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Envenomations
Eunice M. Singletary, MDa, Adam S. Rochman, MDa, Juan Camilo Arias Bodmer, MDb, Christopher P. Holstege, MDa,c,d,e,*
Department of Emergency Medicine, University of Virginia, Charlottesville, VA, USA b Universidad de La Sabana, Bogota, Colombia c Department of Pediatrics, University of Virginia, University of Virginia Health System, Charlottesville, VA, USA d Division of Medical Toxicology, University of Virginia, Charlottesville, VA, USA e Blue Ridge Poison Center, University of Virginia, Charlottesville, VA, USA
a
Numerous marine, crotalid, and arachnid animals in North America are capable of envenomating humans. This article reviews these potential envenomations and discusses the relevant approach to patients who manifest toxicity. Appropriate therapy is discussed, and treatments that may result in no benet or potential harm are highlighted. Marine envenomations With steady growth in the numbers of diving enthusiasts and more than 12,000 miles of coastline in the United States, encounters with marine animals are no longer considered unusual. Many marine animals have developed systems for attack and defense that on accidental exposure to humans result in envenomation. Most envenomations are not lifethreatening, often presenting only as a minor contact dermatitis. Venomous marine organisms can be dicult to identify or may not be seen at the time of envenomation. Knowledge of what venomous organisms are found in local waters assists physicians with management of marine envenomations. Marine animals responsible for envenomation can be broken into two large groupsdinvertebrates and vertebrates. Venomous invertebrates include jellysh, anemones, and re corals, whereas venomous vertebrate marine animals include stingrays, lionsh, and catsh.
* Corresponding author. University of Virginia Health System, Po Box 800774, Charlottesville, VA 22908-0774. E-mail address: ch2xf@virginia.edu (C.P. Holstege). 0025-7125/05/$ - see front matter 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2005.07.001 medical.theclinics.com
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Invertebrates Invertebrates most commonly implicated in envenomations include the coelenterates, such as jellysh, and the echinoderms, such as sea urchins. Coelenterates are divided into three classes: Hydrozoa (hydroids, re corals, Portuguese man-of-war), Schyphozoa (true jellysh), and Anthozoa (sea anemones). Schyphozoa and Hydrozoa Scyphozoa found in North American waters include stinging nettles (Chrysaora quineucirrha), which are commonly found in the Chesapeake Bay during mid to late summer; the purple jellysh (Pelagia noctiluca); the lions mane jellysh (Cyanea capillata); and the chirodropid box jellysh (Chironex species). Chironex eckeri is reputed to be the most lethal jellysh in the world, but it is more common in Australia and the South Pacic [1]. A related chirodropid, Chiropsalmus quadrumanus, was identied as the culprit in a lethal envenomation of a 4-year-old boy at Galveston Island, Texas, in 1990 [2]. The class Hydrozoa includes hydroids and stinging corals. Although both cause various degrees of contact dermatitis, desquamative eruptions, erythema multiforme, and anaphylaxis have been reported [35]. The most dangerous of the hydrozoas is the Portuguese man-of-war (Physalia physalis). Found in the Atlantic Ocean and the Gulf of Mexico during the summer, the Portuguese man-of-war can cause fatal envenomations [6,7]. The portion of the animal that is visible above the surface of the water is the pneumatophore, which is generally 10 to 30 cm in diameter and blue-topurple in color. The tentacles dangle from the pneumatophore. Physalia species and the chirodropids are the only jellysh in North America known to result in human deaths. In Australia, the jellysh species Carukia barnesi (and similarly related species) cause the Irukandji syndrome with severe systemic and potentially life-threatening symptoms [8]. The syndrome was rst described in 1952 by Flecker [8] and named for the Aboriginal tribe that inhabited the region where many of the stings occurred. In 1966, using himself, his son, and another volunteer, Barnes [9] identied the responsible small, peanut-sized, box jellysh as a Carybdeid, with one tentacle arising from each of four corners. The classic sequence of symptoms begins within 5 to 45 minutes after a minor stinging pain at the site of envenomation and includes low back pain; muscle cramps in the limbs, abdomen, and chest; sweating; anxiety; restlessness; nausea; and headache [10,11]. More severe symptoms include hypertension, pulmonary edema, global heart dilation, and cerebral edema [10,12]. Fatalities have followed development of severe hypertension and intracerebral hemorrhages [13]. Reported treatments include the use of narcotic analgesics for pain, muscle relaxants for spasm, and phentolamine for hypertension. Although no antivenom is available, there is one report of dramatic resolution of
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agitation, sympathetic features, and pain after intravenous bolus and infusion of magnesium sulfate [14]. Cardiopulmonary decompensation has been described, and in one review there was an increase in troponin I levels in 22% of 103 patients and varying degrees of systolic dysfunction or hypokinesis on echocardiogram [15]. A symptom complex was described in three divers who sustained envenomations in South Florida similar to the Irukandji syndrome, suggesting the presence of small, previously undetected Carybdeid jellysh [16] in North America. Venom of jellysh. Jellysh envenomate their prey through nematocysts. Nematocysts are venom-containing stinging organelles located in specialized epithelial cells called cnidocytes. The length of jellysh tentacles varies signicantly, from a few millimeters to more than 40 m. Longer tentacles frequently wrap around the legs of swimmers. Tentacles that have separated from the jellysh are still capable of stinging for weeks or months after becoming detached, even if dried. Swimmers and snorkelers occasionally may be stung by a detached tentacle, without any visible jellysh in the area. When a tentacle comes in contact with the epidermis of an unsuspecting person, thousands of venom-lled nematocysts may re simultaneously, causing release of venom resulting in a jellysh sting. Stings vary in severity depending on the species of coelenterate, its size, the time of the year, and the size and health of the victim. Venoms are antigenic and toxic, causing a variety of reactions, including rash, dermatonecrosis, neurotoxicity, cardiotoxicity, and hemolysis. Toxins comprise a complex mixture of heat-labile polypeptides and proteins, including catecholamines; histamine; hyaluronidase; brolysins; kinins; phospholipases; and various hemolytic, cardiotoxic, and dermatonecrotic toxins [17]. The venom is believed likewise to destabilize cell membranes through interference with the sodium-potassium pump [18]. Envenomation from a jellysh causes immediate pain that may be described as a mild-to-moderate stinging or burning. Pain is followed by the development of an erythematous rash, with linear papules or beaded streaks for Portuguese man-of-war envenomations. The rash may be in the pattern of the wrapped tentacles at the site of contact or develop more distantly. The rash progresses to erythematous welts or vesicles within 2 hours and can last 24 hours or longer. Delayed skin changes include pigment changes, fat atrophy, telangiectasias, scarring, keloids, or striae [1921]. Conjunctivitis, chemosis, corneal ulcerations, and facial and lid edema all have been described after envenomation to the eyes [19,22]. Tentacles still may be adherent on patient presentation. For most jellysh stings, symptoms are conned to localized pain and rash that resolve over 24 hours. Multisystem reactions are seen more commonly after envenomation by Chironex, Carybdeid, and Physalia species, with deaths resulting from anaphylaxis or direct toxic eects. Gastrointestinal symptoms include nausea, vomiting, and diarrhea. Headache, malaise, confusion,
