18

Biotoxins

BACTERIA the presynaptic neuron of the neuromuscular junction,

resulting in flaccid paralysis.
Joseph D. Roder
Toxicity and Risk Factors. Botulism occurs from one of
three mechanisms: ingestion of preformed toxin, ingestion of
BOTULISM spores, or contamination of wounds with spores. Toxico-
infectious botulism (shaker foal syndrome) occurs in foals
Synonyms. Botulism, limber neck (avian), and shaker foal that ingest spores, which result in an overgrowth of the
syndrome (horses) are names used for the disease caused organism in the gastrointestinal system. Wound botulism
by toxins produced by Clostridium botulinum. occurs in deep puncture sites or surgical sites such as
castration or hernia repair.
Sources. C. botulinum is an anaerobic, gram-positive, Ingestion of preformed toxin is most common in cattle,
spore-forming rod that is commonly found in soil. Seven adult horses, and birds. Outbreaks of botulism caused by
distinct antigenic botulinum toxins include A, B, C, D, E, F, ingestion of preformed toxin can occur in livestock after
and G.1 In the United States, type A toxin is found mostly in consumption of improperly ensiled poultry litter, small grain
the west and type B toxin is typically found in the mid- haylage, alfalfa silage, or alfalfa hay cubes. Other sources of
Atlantic states and Kentucky. The toxin is heat labile; preformed toxin are poultry litter or hay contaminated with
however, the spores of the bacteria are resistant to drying decaying carcasses of chickens, rodents, or cats.4 Waterfowl
and normal environmental temperatures. are at increased risk of intoxication when eating rotten
vegetation in shallow waters.
Mechanism of Action. The toxin is comprised of a heavy Cattle are most commonly affected by toxins B, C, and D
chain (100-kD) and a light chain (50-kD) that are linked in North America. Horses are most commonly affected by
together by disulfide bonds and noncovalent forces.1 Following type B, but can also be affected by types A and C. Both
ingestion of the toxin, the heavy chain binds a specific domestic and wild avian species are most commonly
presynaptic vesicle protein, synaptotagmin. The botulinum toxin affected by type C. Swine, dogs, and cats are reported to be
is then internalized via endocytosis and the disulfide bond less sensitive to botulism.
linking the heavy and light chains is cleaved. The light chain of
the botulinum toxin cleaves neuronal proteins associated with Clinical Signs. The classic clinical syndrome attribut-
docking and release of the acetylcholine vesicles. There are able to botulism is a progressive flaccid paralysis. Ani-
differences in specific protein binding of the light chain mals suffering from clinical botulism commonly exhibit
depending on the toxin. The light chains of botulinum toxins A weakness and ataxia. These signs may be more pronounced
and E cleave a synaptosome-associated protein of 25 kD when the animal is excited or forced to move. Acute
(SNAP-25).2 The light chains of botulinum toxin B, D, F, and G death may be the first clinical sign noted and large
cleave a specific substrate vesicle-associated membrane protein numbers of animals may die in a short period, especially
(VAMP or synaptobrevin), whereas the light chain of botulinum waterfowl. Weakness of the muscles of the tail are often
toxin C cleaves both SNAP-25 and syntaxin (a synaptic noted and may be used to identify an affected animal.
membrane-associated protein).3 Exercise intolerance and ataxia are common findings
The cumulative result of the proteolytic actions of the in horses.5 Affected animals may also exhibit difficulties
botulinum toxins is a disruption of the protein scaffolding with prehension and swallowing. Other gastrointestinal
within the presynaptic terminus that is responsible for the signs may include ileus, constipation, or ruminal atony.
docking, fusion, and release of the acetylcholine vesicles. The Death is generally thought to be due to respiratory
botulinum toxins block the release of acetylcholine from paralysis.

