North American pit vipers

Journal of Wilderness Medicine 3, 397-421 (1992) REVIEW North American pit vipers T. M. DAVIDSON, MOl', S.F. SCHAFER2 and J. JONES] I Division ofotolaryngology-head and Neck Surgery, University ofcalifornia, School ofmedicine and VA Medical Center, San Diego CA USA 2DepartmentofHerpetology, San Diego Zoo, San Diego CA USA 3 University ofcalifornia, SchoolofMedicine, San Diego CA USA Introduction Rattlesnakes, cottonmouths and water moccasins are pit vipers. They are responsible for the majority of venomous snakebites in North America. Antivenin is the mainstay of medical treatment. This paper reviews the biology of the North American pit vipers, clinical considerations for the evaluation of persons bitten by North American pit vipers, and recommendations for first aid and medical management of bites from these snakes. Key words: North America; pit vipers, Crotalus spp., Sistrurus spp., Agkistrodon spp. Biology According to Russell, there are approximately 2500-3000 species of snake [1]. Approximately 375 of these are considered to be venomous. All snakes belong to the Class Reptilia, Order Squamata, Suborder Serpentes. Within the Suborder Serpentes there are four medically important families: the Viperidae, Elapidae, Colubridae and Hydrophiidae (Fig. 1). Within the family Viperidae, subfamily Crotalinae there are 15 genera. The most notable of these are Crotalus, the rattlesnake; Sistrurus, the massasauga and pigmy rattlesnakes; Agkistrodon, the copperhead and cottonmouth; Lachesis, the bushmaster; Bothrops, the lancehead; and Trimeresurus, the Asiatic pit viper. In North America, rattlesnakes (genera Crotalus and Sistrurus) and cottonmouths and copperheads (genus Agkistrodon) are by far the most common and medically important snakes. The only other venomous snakes native to North America are coral snakes, elapids belonging to the genera Micrurus and Micruroides. Russell lists 49 crotalid species, the large majority of which are found in North America [1]. Scientific and common names for Crotalus, Agkistrodon and Sistrurus are listed in Table 1. Lawrence Klauber lists no less than 70 species [2]. The rattlesnake is a pit viper. Its most distinguishing characteristic is the rattle at the end of the tail (Figs 2,3). A rattle is composed of loosely articulated, interlocking, *To whom correspondence should be addressed at: UCSD Medical Center, 225 Dickenson Street, San Diego CA 92103-8895, USA. 0953-9859 1992 Chapman & Hall

398 Davidson, Schafer and Jones Kingdom Animalia (Animals) I Phylum Chordata (Animals with a notochord) I Subphylum vertebrata (Vertebrates) I Class Reptilia (Reptiles) I Subclass oiapsida (Reptiles with two pairs of temporal openings in the skull).-- ----.----_1'---------.------_--. I I I I Order Squamata Order Chelonia Order Crocodilia Order Sphenodontia (snak:es, Lizards) (Turtles) l(mi~~~~~:: (Tuataras) ~ _and Gavial) Suborder Serpentes (SnakeS) Suborder Sauria (Lizards) r-------------,c--------l..------,---------- etc. : Family Viperidae Family klapidae Family Hy~rOPhiidae Family Boidae (Vipers) (Cobras, Coral Snakes) (Sea Snakes) (Boas, Pythons) ; '1 t Subfam1 y Cro a l' 1nae Subfam11y, I, V1per1nae, (;Pit Vipers).1 (T=e Vipera) Fig. 1. Family tree for North American pit vipers., l Agk1strodon (Copperheads, Cantils,) water Moccasin keratinous rings which, when vibrated as a defensive warning, create a unique sound, Rattlesnakes are ectothermic, which means 'cold-blooded'. Most, but not all, species mate in spring. Eggs are retained in the mother's body and young are born alive in the summer and early autumn. Rattlesnakes feed predominately on warm-blooded animals. Their main food source is small mammals, such as mice, rats, gophers and squirrels. Birds are occasionally eaten and larger rattlesnakes may feed upon mammals as large as a rabbit. Rattlesnakes will feed on small amphibians or other reptiles, a habit more common in smaller snakes. Rattlesnakes hibernate during the cold months. They emerge from hibernation in the spring and return to hibernation each autumn. They are primarily nocturnal, but can be found moving about during the day or night.

North American pit vipers 399 Fig. 2. North American rattlesnake distinguishing characteristics include the wide triangular head, wide thick body and rattle at the tail. Venom To a large degree, snakes lie and wait for their prey. They have no sense of hearing, but perceive vibration. They have a moderately good sense of vision and an acute sense of smell [2]. The warm-blooded prey is primarily sensed by two thermal sensors (called pits) located underneath the eyes (Fig. 4). The pits both localize the prey and help determine its size. When the prey comes within striking distance, the rattlesnake strikes. The venom stored in two large venom glands located on either side of the head is injected into the prey through two maxillary fangs. (Fig. 5). Once bitten, the prey is rapidly paralyzed while the venom, containing digestive and proteolytic enzymes, is circulated throughout the body to commence digestion. The prey dies of cardiovascular collapse within a minute or two, is swallowed whole, and digested externally by gastric and intestinal enzymes and internally by the venom's proteolytic enzymes [1]. The amount of venom injected by a rattlesnake is highly variable, depending on the situation, age and condition of the snake. Klauber suggested that rattlesnakes inject less than half their venom in a bite [2], and other authors agree they never empty their glands in a single bite [3]. It is logical, and Brown has demonstrated, that as a crotalid matures, its venom production increases steadily, up to 15-30 times that produced in the first year of life. A mature snake can inject more venom when it bites than can a juvenile [4]. When biting for food the rattlesnake varies the amount of venom it injects depending

400 Davidson, Schafer and Jones Table 1. Scientific and common names for North American pit vipers [1,2). Scientific name C. mitchellii ange/ensis C. viridis cerberus C. willardi willardi C. unic%r C./annomi C. /epidus k/auberi C. mollossus subspecies A. contortrix /aticinctus C. horridus atricaudatus S. miliarius miliarius C. exsu/ C. durissus durissus C. triseriatus triseriatus C. enyo cerra/vensis C. cerastes /aterorepens A. bilineatus bilineatus C. viridis caliginis C. transversus C. willardi amabi/is S. catenatus edwardsii C. adamanteus, C. atroix, C. rubber, etc. C. triseriatus subspecies and C. pussilus S. m. barbouri A. piscivorus piscivorus C. adamanteus S. catenatus catenatus C. pricei miquihuanus C. m. muertensis A. piscivorus conanti C. viridis abyssus C. viridis /utosus C. viridis nuntius C. scutu/atus sa/vini C. po/ystictus C. stejnegeri C. enyo C. catenatus subspecies C. m%ssus nigrescens C. po/ystictus S. ravus C. basi/iscus basi/iscus C. viridis conc%r C. scutu/atus scutu/atus C. cerastes cerastes C. /epidus /epidus C. durissus subspecies C. m%ssus m%ssus A. contortrix mokeson Common name Angel de la Guarda Island speckled Arizona black Arizona ridge-nosed Aruba Island Autlan Banded rock Black-tailed Broad-banded copperhead Canebrake Carolina pigmy Cedros Island diamond Central American Central-plateau dusky Cerralvo Island Colorado Desert sidewinder Common cantil Coronado Island Cross-banded mountain Del Nido ridge-nosed Desert massasauga Diamond or diamond back Dusky Dusky pigmy Eastern cottonmouth Eastern diamondback Eastern massasauga Eastern twin-spotted EI Muerto Island speckled Florida cottonmouth Grand Canyon Great Basin Hopi Huamantlan Lance-headed Long-tailed Lower California Massasauga Mexican black-tailed Mexican lance-headed Mexican pigmy Mexican west-coast Midget faded Mojave Mojave Desert sidewinder Mottled rock Neotropical Northern black-tailed Northern copperhead