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delirium, coma, seizures, paresthesias, and paralysis are potential neurologic symptoms. Musculoskeletal complaints, which are prominent with Carybdeid envenomations, include myalgias, muscle spasm, cramping, and paralysis. Cardiopulmonary eects include dysrhythmias, hypotension, cardiovascular collapse, respiratory distress, bronchospasm, laryngeal edema, and respiratory failure or arrest [1,23]. Management of jellysh envenomation. Care for a jellysh envenomation begins at the scene. After treatment of life-threatening symptoms, decontamination should be initiated immediately. If specic decontamination agents are not readily available, the skin can be rinsed with seawater or saline solution to remove nematocysts. If a sting is suspected from a Chironex species, decontamination is initiated by ooding the envenomation site and any visible tentacles with 5% acetic acid (household vinegar) for 10 minutes before attempting to remove any adherent tentacles. Vinegar has been shown to inactivate undischarged nematocysts in cubozoan (box) jellysh and theoretically alters the pH of the protein toxin, making it less bioactive [24]. For stings by all other jellysh, decontamination can be accomplished by liberal application of vinegar, baking soda, or a solution of dilute (1/4 strength) household ammonia. Isopropyl alcohol may induce further discharge of unred nematocysts and is not recommended as a decontaminant. Vinegar and ammonia may be applied continuously by applying soaked compresses. A paste made from unseasoned meat tenderizer or papaya also has been reported to relieve signicantly the pain associated with jellysh stings. Papain is believed to inactivate the jellysh venom by hydrolyzing the protein toxin [24]. If meat tenderizer is used, it should be applied for no longer than 15 minutes. The other discussed decontaminants should be applied until pain is relieved or for 30 minutes for maximal benet. After decontamination, any remaining tentacles should be removed. Removal can be accomplished by xing the area with shaving cream or a baking soda slurry and then using a razor. At the scene, a paste of sand and seawater can be used and the area scraped with a shell or a plastic credit card [25]. After removal of the remaining tentacles, the decontaminant should be reapplied for an additional 15 minutes. Pain control, particularly for systemic reactions, may require parenteral narcotics. There is evidence that hot water (4345 C) immersion is more eective than vinegar or papain meat tenderizer at relieving pain [23]. Jellysh protein toxins are heat-labile, and heat immersion may penetrate the intracutaneous depths to inactivate the venom. If jellysh sting victims present to an emergency department within 60 minutes, a hot shower may be useful for individuals with widespread stings. Smaller local reactions may benet from application of topical anesthetic ointments or sprays containing benzocaine or 2.5% lidocaine. Topical hydrocortisone (1%) applied twice daily may be benecial for skin reactions. Tetanus prophylaxis should be
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administered if indicated. Oral antihistamines or steroids are useful if an allergic reaction develops (ie, hives, pruritus, wheezing). Current research is focusing on the development of a topical jellysh sting inhibitor, although denitive clinical studies testing ecacy are lacking [26]. Patients without systemic signs may be discharged with oral analgesics and anti-inammatory agents as needed. Anthozoa Sea anemones are sessile, multicolored animals often found in shallow waters and tidal pools. They have tentacles containing nematocysts that can envenomate humans and sh. Envenomation results in a lesion with a pale center and an erythematous or petechial ring; this is followed by increasing edema and ecchymosis. Although most lesions resolve in 48 hours, more severe envenomations may result in vesicle formation, which can lead to abscess, eschar, or hyperpigmentation. The larval forms of certain anemones and thimble jellysh (Linuche unguiculata) can nd their way under bathing suits, resulting in discharge of nematocysts and tingling sensation while in the water [27]. Itching and burning become more pronounced if a freshwater shower is taken while still wearing the suit. A red, raised or conuent rash develops in the covered areas, which is associated with intense pruritus or pain, sparing exposed areas of skin. This condition is referred to as sea bathers eruption. Severe toxic reactions include headache, fever, chills, and vomiting. Treatment of envenomations from anemones and sea bathers eruption is similar to that for jellysh, beginning with removal of suits before showering and decontamination using vinegar for 30 minutes. Topical 1% hydrocortisone applied twice daily is eective for the eruption, although more severe reactions require oral prednisone. Because nematocysts may remain in the bathing suit after dryingdand result in repeat envenomation after reapplyingdthe suit should be machine washed or rinsed with vinegar followed by hand washing with detergent or soap and water. Phylum Echinodermata Echinoderms include starsh, brittle stars, sea cucumbers, and sea urchins. Sea urchins are involved most commonly in envenomations by echinoderms, with the mechanism of envenomation varying depending on the species. Sea urchins. The sea urchin is a free-living echinoderm covered by a hard shell containing multiple irregular spines that may or may not contain venom. Sea urchins that do not possess venom-lled spines have jawed pedicellariae (pincer organs) that function to inject the venom. The pedicellariae may continue to envenomate even after detachment from the urchin and require prompt removal from the skin. Typically a swimmer, snorkeler, or diver may step on or be thrown by a surge into sea urchins. The spines are brittle and break o easily, leaving calcareous material in the
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wound. Some spines contain a blue-black dye that stain the wound or cause temporary tattooing. This dye is absorbed over 1 to 2 days. Sea urchin venom is poorly characterized, but similar to other marine venoms, it contains heatlabile, high-molecular-weight toxins, including steroid glycosides, hemolysins, proteases, serotonin, and cholinergic substances [27]. Sea urchin envenomations may result in an immediate local reaction. This reaction typically presents with swelling, puncture wounds, and burning pain that is initially minor, but intensies over 30 minutes and lasts several hours. Multiple simultaneous wounds may result in greater envenomation, with symptoms of muscle spasm, weakness, diculty breathing, paresthesias, ataxia, and syncope. Recommended treatment begins with hot water immersion (43.345 C), which provides signicant pain relief and theoretical inactivation of the toxin. Visible spines, if easily accessible, should be removed carefully using forceps. Care should be taken in spine removal because they are brittle and may crumble in the wound. Surgical removal is indicated for spines that penetrate or are in close proximity to a joint or neurovascular structure [28]. Wounds should be irrigated copiously, and tetanus prophylaxis should be administered when indicated. Prophylactic antibiotics generally are not needed. Thin retained spines without symptoms generally are absorbed or extruded, but a delayed secondary reaction sometimes is seen. This reaction may present with induration and swelling of tenosynovitis or sarcoidal granuloma formation [29,30]. Treatment includes a 7- to 14-day course of nonsteroidal anti-inammatory drugs and, for more severe reactions, oral prednisone. Vertebrates Venomous marine vertebrates include stingrays, scorpionsh, lionsh, stonesh, and catsh. Three types of hazards are associated with venomous marine vertebrates: (1) direct wound trauma, (2) pain and swelling from venom or trauma, and (3) subsequent tissue necrosis and infection. Stingrays The stingray is the most common cause of marine envenomations in the United States. It is estimated that approximately 2000 stings occur annually [31], with the Southern stingray (Dasyatis americana) being the main oender in the East and the round stingray (Urolophus halleri) being the main oender in the West. Stingrays are generally peaceful bottom dwellers. Attacks occur most commonly when a swimmer inadvertently steps on a stingray buried in the sand, resulting in the stingray hurling its barbed tail up in a defensive response and striking the foot or leg. Injuries also are sustained to the hand or arm in the process of trying to remove the sh from a stingray caught while shing. The stinging apparatus of a stingray consists of one or more barbs and two ventrolateral venom-containing grooves encased in an integumentary