98
Chapter 18 Biotoxins 99

Unique symptoms occur in foals, which develop tremors neurons. It is thought that these gangliosides are asso-
(shaker foal syndrome), and in waterfowl, which develop a ciated with a tetanus toxin receptor.1 The tetanus toxin is
profound weakness in the neck (limber neck). then internalized into the neuronal cell and the disulfide
bonds that hold the heavy and light chains of the toxin are
Diagnostic Testing. Analysis of serum, gastrointestinal cleaved. The toxin enters into the cytoplasm of peripheral
contents, and feedstuffs for the preformed toxin may support neurons, is incorporated into endocytic vesicles, and travels
a clinical diagnosis of botulism. Ruminal fluids may be retroaxonally to the central nervous system.2 The light chain
obtained from animals exhibiting acute death and analyzed of the tetanus toxin is a zinc endopeptidase that cleaves
for botulism toxins.6 A mouse bioassay is available in most VAMP.1,2 This results in an interruption of translocation and
diagnostic laboratories. An enzyme-linked immunosorbent exocytosis of neurotransmitters from inhibitory neurons at
assay technique is available at some laboratories, but it is the spinal cord.
currently specific for only one toxin type, which limits its
usefulness as a screening method. Toxicity and Risk Factors. The persistent spores are
ubiquitous in the feces and soil in areas where animals are
Treatment. The initial step in treatment is to remove any raised. Spores of the organism are introduced into a wound.
feedstuffs that may be causing the disease. Individual Animals at greater risk include those that have had recent
treatment of affected animals may include antitoxin therapy field surgeries, castrations, shearing, or retained placentas.
if a correct clinical diagnosis can be made early in the course Horses and ruminants are more susceptible to tetanus than
of disease. Antitoxin, antibiotics (penicillin), and debridement are cats and dogs.4 It has been suggested that species
of wounds may be beneficial for animals suffering from sensitivity to tetanus may be due to differences in the
wound botulism.7 Animals should also receive symptomatic gangliosides on the neurons.2
and supportive care; small animals may require artificial
respiration. Clinical Signs. Affected animals exhibit generalized
musculoskeletal stiffness. The nictitating membrane (“third
Prognosis. The prognosis in animals exhibiting clinical eyelid”) is often elevated and fine motor muscles of the
signs is guarded to poor. If a contaminated feedstuff is the eyelids may be affected, resulting in abnormal blinking
source of intoxication, many animals may die. Botulism- response. In carnivores, contraction of the muscles of the lips
related mortality has been reported to continue for 17 days produces a “sardonic grin.” These clinical signs may progress
after a single-day exposure to contaminated feedstuffs.8 to more severe muscular rigidity, leading to the classic
“sawhorse stance,” a fixed stare, erect ears, a reluctance to eat
Prevention and Control. Vaccination against the C. botuli- or drink because of a “locked jaw,” an elevated tail, and flared
num toxins with toxoid can prevent clinical disease. Evalu- nostrils. As the disease progresses, an increase in muscular
ation and management of feedstuffs is essential. Proper rigidity may cause the animal to become recumbent and
ensiling of poultry litter with mixing to allow the surface unable to rise. In all species, convulsions may occur; death is
material to be exposed to elevated temperatures is required. caused by marked contraction of the muscles of respiration.
All feeds should be examined for evidence of decaying These episodes of muscular contraction can be induced by
carcasses.4,5 A rodent control program reduces the number external stimuli such as a sudden loud noise or a flashing light.
of mice or rats in stored feeds. Proper disposal of any dead
animals (deep burial) reduces exposure to botulism toxin. Lesions. No lesions are characteristic of tetanus intoxica-
tion in animals.

TETANUS Diagnostic Testing. A diagnosis can be made by finding

the organism C. tetani in a culture of the wound. Attempts to
Synonyms. Tetanus is also known as “lockjaw.” identify the toxins from affected animals is generally
unrewarding.
Sources. A neurotoxin, tetanospamin, is produced by
C. tetani.1,2 The clostridial organism is a gram-positive, strictly Treatment. The treatment should include antibiotic
anaerobic bacteria. The bacteria are shed in the feces and therapy (penicillin) to eliminate the bacterial replication at
sporulates, and remain in the environment for long periods. the wound site, antitoxin therapy, and cleaning of the
The organism also produces a cytolysin, called tetanolysin, wound. Individual animals may be managed by placing them
which induces pore formation in a variety of cells to aid in the in dark, quiet areas to minimize convulsions from external
replication of the tetanus organism locally at the wound site.3 stimuli.4 Additionally, the use of tranquilizers to control
convulsions may need to be considered.
Mechanism of Action. Tetanus toxin prevents the release The antitoxin is an equine-derived product from healthy
of inhibitory neurotransmitters, particularly glycine, from horses that have been hyperimmunized with repeated doses
neurons in the central nervous system, which results in of C. tetani toxin. Treatment is 10,000 to 50,000 units of
uncontrolled muscular contractions. Tetanus toxin is gener- antitoxin subcutaneously or intramuscularly to horses and
ated from the clostridial organisms in the anaerobic wound cattle; 3,000 to 15,000 units to sheep and swine. Repeated
environment. To gain entry into neurons, the tetanus toxin doses of antitoxin may be required 7 to 10 days later as
interacts with gangliosides (GT1b, GD1b) on the surface of clinical judgment warrants. Serum hepatitis (Theiler’s disease)
100 PART THREE Classes of Toxicants