North American pit vipers 401 C. viridis oreganus C. durissus culminatus C. basiliscus oaxacus C. intermedius gloydi C. intermedius omiltemanus A. contortrix phaeogaster C. v. oreganus or C. v. helleri C. mitchellii stephensi S. miliarius subspecies and S. ravus C. viridis viridis C. triseriatus aquilus C. catalinensis C. ruber ruber C. willardi subspecies C. lepidus subspecies C. enyo furvus C. molossus estebanensis C. ruber lucasensis C. mitchellii mitchellii C. catalinensis C. cerastes subspecies C. intermedius subspecies C. cerastes cercobombus C. durissus terrificus A. contortrix contortrix C. viridis helleri C. willardi meridionalis C. mitchellii pyrrhus C. mitchellii subspecies C. lepidus morulus C. pusillus A. bilineatus taylori C. tigris C. horridus horridus C. tortugensis C. intermedius intermedius C. durissus totanacus A. contortrix pictigaster C. pricei subspecies C. vegrandis C. willardi silus C. viridis subspecies A. piscivorus leucostoma C. atrox S. catenatus tergeminus S. miliarius streckeri C. pricei pricei C. durissus tzabcan Northern Pacific Northwestern Neotropical Oaxacan Oaxacan small-headed Omilteman small-headed Osage copperhead Pacific Panamint Pigmy Prairie Queretaran dusky Rattleless Red diamond Ridge-nosed Rock Rosario San Esteban Island San Lucan diamond San Lucan speckled Santa Catalina Island Sidewinder Small-headed Sonoran Desert sidewinner South American Southern copperhead Southern Pacific Southern ridge-nosed Southwestern speckled Speckled Tamaulipan rock Tancitaran dusky Taylor's cantil Tiger Timber Tortuga Island diamond Totalcan small-headed Totonacan Trans-Pecos copperhead Twin-spotted Uracoan West Chihuahua ridge-nosed Western Western cottonmouth Western diamondback Western massasauga Western pigmy Western twin-spotted Yucatan Neotropical

402 Davidson, Schafer and Jones Fig. 3. Close-up of rattlesnake rattle. upon the size of the prey. Gennaro observed that a crotalid will inject more venom biting into a rat than into a mouse; and Russell used I l3t -Iabelled venom and showed similar results [1,5]. It could be dangerous to extrapolate from a snake eating smaller food prey to a snake biting a human in self-defense. Certain species of rattlesnake are capable of injecting sufficient venom to kill a man [6], however, it is also well-established that 15 30% of the time a crotalid will inject no venom at all, the so-called 'dry bite' [7]. Venom potency varies. The venom of very young snakes may be quite toxic. As an example, the LD so of a canebrake rattlesnake (c. horridus) decreased from 8.9 mg kg- 1 on day 5 of life to 2.8 mg kg- 1 at 1 year of age [4]. Minton found that the toxicity of C. horridus venom peaked at age 6-9 months [8]. A similar pattern followed for copperheads (A. contortrix) [8]. Fiero reported that juvenile C. viridis venom was more toxic than the adult venom [9]. In aging rattlesnakes, Minton found a substantial decline in lethality [10]. Venom composition also changes as the snake matures. When the coagulation effects of juvenile western diamondback (c. atrox) venom were compared to those of an adult, the juvenile's venom clotted fibrinogen (the adult's venom would not), implying that the juvenile venom may possess a thrombin-like enzyme which the adult venom lacks [11]. These in vitro results correlate with the differences often observed in coagulation profiles for patients bitten by juvenile vs adult western diamondback rattlesnakes [1]. Whether or not the juvenile snake venoms are different or more toxic than adult venoms, this difference is far outweighed by the substantially larger venom glands and yields of adult snakes. Hence, the adult snake can deliver a more serious envenomation.

North American pit vipers 403 Fig. 4. Rattlesnake lying under rock with head pointed out. Note the nostrils, eyes and pit, which is located in front of and beneath the eye. No one really knows the relative severity of juvenile versus adult bites. Given the tremendous variabilities in species, size, age and snake behavior, it follows logically that there is tremendous variability in the severity of crotalid envenomation. Replenishment of venom following milking or injection has been studied; results vary from 16 to 54 days [2,12]. Russell reported that a 21 day period is the outside limit for venom glands to regain full venom yield and toxicity [1]. In the wild, a rattlesnake will rarely empty its venom glands in a single bite, so that it is fully capable of inflicting multiple venomous bites [13]. Therefore, one should never assume that because a rattlesnake has just bitten, it is any less dangerous, let alone safe to handle. Defense A rattlesnake's primary defense is avoidance. To a large degree, snakes hide under brush and rocks and rely on camouflage. When alarmed, they coil in a typical stance and attempt to frighten prey by rattle shaking. The rattle is peculiar to the 'new world' snakes. It makes a hissing or buzzing sound. Typically, it vibrates at 45-60 cycles per second [2]. The warmer the snake, the faster it vibrates its rattle. While there are incredible stories of rattlesnakes having up to 70 rattles, it is rare to find one with more than 20 rattles [2]. Since the rattle is easily broken (the most caudal segments typically fracture), the majority of rattlesnakes found in the wild have only 5-10 rattles. Rattlesnakes typically molt or shed three to four times a year. With each molt, an additional rattle is added to the tail. Removing fangs from a rattlesnake does not render it

404 Davidson, Schafer and Jones Fig. 5. North American rattlesnake fangs draped over a glass microscope slide. Note venom dripping down the slide. harmless, because replacement fangs are already present. Klauber believes that the fangs are replaced every 6 to 10 weeks; this replacement frequency in unrelated to molting [2]. Size The smallest adult rattlesnakes may be as short as 60 cm. The largest rattlesnakes, predominantly found in warmer climates, may attain a size of 2 m. An occasional western diamondback rattlesnake (c. atrox) exceeding 2 m in length is found [2]. According to Klauber, the longest believable rattlesnake report is that of an eastern diamondback rattlesnake (c. adamanteus) measured at 2.44 m (approximately 8 it). The heaviest rattlesnake reported by Klauber was a 2.26 m western diamondback that allegedly weighed 10.9 kg. Typically, adults weigh from 0.5 to 4.0 kg. The rattlesnake is not the largest venomous snake. The king cobra, for example, is reported to attain a length of at least 5.5 m (18 it). The rattlesnake, however, is a heavy snake for its length. Clinical considerations Approximately 45000 snake bites are reported in the United States annually. Eight thousand of these involve venomous snakes and approximately 12 deaths occur annually [7,14]. Russell reports that 20% of the bites are dry, meaning that no venom is injected [1]. Sprenger and Bailey estimate that only 10% are dry bites [15]. Most North