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sheath (Fig. 1). The barb is serrated and retropointed and can cause signicant lacerations and puncture wounds. A venom gland is located at the base of the tail. An injury from a stingray is a traumatic puncture wound or laceration and an envenomation. Venom of stingrays. Stingray venom is heat-labile and composed of numerous toxic compounds, including phosphodiesterases, 58-nucleotidase, and serotonin [31]. Vasoconstrictive properties of the venom cause a cyanotic appearance around the wound along with subsequent poor healing, necrosis, or infection. Symptoms of envenomation include immediate, excruciating pain out of proportion for what might be expected based on the wound appearance alone. The pain usually reaches maximum intensity in about 90 minutes and resolves over several hours. Potential systemic symptoms include weakness, nausea, muscle cramps, vomiting, peripheral vasoconstriction, cardiac dysrhythmias, respiratory depression, seizures, and coma. Although fatalities are rare, intrathoracic and intraabdominal wounds have been reported and are associated with higher morbidity and mortality [32,33]. Management of stingray envenomation. After stabilization of potential life threats, the main goals of treatment are pain control, neutralization of venom, and wound care. Initial irrigation of the wound site should be performed with cold normal saline to wash away existing venom, and the resulting vasoconstriction may slow down further absorption of the venom. The aected area should be immersed in hot water (4345 C) for 30 to 90 minutes, which helps destabilize some of the venom and provides signicant pain control. Hot water immersion was shown to be eective at reducing pain from venomous sh stings in 73% of cases in one series [34]. Parenteral narcotics may be necessary for supplemental pain control. Any retained brided gently. Spines and fragments of the barb or its sheath should be de barb material are radiopaque, so plain radiography or ultrasound may aid
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in identifying retained fragments. An anesthetized limb should not be placed in hot water because of the risk of thermal injury. If indicated, tetanus prophylaxis should be provided. Because of the risk of infection, primary closure of traumatic wounds should be avoided. Prophylactic antibiotics, such as ciprooxacin, doxycycline, or trimethoprim-sulfamethoxazole, are recommended in patients with residual foreign bodies or if a patient is immunosuppressed [34]. Scorpaenidae Scorpaenidae are found worldwide in temperate, tropical, and subtropical climates and include lionsh (Pterois), scorpionsh (Scorpaena), and stonesh (Synanceia). All members of this family have 12 to 13 dorsal spines, 2 pelvic spines, and 3 anal spines. Spines are covered with a loose integumentary sheath that is pushed down the spine when tissue is punctured, compressing the two venom glands at the base of the spine and allowing venom to pass up a groove in the spines into the wound. The severity of envenomations seems to be mild for lionsh, more severe for scorpionsh, and most severe or life-threatening for stonesh [35]. Most envenomations by Scorpaenidae in the marine setting occur outside North American waters. In the United States, reported envenomations are typically the result of encounters by home aquarists who keep lionsh in their tanks [36]. Lionsh were introduced in the southeastern United States in 1994, however, and have been spotted by divers from south Florida northward as far as Long Island (Fig. 2). As of January 2004, lionsh numbers seem to be increasing between Florida and North Carolina [37]. Physicians and the public need to be aware of the potential for interaction with this venomous species in North American waters. Scorpionsh and stonesh exposures occur most frequently outside United States waters from wading with inadequate foot protection and inadvertently stepping on the sh.
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Venom of Scorpaenidae. Venom from the Scorpaenidae, similar to other marine venoms, comprises heat-labile, high-molecular-weight proteins with antigenic properties. Scorpionsh and stonesh venom produces intense vasoconstriction, increased vascular permeability, and myotoxicity secondary to blockade of conduction in skeletal, involuntary, and cardiac muscles [38,39]. After puncture by the spine of a lionsh, there is severe localized pain, frequently accompanied by swelling. Systemic symptoms occurred in 13% of one series, without any fatalities [40]. Systemic symptoms included nausea, diaphoresis, diculty breathing, chest or abdominal pain, weakness, hypotension, and syncope. Wounds are accompanied by swelling and redness and in 4% by vesicles and 1% by tissue necrosis. With lionsh envenomations, there is immediate excruciating pain that may radiate to the entire limb and regional lymph nodes. Similar to stingray envenomations, pain peaks at about 60 to 90 minutes, but may last 12 hours without treatment. Wounds are described as anesthetic, with surrounding hypersensitivity. Scorpionsh envenomations also produce severe pain, but less than envenomations from stonesh. Puncture wounds from scorpionsh are surrounded by a ring of pallor and cyanosis, owing to the vasoconstrictive properties of the toxin. Systemic eects include nausea, vomiting, sweating, weakness, motor paralysis, respiratory depression, shock, and possible cardiac arrest [31]. Symptom duration varies from days to weeks or months. Management of Scorpaenidae envenomation. Similar to other marine envenomations, initial resuscitation and stabilization is followed by wound exploration and irrigation. The clinician needs to be prepared to treat an allergic reaction at any time. Because venom is heat-labile, after initial irrigation puncture wounds should be immersed in hot water (43.345 C) for 30 to 90 minutes or until pain is relieved. Limbs that have been anesthetized with local or regional anesthetics are subject to thermal burns if placed into scalding water, so water temperature must be measured and monitored carefully for patients receiving anesthetics before hot water immersion. Parenteral analgesics may be used for additional pain relief. Prophylactic antibiotics are unnecessary, and tetanus prophylaxis should be oered when indicated. Wounds with vesicle formation are dressed with topical antiseptics, such as silver sulfadiazine or bacitracin daily. Because foreign bodies may be retained in 19.5% of marine animal injuries, radiography or ultrasound is advised for suspected retained foreign bodies in soft tissue [41]. Surgical removal of embedded spines is required with spines that penetrate or are in proximity to joints, nerves, or vessels. Antivenom is available only for stonesh envenomation [42]. Catsh More than 1000 species of freshwater and saltwater catsh exist worldwide, and many are venomous to humans. Catsh possess axillary
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venom glands and one dorsal and two pectoral n spines that inict the envenomation. Some species of catsh produce a proteinaceous toxic barbs (tip turned epidermal secretion (crinotoxin). Catsh have retrousse up) and can produce signicant damage and be dicult to remove [41,43]. The heat-labile polypeptide venom is incompletely characterized, but is believed to contain vasoconstrictive and dermatonecrotic factors [31]. Symptoms frequently include intense pain, paresthesias, and numbness that may last 30 minutes to 48 hours. Erythema, hemorrhage, edema, cyanosis, and lymphangitis also are common localized ndings. Rare systemic eects include fever, weakness, syncope, hypotension, and respiratory distress. Death is rare. Puncture wounds frequently are followed by secondary bacterial infections that may take months to resolve [4447]. Emergency treatment of catsh envenomation is as described for stingrays.