is possible following antitoxin administration. Animals altered structural integrity of these cytoskeletal elements.5
suffering from this adverse reaction may exhibit subcuta- Microcystins have also induced apoptosis in a variety of
neous edema, icterus, elevation of hepatic-specific enzymes, mammalian cells in vitro.4 Microcystin causes immediate
and possibly death.5,6 blebbing of the cell membranes, shrinkage of cells, organelle
redistribution, chromatin condensation, DNA fragmentation,
Prognosis. The prognosis for animals showing clinical and DNA ladder formation.4
signs is guarded to poor. The neurotoxin anatoxin-a, most commonly produced by
Anabaena flos-aquae, is a bicyclic secondary amine that
Prevention and Control. All attempts should be made to causes depolarization of nicotinic membranes.1,6 The de-
prevent the introduction of the organism into any wounds or polarization of neuronal nicotinic membranes is rapid and
surgical sites. Good husbandry practices include using clean persistent and can lead to respiratory paralysis.
needles and clean blades for vaccination, tagging, and The neurotoxin anatoxin-a(s) inhibits acetylcholinesterase
castration. in the peripheral nervous system. This toxin does not appear
Optimal tetanus protection includes a vaccination program, to cross the blood-brain barrier.
especially for farms or operations with a history of tetanus. In
general, the manufacturers’ recommendation for bacterin or Toxicity and Risk Factors. The environmental risk factors
toxoid for an unvaccinated animal is two injections separated most commonly associated with intoxication include warm
by 2 to 4 weeks. Furthermore, a preventive, presurgical dose of weather, increased nutrients in the body of water, and wind.
1500 units of antitoxin administered subcutaneously or intra- A rapid increase in the growth of the algae, or a “bloom,” is
muscularly should be considered on farms where there is a more commonly noted in warm weather during the late
history of tetanus or if the animal’s tetanus vaccination status is summer and early fall. This rapid growth is enhanced by
unknown. The tetanus antitoxin may be used concurrently with increased nitrogen and phosphorus in the water, which may
toxoid vaccination. However, these products should be given in be more prevalent in ponds that receive runoff from fertilized
different injection sites to prevent any possible interaction. fields. Increased wind activity concentrates the cyanobacteria
along the shoreline of the pond or lake, thereby increasing
the risk of intoxication.
BLUE-GREEN ALGAE
Clinical Signs. Ingestion of water that contains cyano-
bacteria or their associated toxins may result in acute death
Joseph D. Roder with few clinical signs.7
Within 1 to 4 hours, animals that ingest microcystin or
nodularin can present with a myriad of clinical signs that
Synonyms. Cyanobacteria is another name for blue-green generally relate to damage of the liver: lethargy, vomiting,
algae. diarrhea, gastrointestinal atony, weakness, and pale mucous
membranes.2,3,8 Death often occurs within 24 hours, but may
Sources. Not all algae produce toxins. Cyanobacteria be delayed several days. In animals that survive the initial
intoxication is most commonly associated with ingestion toxicosis, secondary photosensitization may develop.2
of water with excessive growth of Anabaena sp., Animals that ingest anatoxin-a may present acutely with
Aphanizomenon sp., Oscillatoria sp., which produce the muscle tremors, rigidity, lethargy, respiratory distress, and
neurotoxins anatoxin-a and anatoxin-a(s); Microcystis sp., convulsions.1 Death from respiratory paralysis can occur
which produces the hepatotoxin microcystin; or Nodularia within 30 minutes from the onset of clinical signs.
sp., which produces the hepatotoxin nodularin.1-3 Following ingestion of anatoxin-a(s) animals may present
with signs consistent with inhibition of cholinesterase:
Toxicokinetics. The cyanobacteria ingested with water can increased salivation, urination, lacrimation, and defecation as
be rapidly broken down in the gastrointestinal tract. In the well as tremors, dyspnea, and convulsions.1 Death from
acidic environment of the stomach, the bacteria are lysed respiratory arrest can occur within 1 hour.
with the resulting release of toxins. 2 Free toxins can be
rapidly absorbed from the small intestine. The microcystins Clinical Pathology. Animals intoxicated with microcystin-
are transported to the liver and enter this organ using a bile producing cyanobacteria have elevated serum concentra-
acid transporter.3 tions of hepatic enzymes.3,8 Anatoxin-a(s) depresses the blood
cholinesterase activity, but not the brain cholinesterase activity
Mechanism of Action. The hepatotoxic microcystins and because it does not cross the blood-brain barrier.
nodularin alter the cytoskeleton of liver cells. Microcystin
action relates to its ability to inhibit serine/threonine Lesions. Microcystin results in an enlarged liver that is
phosphatases type 1 and type 2A (PP1 and PP2A).3,4 The congested and dark in color (hemorrhagic).1,2,8 Hepatic
microcystins bind covalently to and inhibit the function of the enlargement is thought to be a result of intrahepatic hemor-
protein phosphatases, which regulate the phosphorylation rhage. Histologic examination of the liver reveals a centri-
and dephosphorylation of regulatory intracellular proteins. In lobular to midzonal necrosis and hemorrhage.2,7,8
vitro, microcystins act on intermediate filaments (vimentin or Gross and microscopic lesions are typically not noted
cytokeratin), microtubules, and microfilaments causing following intoxication with the anatoxins or saxitoxin.
Chapter 18 Biotoxins 101