North American pit vipers 405 Fig. 6. Typical appearance of the hand shortly after envenomation by a rattlesnake. The bite occurred between the thumb and forefinger. In this photo, the fang marks are hard to see, but note the typical sausage-like appearance of the swollen hand and fingers. American pit viper venoms are similar and therefore the patient presentations are also similar. Variations occur by genus, species and even subspecies. The greatest variation is the volume of venom injected. The typical case involves an individual bitten on the dorsum of the hand or foot. Within minutes, one notes local pain and swelling (Fig. 6). Most victims present to a hospital within hours of the bite with moderate to intense pain and swelling progressing proximally up the extremity. Ecchymoses soon appear and circumoral paresthesia is often present. Patients mayor may not be weak and diaphoretic, a reaction which may be psychogenic and/or organic. In more advanced cases, with larger volumes of venom injected or longer duration from the time of bite, local and regional muscle fasiculations may be present. Laboratory evaluation characteristically reveals hemoconcentration and hypokalemia. In advanced cases, coagulation abnormalities may be found, presenting first with thrombocytopenia followed by decreased fibrinogen, increased fibrin split products, prolonged prothrombin and partial thromboplastin time, and finally full blown disseminated intravascular coagulopathy. Hematuria may develop. Medical management includes intravenous infusion of crystalloid solution and monitoring of cardiovascular status. Patients are usually skin-tested for sensitivity to horse serum. If they are ill and not sensitive to antivenin, they are often treated with an intravenous infusion of Wyeth Polyvalent Crotalidae Antivenin. The number of vials

406 Davidson, Schafer and Jones infused is titrated against local and systemic signs and symptoms. With most bites, treatment is completed within the first 2-4 h. The patient is observed in the hospital at least overnight. Patient status and laboratory data are monitored. Normally, the patient recovers rapidly and is discharged to home the following day. Depending upon the number of vials of antivenin infused, 30-50% of persons may experience delayed sensitivity to the antivenin. Case 1 A 12-year-old boy was playing in his backyard. He saw a snake under a rock, reached underneath to retrieve the reptile, heard a buzz, and was bitten on his hand between the thumb and first finger. Within minutes, his hand began to hurt and swell. He and his older brother fished the rattlesnake out from underneath the rock and killed it. The boy's mother brought him immediately to an emergency department. On arrival at the hospital, he was noted to have pain and swelling involving the entire dorsum of the bitten hand. Two fang marks were noted in the first web space of the bitten hand. Lactated Ringer's solution was infused intravenously at a rate of 100 ml h- 1 and blood was drawn for determination of CBC, electrolytes, calcium, phosphate, pro time, PTT, platelet count, fibrinogen, creatinine and BUN. The child was intradermally tested for sensitivity to horse serum. There was no reaction at 20 min. Swelling progressed above the wrist and the child reported tingling around his mouth. His respiratory rate increased, he became diaphoretic, and lingual fasciculations developed. Ten vials of antivenin were mixed in 100 ml of warm saline and administered IV piggyback at 10 ml (1 vial) every 5 min. After about 5 min, the child became restless and tachycardic, attributed to an antivenin reaction. Antivenin administration was slowed down to one vial every 10 min; pulse rate and agitation reverted to normal. Antivenin administration rate was then increased to one vial every 7 min. The child tolerated this infusion well. After three vials of antivenin were administered, the local pain ceased and swelling of the wrist stabilized. The first ten vials were infused over one hour and fifteen minutes and the patient appeared stable. Fifteen minutes after discontinuing the antivenin infusion, the child's tongue again began to fasciculate and he noted a return of the pain in his hand. Another five vials of antivenin were mixed in 50 ml of warm saline and infused over approximately 35 min. The symptoms immediately ceased, but once again recurred when the antivenin was stopped. Another five vials of antivenin were administered intravenously, bringing the total to 20 vials. There was no recurrence of local or systemic symptoms. Circumoral tingling persisted for 48 h, but the child was otherwise normal. Initial laboratory data were normal, except for hypokalemia. The laboratory data were normal midway through and following treatment. Serum potassium was normal the following day. Tetanus immunization was current. The patient was discharged from the hospital on the second day, at which time the majority of the swelling was gone and he felt perfectly normal. He returned to the doctor's office three days following the bite with a rash and hives over the trunk and abdomen. He was treated with diphenhydramine and made an uneventful recovery. Case 2 A 29-year-old male motorcycle rider drank at least "3-4 beers" and then reached inside his knapsack, which was hanging on a San Diego canyon scrub brush. He was bitten by a

North American pit vipers 407 Table 2. Laboratory data for 29-year-old male bitten by a Southern California rattlesnake. Admission Hospday 1 Hosp day 2 Na 135 meq I-I (135-145) 140 K 3.8 meq I-I (3.5-5.0) 4.3 HCOz 21 mmi- I (22-30) 30 Cl 103 meq 1-1 (94-107) 103 Calcium 8.9 mg I-I (8.5-10.5) Creatinine 0.9 mg dl- I (0.4-1.5) Bili T 0.9 mg dl- I (0.1-1.5) CPK 128 HU 1-1 (0-100) HCT 47% (40-50) 42 Platelets 265 X 10 3 mm- 3 (150-450) 190 Prothrombin time 14.2 s (11.0-13) 14.7 13.5 Plasminogen 88% (75-124) Urine Ethanol 174 mg dl- I (0) Protein Trace (0) Negative Blood Trace Trace Gravity 1.005 1.005 rattlesnake which had crawled inside the knapsack. He withdrew his hand instinctively to witness a 2 ft rattlesnake hanging onto his left index finger by a single impaled fang. The snake was shaken loose and the mildly inebriated patient was carried to the emergency department 15-20 min after the bite. The patient developed hoarseness and a cough. His eyelids became edematous and upon arrival at the hospital, the patient was diaphoretic, dyspneic and dysphasic. On primary physical examination, his blood pressure was 200/98 mmhg, pulse 121 beats per minute, and respiratory rate 20 per minute, with mild inspiratory stridor. The skin of the left index finger and hand was swollen. A single scratch on the medial side of the finger was present. The patient complained of finger pain. The lungs were clear to auscultation; wheezes and rhonchi were not present. The patient reported perioral paresthesias. Perioral, lingual, and left extremity muscle fasiculations were noted. The patient noted mild diplopia. The reminder of the physical examination, including neurologic exam, was normal. Blood and urine were obtained for laboratory evaluation. Results are shown in Table 2. The patient was given 0.3 ml of epinephrine 1:1000 1M, 50 mg of diphenhydramine IV and 1 g of methylprednisolone IV. The patient's condition improved promptly, with a decrease in blood pressure, dyspnea, and diaphoresis. Antivenin 0.1 ml was injected intradermally. No reaction was noted. Five vials of Wyeth Polyvalent Crotalidae Antivenin was reconstituted in 50 ml of warm lactated Ringer's solution and administered by IV drip at a rate of one vial per 10 min. The patient continued to improve with administration of two additional five vial aliquots of antivenin, bringing the total to 15 vials. Local pain, edema, ecchymosis and generalized muscle fasiculations were used as evidence of venom presence. These signs and symptoms were ultimately neutralized with 30 vials of antivenin.