Snake envenomations More than 6000 people are reported to sustain snakebites annually in the United States, with nearly half from poisonous species [48]. More than 100 people are reported to experience major morbidity and are likely to require critical/intensive care. Although these cases are undeniably underreported, death seems to occur in only a few cases a year. Two families of poisonous snakes are indigenous to North Americadthe crotalids (Crotalidae) and elapids (Elapidae). Crotalid Crotalids are responsible for most snake envenomations in North America. They may be distinguished from other species by their triangular-shaped heads, infrared heat-sensing pits, elliptical-shaped pupils, and a single row of subcaudal scales. Three genera of crotalids inhabit the United Sates: Crotalus (12 species), Sistrurus (2 species), and Agkistrodon (2 species) (Table 1). Although crotalids commonly are referred to as rattlesnakes, this reference is inaccurate because the Agkistrodon species (commonly called cottonmouth and copperhead) do not possess rattles. Clinical presentation The spectrum of clinical presentations from crotalid envenomations ranges from asymptomatic to cardiovascular collapse and death. The presentation depends on the amount and properties of the venom injected, the location of the bite, and the size and general health of the victim. The components of snake venom vary not only with the dierent species of snakes, but also with each snake itself depending on the season, nutritional status, and age. It is impossible to predict accurately the extent of local tissue damage a patient will develop after a snakebite. Bites from Crotalidae
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Table 1 Crotalids of North America Scientic name Crotalus adamanteus Crotalus atrox Crotalus cerastes Crotalus horridus Crotalus lepidus Crotalus mitchelli Crotalus molossus Crotalus pricei Crotalus scutulatus Crotalus tigris Crotalus viridis Crotalus viridis viridis Crotalus viridis abyssus Crotalus viridis helleri Crotalus viridis lutosus Crotalus viridis oreganus Crotalus willardi Agkistrodon contortrix Agkistrodon piscivorus Sistrurus catenatus Sistrurus miliarius Common name Eastern diamondback rattlesnake Western diamondback rattlesnake Mojave Desert sidewinder Timber rattlesnake Rock rattlesnake Speckled rattlesnake Black-tailed rattlesnake Twin-spotted rattlesnake Mojave rattlesnake Tiger rattlesnake Western rattlesnake Prairie rattlesnake Grand Canyon rattlesnake Southern Pacic rattlesnake Great Basin rattlesnake Northern Pacic rattlesnake Ridge-nosed rattlesnake Southern copperhead Eastern/western cottonmouth Massasauga Pigmy Location United United United United United United United United United United United United United United United United United United United United United States States, States, States States States, States, States, States, States, States, States States States, States States, States, States States States, States Mexico Mexico
Mexico
species that do not introduce venom (dry bites) have been estimated to occur in 20% of exposures [49]. Tissue injury. Tissue damage at the site of the bite is the most common complication after envenomation by North American snakes. Numerous enzymes have been isolated from the venom of snakes (Box 1). The mechanism of each of these enzymes is directed at the breakdown of specic components of the tissue in which the venom has been injected, allowing the venom to penetrate further. Hemorrhagic toxins have been isolated from snake venom that cause damage to the capillary endothelial cells and the basement membrane of vessel walls, allowing extravasation of erythrocytes into the surrounding tissues [5052]. As a result, patients initially experience edema at the bite site, which progressively spreads to adjoining tissues. Ecchymosis also may develop and give the area around the bite a bluish hue. In addition, hemorrhagic blebs may develop and become quite large (Fig. 3). Lymphangitis and lymphadenopathy may progress secondary to lymphatic spread of venom components, causing the clinician to assume incorrectly the occurrence of secondary bacterial infection. Venom metalloproteinases cleave protumor necrosis factor-a, releasing activated tumor necrosis factor-a and initiating a cascade of endogenous inammatory responses. This uncontrolled response ultimately results in marked inammation and subsequent tissue necrosis [53,54]. Myotoxin A is one component that causes direct necrosis of skeletal muscle [55].
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Box 1. Venom components Metalloproteinases Arginine ester hydrolase Thrombin-like enzyme Collagenase Hyaluronidase Phospholipase A2 Phospholipase B Phospholipase C Lactate dehydrogenase Phosphomonoesterase Phosphodiesterase Acetylcholinesterase RNase DNase 5#-Nucleotidase Nicotinamide adenine dinucleotide nucleotidase L-Amino acid oxidase Myotoxin A
The presence of fang marks is considered essential to the diagnosis of snakebite. Skin lesions may appear as one or more puncture marks or scratches. Pain is frequently the initial complaint and usually begins at the moment of envenomation or shortly thereafter. Duration of the pain seems to depend on the severity of envenomation and may persist in lesser degrees over several days. Nausea, vomiting, and diaphoresis are seen commonly with mild-to-severe envenomations.
Fig. 3. Finger hemorrhagic blebs after copperhead (Agkistrodon contortrix) envenomation. (Courtesy of Christopher P. Holstege, MD, University of Virginia.)