Diagnostic Testing. A water sample should be carefully variety of illnesses and as a supposed aphrodisiac known as
taken from the area of greatest concentration of algae. Spanish fly.1-3
Examination of fresh or formalin-preserved samples using
light microscopy identifies the toxin-producing cyanobacteria. Sources. Cantharidin is a bicyclic terpenoid (sesqui-
A sample of the water might be used in a mouse bioassay; terpene) vesicant found in the hemolymph and genitalia of
however, this bioassay is not universally available in diag- blister beetles.1,4,5 Production of cantharidin is believed to act
nostic laboratories. Water samples may also be examined by as a chemical defense against predation. 1,3 Hundreds of
a few laboratories using high-performance liquid chromato- beetle species exist; however, those that produce cantharidin
graphy (HPLC)/thin-layer chromatography (TLC) or gas are in the Meloidae family, especially in the Epicauta genus.5
chromatography-mass spectrometry (GC-MS) to identify the Only males synthesize the vesicant, which they transfer to
causative toxin. females during copulation.1-3,5
Recently a colorimetric assay has been developed to iden- Adult beetles feed primarily on plant floral parts; some
tify the presence of microcystin-LR in water.9 This method beetles, particularly the Epicauta spp., eat leaves as well. Most
can detect microcystin-LR at concentrations of 1 µg/L and cases of blister beetle toxicosis occur when livestock eat alfalfa
may be used as a screening tool to identify potentially posi- hay produced in the semiarid regions of the United States,
tive samples with additional confirmation by HPLC or MS especially Texas and Oklahoma, where the three-striped blister
methods. beetles (Epicauta temexa and Epicauta occidentalis) are the
most common species associated with toxicosis.1,3,6
Treatment. None of the cyanobacteria have antidotes;
therefore, therapy is directed toward symptomatic and sup- Mechanism of Action. Cantharidin is rapidly absorbed
portive therapy. Decontamination of dogs includes emesis, from the gastrointestinal tract and excreted in the urine.5
activated charcoal, and a cathartic as well as bathing if algae Because of the vesicant properties of cantharidin, irritation
remains on the haircoat. Decontamination in large animals is characterized by acantholysis and vesicle formation leading
limited to activated charcoal, a cathartic, and possibly to ulcers or erosions occurs where the compound contacts a
bathing. mucosal surface. The exact mechanism for this action is
Animals that present with signs associated with the unclear; however, cantharidin results in an increased mitotic
hepatotoxic algae should be aggressively treated with fluids, rate in epithelial cell tissue cultures.5 It is thought to interfere
corticosteroids, and other elements of shock therapy. Ani- with the oxidative enzyme systems that are involved with
mals that present with signs associated with the neurotoxic active transport across the mitochondrial membrane,
algae require aggressive respiratory support and seizure resulting in permeability changes. 5 Disruption of the
control as needed. Additionally, animals with anatoxin-a(s) membrane results in acantholysis and vesicle formation.5 In
toxicosis may be treated with atropine to reverse muscarinic mouse studies, cantharidin inhibits protein phosphatase 2A,
signs. which controls cell proliferation, modulates phosphatases
and protein kinases involved in cell function, and plays a role
Prognosis. Animals that exhibit clinical signs of intoxica- in the activity of cellular membrane channels and receptors.1
tion have a poor to grave prognosis, depending on the
amount of toxin consumed. Toxicity and Risk Factors. Adult blister beetles feed
principally on lush alfalfa fields as the alfalfa plants mature
Prevention and Control. The key control measure is to and bloom. Some blister beetle species are gregarious,
limit or eliminate animal exposure to water containing the congregating in large numbers, especially near field margins.
algae. If possible, the animals should be moved to a different Livestock poisoning usually is a result of ingestion of alfalfa
pasture or the water source fenced off and an alternate hay that has had beetle swarms baled into the hay.
water supply provided. The use of copper sulfate as an Therefore, blister beetles that exhibit this swarming behavior
algaecide in ponds with a cyanobacterial bloom may be are of greatest concern because of the greater risk of a large
beneficial. After treatment with copper sulfate, animals must number of beetles becoming trapped in a small amount of
be removed from the water source for a period of 3 to 7 days hay.1 The species most commonly recognized for its swarming
to allow for the degradation of the cyanobacterial toxins.3 characteristic is the three-striped blister beetle, Epicauta
lemniscata. However, many other species (E. occidentalis,
E. temexa, E. pennsylvanica, E. maculata, E. vittata) are
commonly associated with cantharidin toxicosis of livestock.
INSECTS Modern hay harvesting practices (e.g., hay crimping)
increase the likelihood that blister beetles are incorporated
into hay.1,5 Cantharidin is released when adults are crushed
BLISTER BEETLES and can contaminate hay even if the beetles are not found in
the hay. Cantharidin is a colorless, odorless, and stable
Eric L. Stair and Konnie H. Plumlee
chemical. Chemically killing the beetles does not diminish
the toxin’s activity. Even the remains or dried juices from
Synonyms. The disease caused by blister beetles is crushed beetles in the hay may cause severe digestive and
referred to as cantharidin toxicosis or cantharidiasis. Can- urinary tract disease in livestock. Toxicity is not affected by
tharidin has been used for centuries as a treatment for a storage time of the hay.5
102 PART THREE Classes of Toxicants