408 Davidson, Schafer and Jones The patient was observed overnight in an intensive care unit. The following day, the laboratory data and physical examination were normal or progressing towards normal. He was placed on a regular diet and discharged the following day. Recovery was uneventful. This case is unusual, because the venom was deposited in a highly vascular area and because one of the snake's fangs was hooked in the skin. We assume that a substantial volume of venom was injected. The early signs and symptoms interpreted to be an allergic 'anaphylactic type' reaction were in fact systemic reactions to the venom. Local symptoms of pain, edema and ecchymosis were dwarfed by the dramatic systemic symptoms. A bolus of methylprednisolone was administered in case the antivenin needed to be infused at a rate more rapid than one vial per 1-5 min [16]. With the airway symptoms stabilized by epinephrine, antivenin neutralized the circulating venom and systemic symptoms were controlled. Venom deposited in the dermis and subcutaneous tissues was absorbed more slowly. Presumably, symptoms from this venom activity were neutralized with the additional antivenin infusion. Antivenin administration Russel reported using 5-8 vials of antivenin for mild envenomation, 8-12 vials for moderate envenomation and up to 40 vials for severe envenomation, with the average being 10 vials [1]. Given his experience, it was his belief that antivenin administration could be life saving and with prompt administration, tissue necrosis could be avoided. In another study by Wingert dealing with bites in Southern California, the median antivenin dose was 10 vials, with a range of 1-43 [17]. With prompt intravenous neutralization of venom, a quick recovery with no significant sequelae is normal. Most patients return to home and work within 1-2 days. An adult rattlesnake carries more than enough venom to kill the average human adult. Fortunately, the amount of venom injected is variable and except under unusual circumstances, is not of sufficient quantity to kill a human. However, morbidity due to local tissue destruction from moderate and severe bites is often so great that treatment with antivenin is considered mandatory by this senior author. Pharmacology Crotalid venom is a complex mixture of proteins, glycoproteins and other substances with a variety of enzymatic and pharamacologic activities. These venom components vary from species to species and probably work synergistically. It is dangerous to extrapolate from in vitro results directly to in vivo effects. Crotalid venoms possess an abundance of potent proteolytic enzymes. Tissue destruction and necrosis associated with crotalid envenomation are common [7,18,19]. Metal ions present in the venom help catalyze the proteolytic reactions [20]. Other enzymes present include arginine ester hydrolase. Its function may be associated with the release of bradykinin and/or the venom's clotting activity [21,22]. Collagenases and hyaluronidase help venom spread beyond its point of injection [2,23]. Phospholipase A z, which exists in varying forms in many snake venoms, may have presynaptic neurotoxic activity and contributes to cellular disruption, hemolysis, and cellular metabolism [24,25]. Phosphodiesterase is also present in crotalid snake venom, attacking RNA and DNA, as well as possibly contributing to the venom's cardiovascular effects [26]. RNase,

North American pit vipers 409 DNase and 5'-nucleotidase are also present. L-amino acid oxidase provides venom with its yellow color, but contributes little to its lethality [27-30]. Another important group of substances found in many crotalid snake venoms includes low molecular weight, non-enzymatic toxic proteins and polypeptides. These substances have been named crotoxin, crotamine and crotactin. They have been found to cause paralysis, hemolysis, respiratory distress and death [31]. Studies on one polypeptide in C. viridis helleri venom indicate that it may correspond to the 'hemorrhagin' that causes changes in capillary endothelium, increasing vascular permeability and contributing to the fluid extravasation, hypotension and shock that frequently accompany crotalid envenomation [32,33]. Many snake venoms, including crotalid venom, affect blood coagulation. These fractions can possess procoagulant activity, anticoagulant activity, or both. Procoagulants, such as factor X activators, have been found in a wide variety of snake venoms, including that of the rattlesnake C. viridis helleri [34]. There are also thrombin-like enzymes present in crotalid venoms which cleave fibrinogen to either fibrinopeptide A or B [34,35]. In vitro, these enzymes clot plasma, but in vivo they produce hypofibrinogenemia and incoagulable blood, a characteristic of envenomation by rattlesnakes as well as of many other Viperidae [36,37]. The mechanism is probably similar to that of the Malayan pit viper, where fibrin produced by these thrombin-like enzymes forms weak, non-crosslinked clots that are easily dissolved by plasmin, resulting in low serum fibrinogen levels and elevated levels of fibrin degradation products (FOP) [38]. Thus, with the thrombin-like Enzymes, a procoagulant activity has an anticoagulant effect in vivo. Fibrinolytic activity has also been found in at least one rattlesnake species, further contributing to the anticoagulant effects of the venom [39,40]. Further anticoagulant activity may consist of the activity of phospholipase or phosopholipids and the action of proteolytic enzymes on various clotting factors [14]. Crotalid envenomation produces a hypotensive effect in man [41,42]. Studies indicate that increased capillary permeability leading to extravasation of fluid, protein and cells is at least partially responsible for this hypotension [41,43]. This fluid extravasation is most apparent in the bitten limb, where edema can be quite extensive. Hemorrhage, thrombosis and pulmonary congestion occur in the lungs of envenomed victims, seen both experimentally and at post-mortem [1,44,45]. At autopsy, extracellular fluid is found in the lungs and in the bitten extremity. This fluid shift occurs early in the bite. Clinically, one may see hypovolemic shock. Hemoconcentration is common. The venom lyses red blood cells and later, particularly once intravenous fluids have been administered, hemodilution is found in the untreated or undertreated bite victim. Hemolysis is evident both on blood smear and by the presence of hematuria. Crotalid venom can also directly affect the heart and kidneys, although these organs are usually affected by hypotension and hemolysis. Neurotoxic effects are not typically a major component of crotalid envenomation in humans. One exception is the Mojave rattlesnake (c. scutu!atus), whose venom has a presynaptic blocking activity resulting in significant neurological symptoms [46]. Envenomation It is important for the treating clinician to recognize the signs and symptoms of snake bite envenomation, for the mainstay of treatment is titration of antivenin against the clinical presence of existing venom (Table 3). The following is our concept of how this complex

410 Davidson, Schafer and Jones Table 3. Signs and symptoms of North American pit viper envenomation [1]. Sign or symptom Fang marks Swelling and edema Weakness Pain Sweating and/or chill Numbness or tingling of tongue and mouth, or scalp or feet Changes in pulse rate Faintness or dizziness Ecchymosis Nausea, vomiting, or both Blood pressure changes Decreased blood platelets Tingling or numbness of affected part Fasciculations Vesiculations Swelling regional lymph nodes Respiratory rate changes Increased blood clotting time Decreased hemoglobin Thirst Change in body temperature Necrosis Abnormal electrocardiogram Increased salivation Glycosuria Sphering of red blood cells Cyanosis Proteinuria Hematemesis, hematuria, or melena Unconsciousness Blurring of vision Muscle contractions Increased blood platelets Retinal hemorrhage Swollen eyelids Convulsions Frequency 100/100 74/100 72/100 65/100 64/100 63/100 60/100 57/100 51/100 48/100 46/100 42/100 42/100 41/100 40/100 40/100 40/100 39/100 37/100 34/100 31/100 27/100 26/100 20/100 20/100 18/100 16/100 16/100 15/100 12/100 12/100 6/100 4/25 2/100 2/100 1/100 picture fits together. Typically, the snake strikes an extremity, most commonly at its distal end [14]. The fangs penetrate the skin and the venom is injected into the skin and and subcutaneous tissue. The venom is absorbed slowly at a variable rate. The proteolytic enzymes exert their influence immediately, initially producing pain and swelling (Fig. 6). Blood in the local tissues is anticoagulated, and the peripheral edema fluid acquires a purple hue. Serosanguinous fluid will frequently ooze for several hours from the fang marks. As the proteolytic process continues, blebs appear on the extremity. They may be filled with clear or serosanguinous fluid. As venom is absorbed into the lymphatic system, edema and tissue destruction spread proximally. Venom is absorbed into the blood