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When envenomation occurs, swelling usually begins within minutes of the bite. Rapid progression may involve the entire extremity in 1 hour. Untreated or inadequately treated with antivenom, the swelling may progress for days. The aected extremity may continue to show edema for a few weeks after the initial recovery. Mild cyanosis at the site of injury is a common nding and does not indicate a need for surgical intervention. Tissue necrosis may follow cyanosis of the tissues or bleb formation over the aected areas. Dierentiation of compartment syndrome from the grossly swollen extremity without intracompartmental swelling may be dicult because the latter may obscure pulse and present with signicant induration (Fig. 4). Direct measurement of intracompartmental pressures with a Stryker needle or similar instrument is essential to determine the presence of compartment syndrome. In addition to direct tissue damage, rhabdomyolysis also has been reported [5658]. Myonecrosis rarely may be associated with compartment syndrome, but also has been reported in the absence of elevated intracompartmental pressures. Coagulopathy. After envenomation, coagulopathy has been reported in 36% to 50% of patients, depending on the species [59,60]. Venom-induced thrombocytopenia, brinolysis, and disseminated intravascular coagulation (DIC) all have been reported (Table 2). Coagulopathy may be manifest as gastrointestinal bleeding, epistaxis, hemoptysis, bleeding from wounds or intravenous sites, or petechial rash. Venom may damage capillaries by disrupting endothelial cells. Dilation of the endoplasmic reticulum and perinuclear space is followed by swelling and eventually bleb formation on endothelial cells with extension into the capillary lumen. The cells subsequently rupture, releasing plasma and erythrocytes into the extravascular space. Smaller blood vessels seem to be more susceptible to the eects of hemorrhagic toxins, explaining the edema and petechiae that accompany many bites. Some venoms contain thrombinlike proteins, which slow the activity of brinogen. They also may contain plasmin-like components, which produce proteolysis of brinogen and brin [61]. Crotalus adamantus venom contains crotalase, a thrombin-like enzyme that cleaves brinopeptide-A from the a chain of brinogen but does not activate or clear platelets. It also fails to cleave the brinopeptide from the b chain of brinogen, activate factor XIII, or complex with antithrombin III. This can cause complete debrination without producing DIC, as shown by normal platelets, antithrombin III, factor XIII, and D-dimer [58,62]. Platelet aggregation occurs as a result of capillary damage and possibly the release of adenosine-5#-phosphate, which seems to be associated with thrombosis [63]. This widespread thrombosis seems to lead to organ damage and consumes platelets; this may explain venom-induced thrombocytopenia and when combined with debrination may look similar to DIC. It also may be a contributing factor to DIC.
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Fig. 4. Arm edema and ecchymosis secondary to timber rattlesnake (Crotalus horridus) envenomation. (Courtesy of Christopher P. Holstege, MD, University of Virginia.)
Neuromuscular toxicity. Although uncommon, neuromuscular blockade has been associated with Crotalus scutulatus scutulatus bites [57]. The mechanism of paralysis seems to be associated with calcium channel blockade in presynaptic neurons, which prevents the release of neurotransmitters at the motor end plate [64]. Less serious but more common neurologic complaints include tingling or numbness of the tongue, mouth, scalp, digits, or bite site. Facial and limb myokymia has been documented after Crotalus horridus envenomations [65,66].
Table 2 Coagulation abnormalities associated with snake envenomation VIT Fibrinogen FSP Platelets PT PTT Overt bleeding RBC destruction Normal Normal Decreased Normal Normal No No DF Decreased Increased Normal Prolonged Prolonged No No DIC Decreased Increased Decreased Prolonged Prolonged Yes Yes
Abbreviations: DF, debrination; DIC, disseminated intravascular coagulation; FSP, brin split products; PT, prothrombin time; PTT, partial thromboplastin time; RBC, red blood cell; VIT, venom-induced thrombocytopenia.
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Treatment Initial snakebite treatment is associated with numerous myths and dangerous practices that can contribute to the morbidity of the patient. The most important steps to ensure a good outcome include immobilization and rapid transport of the victim for evaluation by trained medical personnel. Many rst-aid measures taught in the past are no longer recommended [67,68]. Capture of the snake for identication may lead to another victim. Thorough examination and proper observation dictate treatment regardless of the species involved. Focus should be directed toward immediate access to professional medical care. Performing incisions through the wound [69], application of suction devices [70,71], electric shock therapy [7275], tourniquets, cryotherapy, and heat application all should be avoided in the management of North American crotalid envenomations [76]. In-hospital management. The bite area should be cleansed gently. Circumferential measurement at several points along the aected limb should be started shortly after the patients arrival and repeated at intervals until progression has ceased. A useful technique to ensure consistent measurement is to place a small mark on either side of the paper measuring tape. The bitten extremity should be immobilized with a padded splint and an elastic bandage wrapped gently but rmly from the distal to the proximal aspect of the limb. Elevation to a level above the heart may be achieved with a pillow or other means. When elevated, the edema usually moves proximally; this does not represent progression of toxicity if the edema of the distal extremity decreases simultaneously. Neurovascular checks and new measurements should be performed hourly until swelling subsides. Analgesia. Pain control usually requires parenteral narcotic agents, such as morphine, during the rst 24 to 48 hours of therapy. Anti-inammatory agents should be used with caution, especially in patients with evidence of coagulopathy. Infection and antibiotics. Numerous organisms have been found growing in the mouths of snakes, including gram-negative rods (Enterobacter, Pseudomonas, Aerobacter, Proteus), gram-positive cocci, Clostridium, Salmonella, and fungi [7779]. Case series have shown the incidence of infection to be low after snakebites [80,81]. Venom itself has been shown to have antibacterial properties [82]. Currently, prophylactic antibiotics are not recommended in all cases of snakebites. If a patient develops signs and symptoms of infection that cannot be dierentiated from the venoms reaction itself, consideration should be given to instituting antibiotics to cover the aforementioned organisms [83,84]. Excisional therapy. In the past, early surgical excisional therapy of the envenomated area was advocated as the preferred method of managing
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snakebite victims [85]. It was believed that the bulk of deposited venom would remain in the area of the bite, and that by excision of this tissue the local toxicity would be eliminated [86]. These published reports were merely physicians personal experiences describing individual cases with no controls. In a controlled animal model by Stewart and colleagues [87], excisional treatment combined with antivenom therapy resulted in worse bridement muscle function compared with antivenom therapy alone. De without antivenom did not improve survival, decrease soft tissue edema, or preserve function compared with controls. Excisional therapy is strongly discouraged. Fasciotomy. Appropriate use of fasciotomies in snakebite victims is a topic wrought with misconceptions. The literature is clear that fasciotomy should not be performed unless elevated muscle compartment pressures are documented. If muscle injury does occur after a snakebite, it is nearly always the result of the myotoxins present in the snakes venom, not elevated compartment pressures. Biopsy results in severe cases of snakebite have revealed myopathy distant from the site of envenomation, supporting myotoxin-induced necrosis rather than compartment syndrome [58,88]. Rarely can a snakes fang penetrate through the fascia and into the muscle compartments. Clinically the snakebite extremity appears nearly identical to an extremity with a compartment syndrome. Victims have swelling, tense skin, tenderness, paresthesias, and pain with passive motion secondary to the local inammatory reaction. Past publications have advocated performing fasciotomies on all snakebite victims with edematous extremities and touted an improved outcome with this aggressive management [85,89]. These publications, often inappropriately referenced in the support of fasciotomies, lack scientic methods and are biased by individual physicians personal case reports. Controlled animal studies have shown that fasciotomies are not benecial after snakebite [90]. Antivenom and fasciotomy performed before administration of venom did not prevent muscle necrosis compared with antivenom alone [91]. Administration of antivenom after snake venom injection decreases the elevation in compartment pressures and preserves muscle function [87,92]. In addition, decreased muscle strength was documented in animals receiving fasciotomy plus antivenom compared with the antivenom-alone group, suggesting that fasciotomy is causing further muscle damage [87]. Conservative therapy using antivenom without fasciotomies in individual case reports and large case series has shown good outcomes for victims of snakebites [49,93]. Fasciotomies do have a role in the management of snakebites [94,95]. When compartment pressures are documented to be elevated greater than 30 mm Hg, and the patient already has been treated adequately with antivenom, fasciotomy may be considered [96]. Measurements can be taken easily with a wick catheter, slit catheter, or needle manometer. In addition, other noninvasive techniques are benecial