Even though cantharidin toxicosis is usually localized in Clinical Pathology. The packed cell volume is typically
the southern United States where alfalfa is grown, toxicosis elevated. The serum protein concentration may be normal or
has been reported from Florida to Arizona and as far north as elevated early in the disease, but frequently goes below
Illinois.5,6 However, poisoning can occur anywhere because normal in horses that survive longer than 24 hours.5
of the transport of alfalfa hay contaminated with Increased creatine kinase occurs in some horses; persistently
cantharidin.3 Processed alfalfa products, such as alfalfa increasing levels indicates a poor prognosis.5 The urine
pellets, green chop, cubes, or silage, may also contain specific gravity is often low even in dehydrated horses.5
cantharidin because the compound is heat stable; however, Decreased serum total calcium occurs in many horses;
toxicosis from these sources is unlikely presumably because however, a normal or slightly reduced serum ionized calcium
of dilution during processing. has been reported.5 Serum magnesium is significantly
Cantharidin toxicosis is most commonly reported in decreased in many horses. In experimental toxicosis, hypo-
horses, which may be more susceptible to the toxic effects calcemia and hypomagnesemia were the most persistent
than other livestock.1,6 However, cases have also been findings even after all other values had returned to baseline
reported in sheep and cattle.1,6 Toxicosis occurred in emu levels.4 Potassium is usually within a normal range, but mild
chicks that ingested Pyrota insulata, which is a species of or transient hypokalemia has been reported.5
blister beetles found in Texas and Oklahoma and whose
main food source is blooms of mesquite trees.2 Lesions. Large doses of cantharidin may result in sudden
Studies on common blister beetle species indicate widely death without gross lesions.4,7 However, because of the irritant
varying amounts of cantharidin, from less than 1% to more nature of cantharidin, some animals display gross lesions
than 5% of dry weight.3,6 Such variation in cantharidin throughout the urinary tract and gastrointestinal tract, possibly
content of beetles within the same species makes it difficult including the lips and oral cavity. Lesions are most common
to determine the number of beetles necessary to result in in the terminal portion of the esophagus, stomach, and
toxicosis. intestines.5,7 Classic lesions consist of areas of ulceration or
The toxicity of blister beetles to horses is estimated at a erosion. However, lesions may be limited to reddening of the
minimum lethal dose of 1 mg or less of cantharidin/kg of mucosal lining of the gastrointestinal tract and urinary bladder.7
body weight.1,5,6 The number of beetles necessary to provide Streaks of ventricular myocardial necrosis occur occasionally.1,5
a lethal dose of cantharidin depends on the amount of
cantharidin present in the beetles and the weight of the Diagnostic Testing. Samples of urine or intestinal con-
horse (Table 18-1). tents (500 ml each) are the preferred diagnostic speci-
mens and may be submitted for analysis by HPLC or
Clinical Signs. The severity of clinical signs varies GC-MS.1,5,6 Detection of cantharidin at any level is considered
according to the dose of cantharidin consumed. Signs can clinically significant.1 Urine samples should be collected for
range from depression and discomfort to severe colic.5 analysis as early as possible because renal clearance of
Animals ingesting high doses may experience severe shock cantharidin is rapid (3 to 4 days).1,5 Liver, kidney, and serum
and death within several hours.7 An apparently healthy samples have also been used for chromatographic analysis,
animal may be found dead with little or no signs of struggle but they are not the specimens of choice.
after being fed contaminated hay the night before.7
In horses, the most frequent signs are related to colic: Treatment. Treatment of cantharidin toxicosis should focus
restlessness, depression, sweating, congested mucous mem- on enhancing fecal and urinary elimination of cantharidin,
branes, increased heart rate, and increased respiratory rate. correcting dehydration, managing serum calcium and mag-
Horses with gastric lesions may submerge their muzzles or nesium abnormalities, and controlling pain.7 Intensive sup-
play in water. Other common signs include fever, pollakiuria, portive treatment may be required for 3 to 10 days depending
and diarrhea. Blood is usually not seen in the feces; however, on the severity of illness.7
feces are frequently positive for occult blood.5 Less common Mineral oil should be administered to provide a lipid-
signs include oral lesions, salivation, stiff gait, and blood- soluble substrate to possibly bind cantharidin and to hasten
tinged urine. Synchronous diaphragmatic flutter and muscle movement of poison through the intestinal tract. Repeated
fasciculations are believed to be caused by hypocalcemia. doses of mineral oil may be beneficial. Activated charcoal
may also bind cantharidin.
Commonly prescribed analgesics may not provide ade-
TABLE 18-1 Estimated Number of Beetles Necessary to Provide a quate pain relief. Therefore, α2-adrenergic agonists may need
Lethal Dose of Cantharidin (Assuming the Lethal Dose Is 1 mg/kg) to be administered in horses. Acepromazine maleate is
contraindicated because it may potentiate shock.5
Cantharidin Horse Weight (lbs) Fluid therapy should be established to adequately
Content (mg/beetle) 550 1100 rehydrate the horse, decrease serum cantharidin levels, and
increase toxin excretion via the kidneys.5 Serum calcium and
1 250 500
magnesium levels should be monitored frequently during
2 125 250
treatment and fluids supplemented with these electrolytes
3 83 166
if indicated. Calcium preparations should be diluted in
4 63 126
isotonic fluids that do not contain sodium bicarbonate and
5 50 100
administered slowly.5
Chapter 18 Biotoxins 103