North American pit vipers 411 stream and distributed throughout the body. Membrane pemeability is altered and fluid accumulates in the lungs and in the bitten extremity. The patient can develop hypovolemic shock. Muscle fasciculations typically occur around this time, as do circumoral parathesias. The muscle fasciculations are evident both on the bitten extremity and in large and small muscle groups. One frequently first notices muscle fasciculations on the tongue and face, then on the bitten extremity and then throughout all skeletal muscles. Twelve to 24 h after the bite, the blood may become profoundly anticoagulated and bleeding will occur into the urinary and alimentary tracts. Blood extravasates into the bitten extremity. Petechiae develop throughout the congested lungs. Red cells hemolyze and renal function can become impaired. The patient can die at this point from hypotension or from the complications of coagulopathy. If death does not ensue, the coagulation defect ultimately reverses. The patient is left with a progressively necrotic arm. If gangrene and infection do not ensue, the extremity heals over several months, but the patient may be left with impaired function and a scarred, deformed limb. Antivenin production The mainstay of treatment for crotalid envenomation is infusion of antivenin to neutralize injected venom. That the injection of increasing doses of a snake's venom could produce a protective effect in an animal was demonstrated by Henry Sewall, who conducted experiments in the 1880s. Russell has written an excellent review of the history of the development of antivenin [47]. Antivenin produced in the United States by Wyeth and used for bites of North American crotalids is a purified concentrate of horse serum globulin, extracted after progressively increasing doses of four crotalid venoms have been injected into a horse and antibody formation induced. The venoms used to make Wyeth's Antivenin Crotalidae Polyvalent include those from C. atrox, C. adamanteus, C. durissus terrificus and B. atrox [48]. The antivenin neutralizes a wide range of venoms, including those from all North American pit vipers (rattlesnakes, cottonmouths, water moccasins and massasaugas), albeit to varying degrees [47-49]. While a pure monovalent antivenin is ideal [47,50], polyvalent antivenin has the advantage that one does not need to know the specific species of snake before initiating treatment. Future immunotherapy for rattlesnake envenomation will probably employ a chromatographically purified IgG subclass called IgG(T) [51]. Although there still remains some controversy with regards to the use of antivenin, it is the authors' belief that antivenin is the best treatment for the serious sequelae of pit viper envenomation. Antivenin treats most of the symptoms, including coagulopathy, thrombocytopenia, cardiovascular collapse, pulmonary congestion and tissue necrosis [1,7,52 54]. In a study of fatal rattlesnake bites in Arizona, Hardy found that five out of six deaths resulted from shock inadequately treated with fluids and antivenin [6]. Antivenin treatment efficacy depends greatly on its timely administration. The greater the time between envenomation and antivenin administration, the less effective becomes antivenin treatment [55,56]. While mild envenomation may carry low morbidity and mortality, more serious envenomations require treatment. Studies from the late 1920s report mortality rates of 34% and 11% in humans who did not receive antivenin and mortality rates of 5% and 3% in those who did receive antivenin [57]. Antivenin contains equine antigens. One argument against antivenin treatment is the

412 Davidson, Schafer and Jones potential to induce an allergic or anaphylactic reaction. Fortunately, the general use of horse serum, and consequently sensitization of the general patient population to horse serum antigens, have become rare as vaccines and human immune gamma globulin have replaced the use of horse antiserum [58]. To assess the threat of an allergic or anaphylactic reaction to antivenin, skin testing is recommended. Since skin testing is not innocuous and can incite an allergic reaction, it should be performed only in persons for whom antivenin treatment is required [59]. A positive skin test or allergic reaction is not necessarily a contraindication to antivenin administration, but instructs the clinician to be prepared to administer corticosteroids, epinephrine and/or antihistamines [60,61]. In severe envenomation or intravenous envenomation cases, rapid and immediate infusion of antivenin is necessary and skin testing is not performed [16]. In one study, 23% of patients receiving the Wyeth antivenin developed some degree of immediate allergic reaction, but all were successfully treated with epinephrine and antihistamines; in several, antivenin administration continued [58]. Serum sickness or delayed reaction to the antivenin occurred in 50% of the patients in this study. Skin testing had a 10% false negative rate in this study, and was of no value for predicting serum sickness. Clearly, continuous close observation of the patient is essential during antivenin administration. Antivenin-related research continues on a number of fronts [62]. Enzyme-linked immunosorbent assay (ELISA) has been used in Australia to make species-specific diagnoses in cases of snake envenomation, but it has generally been found to be a lengthy process, so work continues to make the test more efficient and less expensive. Human immunization against snake venom in geographical areas with particularly high prevalence of snake bite has not provided sufficiently long-term protection to make it efficacious. Recent efforts with immunization have yielded a prolonged antibody response and work continues to refine the process further. The use of monoclonal antibodies has also been considered, but with current techniques is considered too difficult to develop for most viperid venoms due to the numerous different toxic fractions. Monoclonal antibodies may prove useful in counteracting neurotoxic elapid venoms. A chromatographically purified IgG subclass, IgG(T), will probably be the next available crotalid antivenin [51]. First aid The most important aspect of first aid is getting the snake bite victim to the hospital as quickly as possible. Measures that can be considered as long as they do not delay transport include quieting and reassuring the victim, immobilizing the limb, removing constricting jewelry, and applying a venous constriction bandage to retard venom absorption, although the last is controversial and can lead to ischemia if applied too tightly [17,63]. Recent experimental work on pigs confirms that a properly applied constricting band retards venom absorption without adversely affecting venom elimination or edema [64]. Some feel that wrapping a crepe bandage is preferable to using a constriction bandage, as it retards venom absorption while limiting the danger of limb ischemia [50]. This wrap/immobilization technique has been thoroughly tested only in elapid bites. Suction at the bite site is not likely to be effective, although a new suction device called the Sawyer Pump Extractor had revitalized this idea [65]. Incision and suction, as well as application of ice, are likely to do more harm than good [17,66].

North American pit vipers 413 Once in the hospital, the patient should be assessed for signs and symptoms of envenomation. When appropriate, antivenin is administered [17,67]. Corticosteroids and electric shock therapy have no place in the routine treatment of snake envenomation [66,68]. An excellent review and condemnation of electrical treatment of venomous bites and stings has been written by Bucknall [69]. There are advocates of excision of the bite site as treatment for snake envenomation, but we do not advocate routine excision or fasciotomy due to their potential for disfigurement, especially given research that shows antivenin to be more effective while inducing less morbidity than surgery [67,70]. Medical management First aid and medical management are based on experience and clinical judgement. For clinicians with limited, or even no, experience with snakebite, the 'cookbook' approach has been useful. More experienced clinicians should view the following as general principles or guidelines. Different experts differ in their approaches and philosophies, which has been particularly evident in the evaluation and management of North American pit viper envenomation. The following is the approach we use at the San Diego Regional Poison Control Center. First aid In the event of an actual or probable bite from a North American pit viper, execute the following first aid measures: 1. Make sure that the bitten patient and other personnel are away from the responsible snake and that no one is at risk to receive an additional bite. 2. Immediately arrange to transport the victim to an appropriate medical facility. 3. Keep the victim calm, supine or prone, with as little movement as possible. rest the bitten extremity at a level lower than the victim's heart. 4. Remove rings, bracelets and other constricting items. 5. Apply a constricting band around the extremity proximal to the bitten site. The constricting band will obstruct lympathic flow and retard superficial venous flow. It should not obstruct arterial or deep venous flow. The ideal constricting band is a one inch penrose drain as used commonly for venipuncture (Fig. 7). 6. Do not remove the constricting band until the victim has reached the hospital and is receiving antivenin. 7. If you bring the patient to a medical facility in the United States, antivenin should be available. If you are outside the United States or antivenin is not available, you should arrange to make it available. The antivenin used is Wyeth Crotalidae Polyvalent Antivenin, which is available in most major hospitals throughout the southern United States and in areas in which snake bite is endemic. If antivenin is not available, contact a regional poison control center in the United States or Wyeth Ayerst Laboratories (Box 8299, Philadelphia, PA 19101, telephone (215) 971 5400). 8. Do not incise the bite site. Do not apply ice to the bite site.