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in performing serial monitoring for elevated compartment pressure [97]. Pulse oximetry should not be used to assess compartment pressure [98]. Despite this literature, victims of snakebites continue to be mismanaged by physicians too eager to decompress edematous tissues surgically. Corticosteroids. Initially, corticosteroids were thought to be benecial in the treatment of snakebites and recommended as a standard of care [99]. Subsequent experimental studies failed to nd benet in their use, however [100]. Steroids should not be routinely administered to victims of snakebites but rather reserved for the treatment of serum sickness. Blood products. Antivenom is the rst choice of treatment for crotalid snakebiteinduced coagulopathy. Blood products also may be indicated if active hemorrhage is occurring or coagulation parameters are not correcting at an acceptable rate. In the latter situation, an increased dose of antivenom is frequently indicated. Blood products that may be benecial in a limited number of patients include fresh frozen plasma, cryoprecipitate, packed red blood cells, platelets, and whole blood. Fluid replacement. Hypotension may be caused by uid loss owing to third spacing, vomiting, hemorrhage secondary to coagulopathy, or vasovagal eects. Crystalloid administration should begin immediately in these patients. In the case of hypotension caused by extravascular uid shifts or hemorrhage, antivenom also is indicated. A common cause of prolonged hypotension in snakebite victims is inadequate uid resuscitation. Antivenom. The most critical decision facing the clinician treating snakebite victims is when to administer antivenom. For North American crotalid envenomation, two antivenom products are available: a partially puried polyvalent crotalid antivenom of equine origin (Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania) and a puried ovine polyvalent Fab immunoglobulin fragment product (CroFab; Protherics, Brentwood, Tennessee). There have been numerous reports of immediate hypersensitivity reactions associated with the use of crotalidae antivenom polyvalent IgG (Wyeth-Ayerst Laboratories). Incidence rates for immediate hypersensitivity reactions associated with the use of this product range from 23% to 56% [101]. This high reaction rate may be due in part to the large amount of nonvenom neutralizing proteins within this partially puried horse antivenom. In addition, this product contains the Fc portion of the antibodies, which may result in cross-linking on cell surface receptors and lead to mast cell and basophil degranulation. Because of the high incidence of hypersensitivity reactions to the Wyeth product, use of this product is gradually diminishing in North America [102]. CroFab is a sterile, puried, lyophilized preparation of ovine polyvalent Fab immunoglobulin fragments that has been approved for use in patients
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with minimal or moderate North American crotalid envenomation. These Fab fragments are obtained from the blood of sheep immunized with one of the four following snake venoms: Crotalus atrox (western diamondback rattlesnake), Crotalus adamanteus (eastern diamondback rattlesnake), Crotalus scutulatus (Mojave Desert rattlesnake), and Agkistrodon piscivrus (cottonmouth). The antivenom is prepared by fractionating the immunoglobulin from the ovine serum, digesting it with papain, and isolating the venom-specic Fab fragments on ion exchange and anity chromatography columns. These four dierent monospecic antivenoms are mixed, creating the polyvalent CroFab. CroFab is reported to have a lower risk of immediate hypersensitivity reactions [103]. The product contains reduced amounts of the immunogenic Fc portion of the antibody. In a review of the literature, a few cases of acute allergic reaction have been reported with CroFab. The incidence of immediate hypersensitivity reactions was reported as 19% in the original randomized multicenter trial of this product [104]. Dart and McNally [101] reported a case series of 42 patients who received CroFab in which 6 patients developed mildto-moderate allergic reactions. Five of these 6 reactions were associated with an improperly puried lot of antivenom, however, containing higher amounts of the Fc portion. Another case series from Dart and colleagues [105] reported no acute reactions with 11 consecutive patients. Ruha and colleagues [106] described a case series of seven patients who received CroFab infusions of up to 28 vials per case with no immediate hypersensitivity reactions noted. Antivenom is less often administered with copperhead (Agkistrodon contortix) envenomation. Because of the past high risk of hypersensitivity reactions associated with the equine-derived product, it was reserved for patients with marked systemic signs of toxicity. With the availability of the less antigenic and safer Crotalidae polyvalent immune Fab (ovine), antivenom treatment for copperhead bites is more commonly considered, although its exact indications have not yet been delineated clearly [107,108]. The major indications for antivenom therapy are as follows: 1. 2. 3. 4. Rapid progression of swelling Signicant coagulation defect Neuromuscular paralysis Cardiovascular collapse
Attempts have been made to quantitate these signs and symptoms [109]. If in question, the most reliable means of determining the indication for antivenom is through consultation with a regional medical toxicologist or poison center. Patients who are asymptomatic or have minimal symptoms should not be treated with antivenom. Instructions for mixing antivenom are in the package insert. Full resuscitation capabilities should be available during infusion of antivenom in the event that anaphylaxis develops. Asymptomatic patients may be observed for 6 hours after the bite. If no coagulopathy or symptoms develop, they may be released. There are a few
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reports of patients developing symptoms beyond 6 hours [110,111]. Although rare, the patient should be instructed to return if symptoms develop, and a follow-up call should be made to the patient the following day. Disposition Patients who remain asymptomatic for 6 hours and have normal coagulation studies (brinogen, brin split products, platelets, prothrombin time, partial thromboplastin time) may be released with instructions to return if symptoms occur. Follow-up contact within 12 to 24 hours should be made. Symptomatic patients should be hospitalized and the need for antivenom therapy should be determined. If symptoms have not progressed, and coagulation studies are not altered signicantly by 24 hours, the patient may be released with follow-up arranged for the following day. The patient should be instructed to return if symptoms recur. The patient who has received antivenom therapy should be observed for 24 hours or until the progression of edema has stopped, coagulation studies have been reversed to near-normal, and all signs of neuromuscular impairment are gone. Wound management often requires repeated followup visits. The patient should be instructed as to the appearance of serum sickness and should contact the physician if that occurs. Some clinicians prefer to give the patient prescriptions for histamine blockers (ie, hydroxyzine) and steroids at the time of dismissal so that there is less delay in treatment when symptoms occur; this does not preclude the need for the patient to contact the physician at the onset of symptoms. Patients who have full-thickness tissue destruction may require referral to an appropriate surgical consultant. This referral is best done during the initial phase of treatment while the patient is hospitalized. Follow-up should be arranged for outpatient management before discharge. Pain control usually requires oxycodone or hydrocodone for 1 or 2 weeks after discharge. After that time, nonsteroidal anti-inammatory drugs may be substituted.