Prognosis. A prognosis of poor to guarded is warranted in 6. Scout fields before and during harvest. Beetles disperse
most cases, depending on the amount of cantharidin when encountered, so swarms can be detected just in
ingested. A more favorable prognosis may be given if the front of the harvester. Drivers spotting swarms can stop
animal is diagnosed early and responds to aggressive and allow swarms to disperse before proceeding with
treatment. Experimental cantharidiasis resulted in a higher the harvesting.
incidence of nonsurvival when a persistent increase in pulse
and respiratory rate or an increasing creatine kinase level FIREFLIES
was observed.4
Konnie H. Plumlee
Prevention and Control. Prevention centers on feeding
alfalfa hay that is free of beetles. Contaminated hay is usually
the result of beetles being crushed before baling. Beetles Sources. Fireflies of the genus Photinus contain steroidal
disperse in the field as the cut hay dries. However, beetles pyrones called lucibufagins, which are structurally related to
are often crushed during harvesting especially if the swather the cardiotoxic bufodienolides of toads and cardenolides of
is equipped with a crimper to speed drying of the hay. Beetle plants. Lucibufagins protect fireflies against predators such as
body parts may be concentrated in small portions of bales spiders and birds.1
and consumed by livestock. Suggested means of combating
blister beetle problems in alfalfa include the following: Mechanism of Action. The mechanism of action is
1. Feed small rectangular bales instead of large round unknown. However, because of their structural similarity to
bales so that individual flakes make be hand inspected bufodienolides and cardenolides, it is likely that lucibufagins
before feeding. are also cardiotoxic.
2. Cut hay early before the bloom stage so that plants do
not attract adult blister beetles. First-cutting hay and Toxicity and Risk Factors. Toxicosis has been reported in
late cuttings of hay (especially after the first frost) often two bearded dragons, an African chameleon, two White’s
escape contamination because they are produced tree frogs, and a Lacerta derjugini lizard that were kept as
before and after peak periods of beetle activity. pets and fed fireflies by their owners.1
3. Cut hay without using crimpers. This suggestion does
not usually interest producers, because drying time of Clinical Signs. Signs that have been reported by owners
hay is increased when crimping is not used. are summarized in Table 18-2.
4. Use a sickle bar mower without conditioner, which is
generally slower and does not crimp. Lesions. Postmortem examination of two bearded dragons
5. Avoid wheel traffic on standing or cut hay. This can be revealed no gross internal lesions.1
difficult because mowers often require driving the
tractor over previously cut hay. However, some mowers Treatment. Because of the acute onset of signs, veterinary
or conditioners allow the swath to be straddled by care could not be instituted before death in any animals so
subsequent wheel traffic. far.1

TABLE 18-2 Course of Disease in Animals That Have Ingested Fireflies

Animal Number of Fireflies Ingested Onset of Signs after Ingestion Clinical Signs

Bearded dragon About 9 30 minutes Head-shaking, oral gaping, dyspnea; color

change to black on dorsal trunk and nape;
died about 60 minutes after ingestion

Bearded dragon 1 60-90 minutes Oral gaping; color change to black on ventral
neck, abdomen, tail; died at unknown time

African chameleon 5-6 Unknown Clinical signs not described; died at unknown
time

White’s tree frog About 3 Unknown Found dead next morning

Lacerta derjugini (lizard) 1 5 minutes Oral gaping, regurgitation; died 15 minutes