414 Davidson, Schafer and Jones Fig. 7. Penrose drain used as a constricting band to retard distal lymphatic and superficial venous flow. Hospital management A summary of the evaluation and treatment of North American pit viper envenomation is depicted in Fig. 8. 1. A constricting band has been applied to retard the absorption of venom. Do not remove this until the patient has arrived at the hospital and is receiving antivenin. 2. Make sure that twenty vials of Wyeth Crotalidae Polyvalent Antivenin are available. If you need assistance locating appropriate antivenin, call the Regional Poison Control Center, the San Diego Regional Poison Control Center ((619) 543-6000), or Wyeth-Ayerst Laboratories. 3. Envenomation is diagnosed by the presence of characteristic signs and symptoms (Table 3). Pain and swelling are usually the earliest indicators of envenomation. Progression of swelling and systemic symptoms are variable in onset and appearance. Fang marks may appear as one or more well-defined punctures, as a series of small lacerations or scratches, or be absent. Absence of fang marks does not negate the presence of a bite, especially ifa juvenile snake is involved. Conversely, the presence of fang marks does not always confirm envenomation, for 10-20% of snake bites are 'dry,' meaning that no venom is injected. Envenomation grading is summarizerd in Table 4. 4. Admit the patient to the emergency department or other intensive care setting. Begin

North American pit vipers 415 a peripheral IV infusion of lactated Ringer's solution at a rate sufficient to maintain a brisk urine output. It is not uncommon in a 70 kg adult to require an initial infusion of 1000-2000 ml of fluid to initiate a brisk urine output. The reason for this is that the venom causes transudation of fluid into tissues, so that even a well-hydrated individual may have low intravascular volume and low urine output. Children and individuals with compromised cardiovascular or renal function may not tolerate a fluid challenge without invasive monitoring, to allow judicious administration of osmotic or loop diuretics. 5. Draw blood from the contralateral arm to obtain the laboratory tests listed in Table 5. If the patient is envenomated, it will be necessary to repeat these tests during the hospital course to monitor the effects of antivenin therapy. 6. Observe the patient for signs and symptoms of envenomation. If no sign or symptom is noticed, remove the constricting band and observe carefully. If any change occurs, assume the patient has been envenomated. If signs and symptoms still fail to appear, continue observation for an additional 24 h. The first two hours should be in a medical facility and then observation may occur at home, if appropriate. One notable exception is the bite of the Mojave rattlesnake (c. scutulatus scatulatus), which may not generate significant local effects prior to rapid and profound systemic demise. 7. If any sign or symptom becomes apparent, antivenin therapy should be considered. In a mild bite with minimal pain, minimal swelling, and very little progression of swelling up the extremity, one need not treat the patient. For more serious envenomations, antivenin therapy is indicated. Administer a skin test by injecting 0.1 0.2 ml of the 1: 10 horse serum dilution into the dermis. Do not use a conjunctival test. Examine the test site after 15-20 min; if there is no evidence of erythema or edema, the test may be considered negative. A positive test is not a contraindication to administering antivenin, but should alert the clinician that the rate at which antivenin is delivered must be monitored. The use of corticosteroids and epinephrine need to be considered to control potential untoward responses. 8. Assuming that the skin test is negative or that the decision has been made to proceed with antivenin therapy, reconstitute five vials of Wyeth Crotalidae Polyvalent Antivenin in lactated Ringer's solution or the diluent supplied. Vigorously shake the vials to assure that the contents are thoroughly mixed and that there is a minimum of undissolved particulate matter. Mixing the antivenin into room temperature or even slightly warmed fluid will facilitate reconstitution. Transfer the dissolved solution to an IV piggyback set-up with a volumetric regulator. 9. Administer the antivenin intravenously at a rate of 1 vial every 7-10 min (0.7 1.0 ml min-i). Anticipate using 5-10 (including the initial five) vials for a minor bite, 10-20 vials for a moderate bite, and up to 40-45 vials for a severe envenomation. 10. Should any signs of allergy/anaphylaxis (e.g. cough, dyspnea, urticaria, itching, increased oral secretions, hypotension) develop, immediately discontinue antivenin administration and treat the patient with epinephrine, steroids and/or antihistamines. As soon as the patient is stabilized, continue antivenin infusion at a slower rate. 11. After two vials of antivenin administration, the constricting band should be removed. Circumferential measurements at strategic points along the bitten extremity should be recorded at 30 min intervals. These may be useful in documenting progression of envenomation.

416 Davidson, Schafer and Jones ALGORITHM SNAKE BITE ENVENOMATION DATA SKIN TEST 1 POSITIVE IDENTIFICATION HX, PX & LAB DATA INTRA- OF SNAKE YES cac, LYTES, CA++, P04 Rx DERMAL 2. FANG MARK SGPT, PT, PD, PLATELET- TEST FOR NO,-----------. 3. PAIN COUNT, FIBRINOGEN, BUN, HORSE SERUM SENSITIVITY 4. SWELLING CREATINE AND T&C SENSITIVITY NO ~ ~ REACTION OBSERVATION 2 HRS. IN HOSPITAL 24 HRS. AT HOME I FIRST AID IMMUNOLOGY OR ALLERGY CONSULT 1. STAY CALM 1 MIX 5 VIALS OF 2. APPLY CONSTRICTING BAND ANTIVENIN IN PROXIMAL TO BITE 50 ML WARM 3. TRANSPORT TO MEDICAL SALINE FACILITY 2. INFUSE 1 CC/MIN = 1 VIAL/10 MIN 3. TETANUS PROPHYLAXIS 1 MIX 5 VIALS OF ANTIVENOM IN 50 ML WARM SALINE 2 INFUSE 1 MLiMIN = 1 VIALI10 MIN 3. MONITOR LABORATORY PARAMETERS. SX PERSIST I SX ABATE ~ OBSERVATION OBSERVE LOCAL & SYSTEMIC SYMPTOMS ALLERGY SX REAPPEAR OBSERVATION ANAPHYLAXIS 1. EPINEPHRINE 2. STEROIDS 3. IMMUNOLOGY CONSULT CUTANEOUS ALLERGIC REACTION ANAPHYLAXIS Fig. 8. Algorithmic display of the evaluation and treatment for North American pit viper envenomation. Table 4. Grade of envenomation [71]. Minimal envenomation Manifestations remain confined to or around the bite area. No systemic symptoms or signs. No significant laboratory changes. Moderate envenomation Manifestations extend beyond immediate bite area. Significant systemic symptons and signs. Moderate laboratory changes; i.e., hemoconcentration, decreased fibrinogen and/or platelets. Severe envenomation Manifestations involve entire extremity or part. Serious systemic symptoms and signs. Very significant laboratory changes. Used with permission of the Arizona Poison and Drug Information Center,

North American pit vipers 417 Table 5. Laboratory tests recommended in the evaluation of North American pit viper envenomation. CBC with differential and platelet count. Coagulation Parameters: a. Prothrombin time (PT) b. Partial thromboplastin time (PTT) c. Fibrinogen levels d. Fibrin degradation products Serum electrolytes, BUN/creatinine, calcium, phosphorus, lactate dehydrogenase (with ism:nzyme analysis) Urinalysis Electrocardiogram 12. The key to medical therapy is titration of antivenin against signs and symptoms of envenomation. Pain is an excellent symptom against which to titrate. Progression of swelling is also an indication for additional antivenin. However, do not anticipate rapid regression of swelling. Systematic signs and symptoms, such as muscle fasciculations, are also indicators that more antivenin is required. If a change in coagulation parameters has been noted, then progression of envenomation can be followed with laboratory parameters. Probably the best indicator of continued pro- or anticoagulant activity is a decreasing platelet count. Circumoral tingling may persist long after venom neurtralization has been accomplished and should not be used as an indication for additional antivenin therapy. It is common to have decreased serum potassium; unless this becomes symptomatic, it need not be corrected. 13. Additional antivenin should be administered in five vial increments. Antivenin's neutralizing capacity is extremely low, so it makes little sense to administer a single vial. Antivenin should be administered at a maximum rate of one vial every 7 10 min. Exceeding this rate puts the patient at risk for an allergic reaction. Throughout antivenin administration, a brisk diuresis should be maintained to prevent microvascular renal obstruction with hemolyzed red blood cells or immune complexes. Figure 8 is an algorithm depicting the evaluation and treatment for North American pit viper bite. General considerations 1. Even in situations with severe envenomation, the majority of therapy should be accomplished in the first 2-4 h. It is not uncommon to err by administering too little antivenin too slowly, needlessly incurring morbidity and prolonged hospitalization. Even if a patient presents several hours after being bitten, antivenin therapy is indicated and will generally reverse much of the venom's actions. 2. Tetanus prophylaxis should be current. Antibiotic prophylaxis is not indicated. Appropriately treated wounds will rarely break down. Should the question of a compartment syndrome arise, wick measurements of compartment pressures are indicated. Fasciotomy is only indicated if a documented elevated compartment pressure is measured, which is rare.