Arachnids Brown recluse Description The brown recluse spider, also known as the ddleback or violin spider owing to the dark violin-shaped coloring on its cephalothorax, is 1 of 13 brown spiders in the family Loxoscelidae found in the United States. They are light tan to gray in color and are on average 9 mm long with a leg span of approximately 25 mm. They are unique from most other spiders because they possess three sets of eyes compared with most other spiders, which possess four (Fig. 5).
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The brown recluse is distributed throughout the southeastern and midwestern United States, but is most concentrated in Kansas, Arkansas, Oklahoma, and Missouri [112]. They inhabit outdoor and indoor areas, but are commonly found within human habitats, such as basements, storage sheds, under piles of wood and rock, and infrequently used drawers. Although these spiders are not aggressive, brown recluse bites can occur because of the close proximity of their habitat with humans. Common scenarios include reaching into an infrequently used drawer, picking up wood from a stored pile, or putting on old clothing where the spider is located. In most instances, the bite is painless and goes unnoticed for hours, making diagnosis dicult. Venom The venom of brown recluse spiders is composed of at least nine dierent enzymes; the most signicant is thought to be sphingomyelinase D2 [113,114]. In conjunction with host factors and its accompanying enzymes, sphingomyelinase D2 causes local endothelial damage, neutrophil and platelet aggregation, and factor activation leading to small vessel occlusion and eventual tissue necrosis. Sphingomyelinase D2 also causes calcium-
Fig. 6. Black widow spider. (Courtesy of Christopher P. Holstege, MD, University of Virginia.)
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dependent erythrocyte lysis and is responsible for the hemolytic anemia that can be seen after brown recluse bites [115]. Clinical presentation The presentation of a brown recluse bite ranges from a mild local skin reaction to severe systemic illness. The varying severity of peoples reactions is thought to depend on the amount of venom injected, location of the bite, and inclusion of gastric contents with the venom [116118]. Initially the bite is painless, but within 6 hours patients may develop pain, erythema, and pruritus at the site of the bite. A small blister with a blue discoloration may develop surrounded by a ring of erythema. Over the next 2 to 3 days, the blister may enlarge and can be become necrotic. An escar can develop that with time sloughs o, leaving an ulcer. The ulcer varies in size from 1 cm to 30 cm and can become large enough to require skin grafting. A small percentage of patients develop systemic symptoms, referred to as loxoscelism. Systemic symptoms typically begin 2 to 3 days after the bite. Symptoms are ulike and may include fever, chills, nausea, vomiting, arthralgias, convulsions, and rash [119,120]. Rarely, patients develop severe systemic illness, such as hemolytic anemia, DIC, thrombocytopenia, and kidney failure [113]. A study by Wright and colleagues [121], evaluating the clinical presentations of suspected brown recluse bites to their institution, found that only 14% of patients presented with systemic symptoms, and only 5% of patients were sick enough to warrant hospitalization. The diagnosis of brown recluse spider bite is overused for necrotic skin wounds of uncertain etiology [122126]. Misdiagnoses are common [127]. Clinicians should be careful not to fall into the trap of diagnosing all necrotic skin lesions as brown recluse spider bites. Treatment Most brown recluse spider bites cause minor local reactions and heal without medical treatment in several weeks [128]. Patients who present with minor lesions should have their wound cleansed thoroughly, given tetanus vaccine if necessary, instructed to elevate the aected extremity, and be given analgesics. For bites with larger skin necrosis or systemic symptoms, a variety of treatment modalities have been advocated with varying success; however, all remain controversial. Treatments that have been advocated include early surgical excision, steroids, dapsone, hyperbaric oxygen, topical nitroglycerin, and brown recluse antivenom. Early surgical excision was theorized to help decrease wound propagation and the need for skin grafting through early curettage of the necrotic area around the bite. Studies have now shown that early surgical excision has been associated with increased scarring and skin graft rejection and is no longer recommended [113,129131]. Delayed skin grafting, if needed, is best done after wound stabilization, which usually occurs in 6 to 10 weeks [132,133].
