering on pain of infiltration of local. Acad Emerg Med. 1995; 2:254–258.
72. Masters J. Randomized control trial of pH buffered lignocaine with adrenalin in outpatient operations. Br J Plast Surg. 1998;51:385–387.
73. Colaric K, Overton D, Moore K. Pain reduction in lidocaine administration through buffering and warming. Am J Emerg Med. 1998; 16:353–356.
74. Fitton A, Ragbir M, Milling M. The use of pH adjusted lignocaine in controlling operative pain in the day surgery unit: a prospective randomized trial. Br J Plast Surg. 1996;49:404–408.
75. Mader T, Playe S. Reducing the pain of local anesthetic infiltration: results of a national clinical practice survey. Am J Emerg Med. 1998; 16:617.
76. Calatayud J, Gonzalez A. History of the development and evolution of local anesthesia since the coca leaf. Anesthesiology. 2003;98:1503–1508.
77. Buckenmaier C, Bleckner L. Anesthetic agents for advanced regional anesthesia: a North American perspective. Drugs. 2005;65:745–759.
78. Mather L, Copeland S, Ladd L. Acute toxicity of local anesthetics: underlying pharmacokinetic and pharmacodynamic concepts. Reg Anesth Pain Med. 2005;30:553–566.
79. Crystal C, Blakenship R. Local anesthetics and peripheral nerve blocks in the emergency department. Emerg Med Clin North Am. 2005;23: 477–502.
80. Hauser C, Adams CJ, Eachempati S. Surgical Infection Society: prophylactic antibiotic use in open fractures: an evidence-based guideline. Surg Infect. 2006;7(4):379–405.
81. Bergman B. Antibiotic prophylaxis in open and closed fractures. A controlled clinical trial. Acta Orthop Scand. 1982;55:57–62.
82. Patzakis M, Harvey J, Ivler D. The role of antibiotics in the management of open fractures. J Bone Joint Surg Am. 1974;56:57–62.
83. Benson D, Riggins R, Lawrence R, et al. Treatment of open fractures: a prospective study. J Trauma. 1983;23:25–30.
84. Weigelt J. Risk of wound infection in trauma patients. J Trauma. 1985; 150:782–784.
85. Vermeulen H, Ubbink D, Goossens A, et al. Systematic review of dressings and topical agents for surgical wounds healing by secondary intention. Br J Surg. 2005;92:665–672.
86. Rose A. Continuous water baths for burns. JAMA. 1906;47:1042–1046.
87. Winter G. Formation of the scab and the rate of epithelialization of superficial wound in the skin of the young domestic pig. Nature. 1962; 193:293–294.
88. Lewis R, Whiting P, ter Riet G, et al. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of debriding agents in treating surgical wound healing by secondary intention. Health Technol Assess. 2001;5:1–131.
89. Truscott W. Impact of microscopic foreign debris on post-surgical complications. Surg Technol Int. 2004;12:34–46.
90. McGuiness W, Vella E, Harrison D. Influence of dressing changes on wound temperature. J Wound Care. 2004;13:383–385.
91. Ip M, Lui S, Poon V, et al. Antimicrobial activities of silver dressings: an in vitro comparison. J Med Microbiol. 2006;55:59–63.
92. Phaneuf M, Bide M, Hannel S, et al. Development of an infection-resistant, bioactive wound dressing surface. J Biomed Mater Res A. 2005; 74:666–676.
93. Lee A. Enhancing dermal matrix regeneration and biochemical properties of 2nd degree burn wounds by EGF-impregnated collagen sponge dressing. Arch Pharm Res. 2005;28:1311–1316.
94. Argenta L, Morykwas M. Vacuum-assisted closure: a new method for wound control and treatment: clinical experience. Ann Plast Surg. 1997; 38:563–677.
95. Morykwas M, Argenta L, Shelton-Brown E, et al. Vacuum-assisted closure: a new method for wound control and treatment: animal studies and basic foundation. Ann Plast Surg. 1997;38:553–562.
96. Olenius M, Dalsgaard C, Wickman M. Mitotic activity in the expanded human skin. Plast Reconstr Surg. 1993;91:213–216.
97. Ubbink D, Westerbos S, Nelson E, et al. A systematic review of topical negative pressure therapy for acute and chronic wounds. Br J Surg. 2008; 95(6):685–692.
98. Gabriel A, Shores J, Bernstein B, et al. A clinical review of infected wound treatment with vacuum assisted closure (V.A.C.) therapy. Experience and case series. Int Wound J. 2009;6(2):1–25.
99. Driver V. Silver dressings in clinical practice. Ostomy Wound Manag. 2004;50(9A suppl):11S–15S.
100. Cochrane C, Walker M, Bowler P, et al. The effect of several silver containing wound dressings on fibroblast function in vitro using the collagen lattice contraction model. Wounds. 2006;18(2):29–34.
101. Erdmann D, Drye C, Heller C, et al. Abdominal wall defect and enterocutaneous fistula treatment with the vacuum-assisted closure (V.A.C.) system. Plast Reconstr Surg. 2001;108:2066–2068.