418 Davidson, Schafer and Jones 3. Narcotics are generally contraindicated, as they suppress respiration and alter mental status. Tranquilizers such as diazepam are rarely required, but can be given in small doses to decrease anxiety. 4. With a severe envenomation, disseminated intravascular coagulopathy may develop. Venom neutralization is key. Appropriate platelet and factor replacement is administered as with other consumption coagulopathies, but will be relatively ineffective unless the venom is neutralized. 5. There are two potential unique problems. The first is intravenous envenomation [16]. The second is anaphylactic reaction to horse serum. Intravenous envenomation occurs when a fang pierces a superficial vein and the venom is injected directly into the vessel. Under this circumstance, the victims become acutely ill in minutes, and if not attended to emergently, will often die. The mainstay of treatment is intravenous antivenin [16]. One gram of methylprednisolone is infused intravenously followed by 20 vials of antivenin infused as quickly as possible, at a rate of one vial per minute. An anaphylactic reaction mandates aggressive resuscitation. The principles of treatment are the same as for other anaphylactic reactions [72]. 6. In most cases, when the patient presents to the hospital within 1-2 h of the bite, venom neutralization should be completed within 4-6 h, and the patient should then be stable. These individuals should be observed in an intensive care unit setting for 12-24 h. Many can be discharged the following day. Those treated a little later after the bite or with more prolonged signs and symptoms may require an additional one or two days of hospitalization. 7 Individuals who receive more than 5-10 vials of antivenin may develop a cutaneous allergic reaction. This usually appears as urticaria, beginning between 7 to 21 days after treatment. This is treated with oral antihistamines, but occasionally a course of cortico steroids will be required. References 1. Russell, F.E. Snake Venom Poisoning, Great Neck, NY Scholium International, 1983. 2. Klauber L.M. Rattlesnakes: Their Habits, Life Histories, and Influence on Mankind. 2nd vols. Berkeley: University of California Press, 1982. 3. Rosenfeld, G. Symptomatology, pathology and treatment of snake bites in South America. In: Bucherl, W. and Buckley, E.E., eds. Venomous Animals and Their Venoms. Vol. 2. New York, NY: Academic Press, 1971. 4. Brown, J.H. Toxicology and Pharmacology of Venoms from Poisonous Snakes. Springfield, IL: Charles C. Thomas, 1973. 5. Gennaro, J.F., Leopold, RS. and Merriam, T.W. Observations on the actual quantity of venom introduced by several species of crotalid snakes in their bite. Anat Rec 1961; 139,303. 6. Hardy, D.C. Fatal rattlesnake envenomation in Arizona. l. Toxicol Clin Toxicol1986; 24, 1. 7. Russell, F.E., Carlson, RW., Wainschel, J., et al. Snake venom poisoning in the United States: experiences with 550 cases. lama 1975; 233,341-4. 8. Minton, S.A. Observations on toxicity and antigenic make-up of venoms from juvenile snakes. In: Russell, F.E. and Saunders, D.R, eds. Animal Toxins. Oxford: Pergamon Press, 1967: 211. 9. Fiero, M.K., Seifert, M.W., et al. Comparative study of juvenile and adult prairie rattlesnake (Crotalus viridis viridis) venoms. Toxicon 1972; 10, 81.

North American pit vipers 419 10. Minton, S.A. Short communication: a note on the venom of an aged rattlesnake. Toxicon 1975; 13, 73. 11. Reid, H.A. and Theakston, R.D.G. Changes in coagulation effects byvenoms of Crotalus atrox as snakes age. Am J Trap Med 1978; 27, 1053. 12. Kochva, E. Oral glands of the repitilia. In: Gans, C. and Parson, T., eds. Biology of the Reptilia. Vol. 8, pp. 43-161. London: Academic Press, 1978. 13. Russell, F.E. Consecutive bites on three persons by a single rattlesnake. Toxicon 1978; 16, 79. 14. Parrish, H.M. Incidence of treated snakebites in the United States. Public Health Rep 1966; 81,269-76. 15. Sprenger, T.R. and Bailey, W.J. Snakebite treatment in United States Int J Dermatol1986; 25, 479-84. 16. Davidson, T.M. Intravenous rattlesnake envenomation. West J Med 1988; 148,45. 17. Wingert, W.A. and Chan, L. Rattlesnake bites in Southern California and rationale for recommended treatment. West J Med 1988; 148, 37. 18. Russell, F.E. Pharmacology of animal venoms. Clin Pharmacol Ther 1967; 8, 849. 19. Tu, A. Venoms: Chemistry and Molecular Biology. New York: John Wiley and Sons 1977. 20. Wagner, F.W. and Prescott, J.M. A comparative study of proteolytic activities in the venoms of some North American snakes. Comp Biochem Physiol1966; 17, 191. 21. Deutsch, H.F. and Diniz, c.r. Some proteolytic activities of snake venoms. J Bioi Chem 1955; 216, 17. 22. Rocha e Silva, M., Beraldo, W.T. and Rosenfeld, G. Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin. Am J Physiol1949; 156, 261. 23. Favilli, G. Occurrence of spreading factors and some properties of hyalaronidases in animal parasites and venoms. In: Buckley, E. and Porges, N. eds. Venoms, Washington, D.C.: AAAS, 1956: 281. 24. Rosenberg, P. Pharmacology of phospholipase A z from snake venoms. In: Lee, C.Y., ed. Snake Venoms. Handbook of Experimental Pharmacology 52. Berlin: Springer-Verlag, 1979, pp. 403 47. 25. Breithaupt, H. Enzymatic characteristics of Crotalus phospholipase A z and the crotoxin complex. Toxicon 1976; 14,221. 26. Russell, F.E., Strassberg, J. and Buess, F.W. Zootoxicological properties of venom phosphodiesterase. Fed Proc 1962; 21, 242. 27. McLennan, B.D. and Lane, B.G. The chain termini of polynucleotides formed by limited enzymatic fragmentation of wheat embryo ribosomal RNA. II. Studies of a snake venom ribonuclease and pancreas ribonuclease. Can J Biochem 1968; 46, 93. 28. Laskowski, J., Sr, Hagerty, G. and Laurila, V. Phosphodiesterase from rattlesnake venom. Nature 1957; 180, 1181. 29. Diniz, C.R. Bradykinin formation by snake venoms. In: Bucherl, W., Buckley, E. and Dudofer, V., eds. Venomous Animals and Their Venoms. Vol. 1. New York: Academic Press, 1978: 217. 30. Russell, F.E., Buess, F.W., Woo, M.Y. and Eventov, R. Zootoxicological properties of venom L-amino acid oxidase. Toxicon 1963; 1, 229. 31. Goncalves, J.M. Purification and properties of crotamine. In: Buckley, E. and Porges, N., eds. Venoms. Washington, DC, AAAS, 1956: 261. 32. Schaeffer, R.c., Jr, Pattabhiraman, T.R., Carlson, R.W., Russell, F.E. and Weil, M.H. Cardiovascular failure produced by a peptide from the venom of the Southern Pacific Rattlesnake, Crotalus viridis helleri. Toxicon 1979; 17,447. 33. Michaelis, B.A. and Russell, F.E. Effects of Crotalus venom on integrity of capillary wall. Toxicon 1963; 1, 245. 34. Denson, K.W.E., Russell, F.E., Alveagro, D. and Bishop, R.L. Characterization of the