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Intralesional and systemic steroids do not seem to aect lesion size and are not recommended for wound protection [134,135]. Steroid use has been proposed, however, to be kidney protective in patients who are undergoing hemolysis and subsequently experience hemoglobinuria [136]. Dapsone, a drug that suppresses neutrophil diapedesis, is thought to work by preventing neutrophil inltration into the wound and its subsequent inammatory response. Studies of dapsone suggest little, if any, benet [137,138]. Side eects of dapsone use include hemolysis, agranulocytosis, aplastic anemia, methemoglobinemia, sore throat, pallor, jaundice, and hyperbilirubinemia. Hyperbaric oxygen also has been used with mixed results. The exact mechanism of preventing wound propagation is unknown, but theories include inactivating free radicals; sequestering neutrophils in the lung, limiting their response to the wound; and production of broblasts [139,140]. Clinical trials have produced mixed results, and it is unknown whether hyperbaric oxygen is helpful [141,142]. The use of topical nitroglycerin and brown recluse antivenom has been shown to decrease wound size in certain studies, but comparison studies have found no change in wound size compared with controls [143145]. These treatment modalities must be applied with care until more research has been done. Latrodectus Description Latrodectus species (black widow) are present throughout much of North America except for the northern reaches. The female spider is responsible for the characteristic toxicity and is shiny black in color with a red hourglass of varying size on its ventral abdomen (Fig. 6). Its webs are disorganized, appear abandoned, and are often found near human habitation. Venom The venom of the black widow contains a-latrotoxin. This toxin binds to multiple sites, resulting in the unregulated opening of cation channels and the subsequent inux of calcium [146,147]. Elevated cytosolic calcium causes unregulated release of neurotransmitters [148]. As a result, neurotransmitters, such as acetylcholine and norepinephrine, are increased. This increase in neurotransmitters results in activation of the sympathomimetic and cholinergic systems and causes increased stimulation at the neuromuscular junction. Clinical presentation Initially a pinprick sensation may be felt at the bite site. The initial pain may go unnoticed, however. Locally a small circle of erythema or induration may be seen at the bite site. Within the ensuing hours, systemic signs and
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symptoms may develop, progress, and last for days [149]. Muscle cramping is a characteristic nding associated with black widow envenomation [150]. The cramps my be mild and remain localized to the site, or the cramps can involve all muscle groups diusely and become severe and unrelenting [151]. The worst cases may develop opisthotonus posturing and abdominal rigidity. Nausea, vomiting, headache, palpitations, hypertension, tachycardia, diphoresis, priapism, facial edema, renal failure, and anxiety all may be seen clinically [152154]. The diagnosis of black widow envenomation is made solely on the clinical presentation; no clinical laboratory tests are available to conrm the diagnosis [155]. Treatment Wounds should be cleansed, and if needed tetanus prophylaxis should be administered. Patients should be monitored for at least 6 hours. In patients manifesting muscular spasms, opioid analgesics orally or intravenously should be considered. Antispasmodics, such as diazepam, also may provide additional relief. Methocarbamol and dantrolene have been used for treatment, with mixed results [156158]. Intravenous calcium initially was touted to be ecacious to alleviate the pain associated with cramps, but subsequent studies have not found it to be of signicant benet [149,156]. Latrodectus mactans antivenom (equine-derived) is rapidly eective at relieving the clinical eects associated with toxicity [159161]. Its use is limited, however, to patients manifesting signicant toxicity not relieved by conventional therapy or patients with health problems that place them at increased risk for complications. The antivenom has an associated risk of anaphylaxis and, if used, should be administered in a hospital with full resuscitation capabilities [151]. Summary Numerous types of envenomations may be encountered by health care workers depending on where in North America they work. Clinicians should be familiar with the animals in their region that may lead to envenomation. A rational approach with use of poison center or medical toxicology consultation services ensures that cases are managed appropriately. References
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[31] Auerbach PS. Envenomation by aquatic invertebrates. In: Auerbach PS, editor. Wilderness medicine. 4th edition. St. Louis: Mosby; 2001. p. 1488. [32] Fenner PJ, Williamson JA, Skinner RA. Fatal and non-fatal stingray envenomation. Med J Aust 1989;151:621. [33] Meyer PK. Stingray injuries. Wilderness Environ Med 1997;8:24. [34] Isbister GK. Venomous sh stings in tropical northern Australia. Am J Emerg Med 2001; 19:561. [35] Gallagher SA. Lionsh and stonesh. Emergency Medicine. Available at: http://www. emedicine.com/emerg/topic300.htm. Accessed 2004. [36] Aldred B, Erickson T, Lipscomb J. Lionsh envenomations in an urban wilderness. Wilderness Environ Med 1996;7:291. [37] Hare JA, Whiteld PE. An integrated assessment of the introduction of lionsh (Pterois volitans/miles) to the western Atlantic Ocean. In: NOAA Technical Memorandum NOS NCCOS 2. Silver Spring (MD): NOAA/NOS/NCCOS; 2003. p. 21. [38] Gwee MC, Gopalakrishnakone P, Yuen R, et al. A review of stonesh venoms and toxins. Pharmacol Ther 1994;64:509. [39] Lyon RM. Stonesh poisoning. Wilderness Environ Med 2004;15:284. [40] Kizer KW, McKinney HE, Auerbach PS. Scorpaenidae envenomation: a ve-year poison center experience. JAMA 1985;253:807. [41] Taylor DM, Ashby K, Winkel KD. An analysis of marine animal injuries presenting to emergency departments in Victoria, Australia. Wilderness Environ Med 2002;13:106. [42] Sutherland SK. Antivenom use in Australia: premedication, adverse reactions and the use of venom detection kits. Med J Aust 1992;157:734. [43] Ashford RU, Sargeant PD, Lum GD. Septic arthritis of the knee caused by Edwardsiella tarda after a catsh puncture wound. Med J Aust 1998;168:443. [44] Ajmal N, Nanney LB, Wolfort SF. Catsh spine envenomation: a case of delayed presentation. Wilderness Environ Med 2003;14:101. [45] Baack BR, Kucan JO, Zook EG, et al. Hand infections secondary to catsh spines: case reports and literature review. J Trauma 1991;31:1432. [46] Blomkalns AL, Otten EJ. Catsh spine envenomation: a case report and literature review. Wilderness Environ Med 1999;10:242. [47] Murphey DK, Septimus EJ, Waagner DC. Catsh-related injury and infection: report of two cases and review of the literature. Clin Infect Dis 1992;14:689. [48] Watson WA, Litovitz TL, Klein-Schwartz W, et al. 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2004;22:335. [49] Russell FE, Carlson RW, Wainschel J, et al. Snake venom poisoning in the United States: experiences with 550 cases. JAMA 1975;233:341. [50] Bjarnason JB, Fox JW. Hemorrhagic metalloproteinases from snake venoms. Pharmacol Ther 1994;62:325. [51] Homma M, Tu AT. Morphology of local tissue damage in experimental snake envenomation. Br J Exp Pathol 1971;52:538. [52] Obrig TG, Louise CB, Moran TP, et al. Direct cytotoxic eects of hemorrhagic toxins from Crotalus ruber ruber and Crotalus atrox on human vascular endothelial cells, in vitro. Microvasc Res 1993;46:412. [53] Laing GD, Clissa PB, Theakston RD, et al. Inammatory pathogenesis of snake venom metalloproteinase-induced skin necrosis. Eur J Immunol 2003;33:3458. [54] Moura-da-Silva AM, Laing GD, Paine MJ, et al. Processing of pro-tumor necrosis factoralpha by venom metalloproteinases: a hypothesis explaining local tissue damage following snake bite. Eur J Immunol 1996;26:2000. [55] Ownby CL, Colberg TR, White SP. Isolation, characterization and crystallization of a phospholipase A2 myotoxin from the venom of the prairie rattlesnake (Crotalus viridis viridis). Toxicon 1997;35:111.
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