following ingestion
Data from reference 1.
104 PART THREE Classes of Toxicants

Mechanism of Action. Neurotoxins affect the postsynaptic

REPTILES motor nerve membranes with a curare-like action. The
multiple neurotoxic fractions combine to induce a non-
Michael E. Peterson depolarizing postsynaptic neuromuscular blockade. This
activity is clinically manifested as vasomotor instability,
muscle paralysis, and central nervous system depression.
CORAL SNAKES The enzymatic fraction can cause local tissue damage,
and in dogs can cause hemolytic anemia with a resultant
Sources. Coral snakes belong to the reptilian family hemoglobinuria.5,6 Phospholipase A may trigger damage to
Elapidae. Two genera of coral snakes are indigenous to the red blood cell membranes. In cats, myoglobin release can be
United States. The Sonoran coral snake (Micururoides induced as a result of enzymatic effects.
euryxanthus) inhabits central and southeastern Arizona and Intravenous (IV) injection of venom can cause a dramatic
southwest New Mexico. The other genus is composed of decrease in blood pressure as cardiac output declines as a
several subspecies of Micrurus fluvius, including the Texas result of vasodilatation in the primary shock organs of the
coral snake (M. f. tenere), the Eastern coral snake victim species.7
(M. f. fulvius), and the South Florida coral snake
(M. f. barbouri). The Eastern coral snake inhabits eastern Toxicity and Risk Factors. The severity of the enveno-
North Carolina south to central Florida, west to Alabama and mation is directly related to the size of the victim and
Mississippi, and throughout eastern Louisiana to the amount of venom injected. The amount of venom available
Mississippi River. The South Florida coral snake is found in to be injected is directly related to the size of the snake.8
southern Florida. The Texas coral snake inhabits eastern and The volume of venom injected is proportional to the
south central Texas north into southern Arkansas and motivation of the snake (defensive vs. offensive bite) along
Louisiana. with the duration of the bite and intensity of the chewing
Coral snakes are relatively uncommon, generally shy, and action.
often nocturnal. The Sonoran coral snake is rarely significant
medically. This snake is small, nocturnal, burrowing, Clinical Signs. Clinical signs vary depending on the victim
nonaggressive, and shy, which limits exposure to dogs and species. In cats, the primary clinical issues are neurologic
cats. Bites to livestock are unlikely. Their venom potency is with ascending flaccid quadriplegia, reduced nociperception,
relatively low.1 and central nervous system depression. Decreased blood
Coral snakes belonging to the genera Micrurus are pressure, respiratory depression, loss of spinal reflexes in all
generally small mouthed, diurnal, and reclusive. In limbs, anisocoria, and hypothermia can also manifest. There
North America they can be identified by their bright is no evidence of intravascular hemolysis in envenomated
coloration of fully encircling bands beginning with a black cats, but significant release of myoglobin does occur.4
head then alternating yellow, red, and black color pat- Canine patients also exhibit central nervous system
tern. The yellow bands may be a bright primary yellow depression, decreases in spinal reflexes in all limbs, and respi-
to an almost white or cream color. Several species of ratory depression. Additionally, they may vomit and salivate
tricolored kingsnakes mimic the coral snake color pat- excessively, and hypotension and ventricular tachycardia
tern; however, they have yellow and black bands touch- may develop. Hemolysis can occur within the first 72 hours
ing. The identifying key for North American coral snakes is with hemoglobinuria, anemia, and alterations of red cell
the yellow (caution) and red (danger) colored bands morphology.5
touching. The usual cause of death is respiratory collapse. Addi-
These snakes have small heads, round pupils, and a tionally, dysfunctional swallowing facilitates the primary
relatively primitive and inefficient venom delivery apparatus complication of aspiration and subsequent pneumonia.9
with fixed front fangs.2 They are known to bite pugnaciously,
employing a vigorous chewing action to facilitate venom Clinical Pathology. Early elevations of fibrinogen or
delivery; human victims often have to manually remove the creatine kinase can be indicators that envenomation has
biting snake (often describing a separating Velcro sound).2 occurred.4 In canines, intravascular hemolysis, anemia, and
hematuria can occur. Dogs can exhibit burring and sphereo-
Toxicokinetics. Coral snake venom is composed of many cytosis of red blood cells.5 Feline patients can exhibit
small polypeptides and possibly cholinesterase. Acetylcholine increased myoglobin and alkaline phosphatase as a result of
and some poorly defined enzymatic fractions to the venom rhabdomyolysis.
may be involved.
The toxicokinetics are poorly understood. Onset of Lesions. Local lesions are primarily small (often bleeding)
neurologic signs is often delayed up to 12 or more hours and puncture wounds with minimal tissue swelling.
binding at the site of action seems irreversible. Unlike curare,
the onset of action is slow and the duration of the syndrome Diagnostic Testing. No specific diagnostic test is available
is prolonged. The venom can take up to 14 days to totally to identify envenomation by coral snakes. Diagnosis relies on
clear the body.3 In envenomated cats, clinical improvement witnessing the bite (snake attached to victim), onset of
began at 36 hours and the cats were able to move their clinical signs, or educated supposition based on circum-
limbs after 48 hours.4 stances (e.g., location, probability of snake interaction).
Chapter 18 Biotoxins 105