420 Davidson, Schafer and Jones coagulant activity of some snake venoms. Toxieon 1972; 10, 557. 35. Markland, F.S. and Pirkle, H. Thrombin-like enzyme from the venom of Crotalus adamanteus (eastern diamondback rattlesnake). Thrombosis Res 1977; 10, 487. 36. Weiss, HJ., Allan, S., Esmond, D. and Kochva, S. A fibrogenemia in man following the bite of a rattlesnake (Crotalus adamanteus) Am J Med 1960; 47, 625. 37. Hasiba, V., Rosenbach, L.M., Rockwell, D. and Lewis, J.H. DIC-like syndrome after envenomation by the snake Crotalus horridus. N Engl J Med 1975; 292, 505. 38. Pizzo, S.W., Schwartz, M.L., Hill, RL. and McKee, P.A Mechanism of ancrod coagulation. A direct proteolytic effect on fibrin. J Clin Invest 1972; 51, 2841. 39. Bajwa, S.S., Markland, F.S. and Russell, F.E. Isolation and characterization of a fibrinolytic enzyme from the western diamondback rattlesnake. Fed Proe 1979; 383041 (abst.). 40. Rosenfield, G., Nahas, L. and Kelen, E.M.A Coagulant, proteolytic and hemolytic properties of some snake venoms. In: Bucherl, W., Buckley, E. and Dudofer, V., eds. Venomous Animals and their venoms. Vol. 1. New York: Academic Press, 1978: 229. 41. Witham, AC., Remington, J.W. and Lombard, E.A Cardiovascular response to rattlesnake venom. Amer J. Physiol1953; 173, 535. 42. Russell, P.E., Buess, F.W. and Strassberg, 1. Cardiovascular response to Crotalus venom. Toxieon 1962; 1, 5. 43. Halmagyi, D.FJ., Starzecki, B. and Horner, G.F. Mechanism and pharmacology of shock due to rattlesnake venom in sheep. J Appl Physiol1965; 20, 709. 44. Bonta, I.L., Vargaftig, B.B., Bhargava, N. and DeVos, CJ. Method for study of snake venom induced hemorrhages. Toxieon 1970; 8, 3. 45. Gennaro, J.F., Jr and Ramsey, H.W. Distribution in the mouse of lethal and sublethal doses of cottonmouth moccasin venom labelled with Iodine-131. Nature 1959; 184, 1244. 46. Castilonia, R, Pattabhiraman, T.R, Russell, F.E. and Gonzalez, H. Electro-physiological studies on a protein fraction (K') from Mojave rattlesnake (Crotalus seutulatus) venom. Toxieon 1981; 19,473. 47. Russell, F.E. Snake venom immunology: historical and practical considerations. J Toxieol Toxin Rev 1988; 7, 1. 48. Wyeth Crotalidae Polyvalent Antivenin; Wyeth Laboratories. Lyophilized polyvalent antisnake venom: Directions for Use (Package insert with antivenin). January, 1984. 49. Criley, B.R. Development of multivalent antivenin for the family Crotalidae. In: Buckley, E. and Porges, N., eds. Venoms. Washington, DC: AAAS 1956: 373. 50. Sutherland, S.K., Coutler, AR and Harris, RD. Rationalization of first aid measures for elapid snakebite. Lancet 1979; 1, 183. 51. Sullivan, J.B. Past, present and future immunotherapy of snake venom poisoning. Ann Emerg Med 1987; 16, 938-44. 52. Hasiba, U., Rosenbach, L.M., Rockwell, D. et al. DIC-like syndrome after envenomation by the snake, Crotalus horridus. N Engl J Med 1975; 292, 505. 53. Riffer, E., Curry, S.c. and Gerkin, R Successful treatment with antivenin of marked thrombocytopenia without significant coagulopathy following rattlesnake bite. Ann Emerg Med 1987; 16, 1297. 54. Hardy, D.C., Jeter, J. and Corrigan, J.L. Envenomation by the northern blacktail rattlesnake (Crotalus molossus): report of two cases and the in vitro effects of the venom on fibrinolysis and platelet aggregation. Toxieon 1982; 20, 487. 55. Dart, RC., Goldner, AP. and Lindsey, D. Efficacy of delayed administration of crotalid antivenin and crystalloid fluids. Toxieon 1988; 26, 1218. 56. Russell, F.E., Ruzic, N. and Gonzales, H. Effectiveness of antivenin (Crotalidae) polyvalent following injection of crotalus venom. Toxieon 1973; 11,461. 57. Hutchinson, R.H. On the incidence of snake bite poisoning in the United States and the results of the newer methods of treatment. Bull Antivenin Inst Amer 1929; 3, 43.

North American pit vipers 421 58. Jurkovich, G.J., Luterman, A., et al. Complications of crotalidae antivenin therapy. J Traum 1988; 28, 1032. 59. Spaite, D., Dart, R and Sullivan, J.B. Skin testing in cases of possible crotalid envenomation. Ann Emerg Med 1988; 17, 105. 60. Otten, E. and McKinim, D. Venomous snakebite in a patient allergic to horse serum. Ann Emerg Med 1988; 12, 624. 61. Griffen, D. and Donovan, 1. Significant envenomation from a preserved rattlesnake head (in a patient with a history of immediate hypersensitivity to antivenin). Ann Emerg Med 1986; 15, 955. 62. Theakston, RD.G. Snake venoms in science and clinical medicine. 2. Applied immunology in snake venom research. Trans Royal Soc Trop Med Hyg 1989; 83, 741. 63. Clement, J.F. and Pietrusko, RG. Pit viper snakebites in the United States. J. Fam Pract 1978; 6,269. 64. Burgess, J.L., Dart, R.C and Mayersohn, M. Effect of constriction bands on rattlesnake venom absorption: a pharmacokinetic study. Ann Emerg Med 1991; 20,459. 65. Bronstein, A.C, Russell, F.E. and Sullivan J.B. Negative pressure suction in field treatment of rattlesnake bite. Vet Hum Toxico11985; 25, 297. 66. Clark, R.W. Cryotherapy and corticosteroids in the treatment of rattlesnake bite. Milit Med 1971; 136, 42. 67. Stewart, RM., Carey, P.O., et al. Antivenin and fasciotomy/debridement in the treatment of the severe rattlesnake bite. Am J Surg 1989; 158, 543. 68. Johnson, E.K., Kardong, K.U. and Mackessy, S.P. Electric shocks are ineffective in treatment of lethal effects of rattlesnake envenomation in mice. Toxicon 1987; 25, 1347. 69. Bucknall, N.C Electrical treatment of venomous bites and stings. Toxicon 1991; 29, 397-400. 70. Christopher, D.G. and Rodning, CB. Crotalidae envenomation South Med J 1986; 79, 159. 71. American Association of Poison Control Centers and the Arizona Poison and Drug Information Center. Snake Venom Poisoning. August 1984. 72. Bielory, L. Clinical complications of heterologus antisera administration. J Wild Med 1991; 2, 127-139.