102. Fishbein D, Robinson L. Rabies. N Engl J Med. 1993;329(22): 1632–1638.
103. Teixeira CF, Fernandes C, Zuliani J, et al. Inflammatory effects of snake venom. Mem Inst Oswaldo Cruz. 2005;100(suppl 1):181–184.
104. Dart R, Hurlbut K, Garcia R, et al. Validation of a severity score for the assessment of crotalid snakebite. Ann Emerg Med. 1996;27(3):321–326.
105. Snyder C, Pickins J, Knowles R, et al. A definitive study of snake bite. JFMA. 1968;55:330.
106. Gudarian R, MacKenzie C, Williams J. High voltage shock treatment for snakebite. Lancet. 1986;2:229.
107. Stewart M, Greenland S, Hoffman J. First-aid treatment of poisonous snakebite: are current recommended procedures justified? Ann Emerg Med. 1981;10(6):331–335.
108. Sutherland S, Coulter A, Harris R. Rationalisation of first-aid measures for elapid snakebite. Lancet 1979;1:183.
109. Gold B, Barish R, Dart R. North American snake envenomation: diagnosis, treatment and management. Emerg Med Clin North Am. 2004; 22:423–443.
110. Lindsey D. Controversy in snakebite—time for a controlled appraisal. J Trauma. 1985;25:462.
111. Stewart R, Page C, Schwesinger W, et al. Antivenin and fasciotomy/debridement in the treatment of the severe rattlesnake bite. Am J Surg. 1989;158:543.
112. Hall E. Role of surgical intervention in the management of crotaline snake envenomation. Ann Emerg Med. 2001;37:175–180.
113. Burch J, Agarwal R, Mattox K, et al. The treatment of crotalid envenomation with antivenin. J Trauma. 1988;28(1):35–43.
114. Schmidt J. Antivenom therapy for snakebites in children: is there any evidence? Curr Opin Pediatr. 2005;17:234–238.
115. Dart R, Seifert S, Boyer L, et al. A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States. Arch Intern Med. 2001;161: 2030–2036.
116. Glass T. Early debridement in pit viper bites. JAMA. 1976;235:2513.
117. Russell F, Carlson R, Wainschel J, et al. Snake venom poisoning in the United States: experiences with 550 cases. JAMA. 1975;233:341.
118. Ledbetter E, Kutscher A. Aerobic and anaerobic flora of rattlesnake fangs and venom. Arch Environ Health. 1969;19(6):770–778.
119. Clark R, Selden BS, Furbee B. The incidence of wound infection following crotalid envenomation. J Emerg Med. 1993;11:583–586.
120. Kerrigan K, Mertz B, Nelson S, et al. Antibiotic prophylaxis for pit viper envenomation: prospective, controlled trial. World J Surg. 1997;21: 369–373.
121. Blaylock R. Antibiotic use and infection in snakebite victims. S Afr Med J. 1999;89:874–876.
122. White J. Snake venoms and coagulopathy. Toxicon. 2005;45(8): 951–967.
123. McCollough N, Gennaro J. Coral snake bites in the United States. JFMA. 1963;49:968.
124. Nimorakiotakis B, Winkel K. Marine envenomations. Part 1—jellyfish. Aust Fam Physician. 2003;32:969–974.
125. Nimorakiotakis B, Winkel K. Marine envenomations—part 2—other marine envenomations. Aust Fam Physician. 2003;32:975–979.
126. Church J, Hodgson W. Adrenergic and cholinergic activity contributes to the cardiovascular effects of lionfish (Pterois volitans) venom. Toxicon. 2002;40:787–796.
127. Haddad V, Sazima I. Piranha attacks on humans in southwest Brazil: epidemiology, natural history, and clinical treatment, with description of a bite outbreak. Wilderness Environ Med. 2003;14(4):249–254.
128. Caldicott D, Mahajani R, Kuhn M. The anatomy of a shark attack: a case report and review of the literature. Injury. 2001;32:445–453.
129. Burke W. The red imported fire ant (Solenopsis invicta). A problem in North Carolina. N C Med J. 1991;52:153–158.
130. Swanson D, Vetter R. Bites of brown recluse spiders and suspected necrotic arachnidism. N Engl J Med. 2005;352(7):700–707.
131. King L, Rees R. Dapsone treatment of a brown recluse bite. JAMA. 1983;250:648.
132. Mold J, Thompson D. Management of brown recluse spider bites in primary care. J Am Board Fam Pract. 2004;17:347–352.
133. Saucier J. Arachnid envenomation. Emerg Med Clin North Am. 2004;22:405–422.
134. Ryan P. Preliminary report: experience with the use of dantrolene sodium in the treatment of bites by the black widow spider Latrodectus hesperus. J Toxicol Clin Toxicol. 1983;21(4–5):487–489.
135. Key G. A comparison of calcium gluconate and methocarbamol (robaxin) in the treatment of latrodectism (black widow spider envenomation). Am J Trop Med Hyg. 1981;30(1):273–277.