Treatment. Recommended field management is primarily foreign protein), and delayed serum sickness (rare). Anaphy-
rapid transport to veterinary care. The use of a compression lactoid reactions should be treated by stopping the infusion
bandage around and over the bite site is advocated in Elapid of antivenin, administering diphenhydramine, waiting 5 min-
bites in other countries. This method of first aid is often utes, and then restarting the antivenin infusion at a slower
precluded in veterinary patients with their proclivity for rate. If delayed serum sickness occurs 1 to 2 weeks after
receiving bites to the head. The key to medical management infusion, it can be treated with corticosteroids and anti-
of coral snake envenomations is to be aware that onset of histamines. Anaphylaxis should be treated with intravenous
clinical signs may be delayed 12 hours. The primary medical fluids for volume support and epinephrine.
goal with a coral snakebite victim is to institute therapy If antivenin is not available or its administration is delayed
before the onset of clinical signs if possible. for a significant time period, respiratory support may be
On arrival at the veterinary facility, the patient should have needed. Patients can be placed on a ventilator until the
pretreatment blood samples collected and evaluated respiratory effect of the venom is cleared, but this may
including a complete blood count and serum chemistries to require 48 to 72 hours or longer.11
establish a baseline and identify underlying disease proc- Broad-spectrum antibiotics are generally recommended in
esses. Red blood cells should be examined for alterations in veterinary patients.12,13 Corticosteroid use is unjustified in the
morphology that might be indicative of envenomation. The treatment of coral snake envenomations.
patient should be hospitalized for observation for a Treatment of Sonoran coral snake envenomations is
minimum of 24 hours. In anticipation of progression of the limited to providing adequate supportive care and respond-
envenomation syndrome, the clinician should be prepared to ing to clinical signs as they appear.14,15
respond to possible respiratory collapse, dysphagia, and
aspiration pneumonia. Often this requires transporting the Prognosis. The prognosis is fairly good with early medical
victim to a 24-hour intensive care facility with the capacity for intervention. Patients sometimes need prolonged supportive
vigilant observation and ability to supply ventilatory support. care, and complete resolution of neurologic signs can take
The only definitive treatment for coral snake envenoma- months. The major complication is aspiration pneumonia,
tion is the use of specific antivenin. Antivenin (M. fulvius, which worsens the prognosis.
equine origin) is manufactured by Wyeth Laboratories of
Marietta, PA, and is effective against the venom of all coral LIZARDS
snakes in North America except the Sonoran coral snake
(Micruroides euryxanthus).10 Antivenin can block further Source. Two thousand species of lizards exist, but only two
action of venom but is less effective against venom are venomous. The North American continent is home to the
components already attached to receptor sites. Early only poisonous lizards in the world. Both are members of the
administration of the antivenin is important for maximum genus Heloderma, which comprises two species and five
effectiveness; clinical signs can progress rapidly and are subspecies. The Gila monsters (Heloderma suspectum) are
difficult to reverse after they manifest. found in Arizona, parts of New Mexico, southern Utah, parts
Antivenin is reconstituted with the provided sterile diluent; of Nevada, and portions of southern California. In Mexico,
it can be swirled but should not be shaken. Warming the they are found in the state of Sonora west to the Gulf of
diluent to body temperature facilitates the reconstituting Mexico. The other, larger lizard is the Mexican beaded lizard
process, which usually takes 10 to 15 minutes. The antivenin (Heloderma horridum), which inhabits parts of Mexico and
should only be administered intravenously; this can be Guatemala.1
facilitated by mixing the reconstituted antivenin in crystalloid These lizards are large (maximum size Gila monster is
fluids at a rate of one vial to 100 to 250 ml of fluid 55 cm; Mexican beaded lizard is larger) and stout bodied.
(depending on patient size). Administration should be slow The snout is rounded, the muzzle is flat and large, and the
initially, and the patient should be monitored for allergic mandibles are heavily muscled. They generally are slow
reactions such as nausea, hyperemia of the pinna, fluffing moving and lethargic but can strike rapidly and aggressively
of the tail hair, and pruritus. If no reaction occurs within the when disturbed. They have thick, beadlike scales over their
first 5 minutes then the infusion rate can be increased to bodies. Gila monsters are colorful with an orange-yellow to
allow the entire dose to be given over a 30-minute period. pink background, a black banded tail, and a dark, reticular
Multiple vials may be necessary; smaller patients often body pattern. Mexican beaded lizards are dark brown or
require higher dosages and progression of the envenomation black and are less regularly banded.
syndrome is the indicator for additional administration.5 A The lizards generally inhabit desertlike environments,
single vial binds 2 mg of coral snake venom; a large coral living around small shrubs, cacti, and rocks. In the cooler
snake could deliver a venom load of 20 mg. times of the year, the lizards are diurnal, but they are noc-
Antivenin contains equine antiglobin IgG (T) and a turnal during the hotter summer months. They hunt in
significant amount of other proteins; approximately 50% of burrows or protected shady areas looking for their pri-
the final product is equine albumin. The veterinarian should mary food sources including bird eggs, young birds, and
be prepared to respond to an allergic reaction caused by the mammals.
extraneous protein content of this product. Allergic reactions Unlike other venomous reptiles, these lizards use their
to the antivenin can be exhibited in one of three forms: true venom for defensive purposes only. They do not have the
anaphylaxis (which is rare), complement-mediated anaphy- ability to inject their venom, but rather infuse the venom as
lactoid (more common secondary to rapid administration of they bite, holding on tenaciously and chewing to allow the
106 PART THREE Classes of Toxicants

venom to mix with the saliva into the wound. The venom is Lesions. The bite wound is the only apparent lesion.
released from two venom glands on the lower jaw, onto the
gums, and then flows up the grooved teeth by capillary Treatment. It is not uncommon for the patient to be
action.2 The teeth are extremely sharp, arch backward, and presented for veterinary care with the lizard still attached.
are fragile, often breaking off in the bite wound. Because of There are several methods for extracting the lizard, but prying
the method of venom delivery, the severity of the envenoma- the mouth open with some instrument is recommended.
tion is directly related to the duration of the bite. The lizards Victims should be hospitalized for a few hours to monitor for
are so pugnacious that often the victim is presented for progression of the envenomation syndrome. No specific
veterinary care with the lizard still attached. antivenin is available.
Treatment is largely supportive. Intravenous fluid adminis-
Mechanism of Action. The venom is a mixture of tration for volume support may be necessary to treat
biologically active proteins. Heloderma venoms do not have systemic hypotension. Pain control may be achieved with
neurotoxins and generally do not affect coagulation. The narcotics or fentanyl drip. Nonsteroidal antiinflammatory
venom contains multiple proteins, including an extremely drugs may not be aggressive enough to control pain and
active kallikrein, arginine ester hydrolase, phospholipase A2, might affect coagulation. The wound should be irrigated with
very active hyaluronidase, gilatoxin, helothermine, and lidocaine and, using a 25-gauge needle, probed for broken
helospectin.3,4 lizard teeth. Broad-spectrum antibiotics are indicated to
Kallikrein releases bradykinins, inducing pain and hypo- combat secondary infection.
tension. Gilatoxin is a glycoprotein with a lethal dose
50 (LD50) similar to the crude venom itself. Another venom Prognosis. As a general rule, the prognosis is good;
component is arginine ester hydrolase, which hydrolyzes amino however, fatalities do occur in smaller animals such as dogs
acid esters. One of these esters can cause massive hemorrhage and cats. The single largest predictor of the prognosis is the
experimentally in several organs of laboratory animals, but this duration of the bite. The longer the bite, the more venom
hemorrhage has not been seen in clinical cases. Phospholipase delivered, thereby worsening the prognosis. Patients with
A2 is present and has more than 50% homology with bee underlying cardiac or pulmonary conditions are at higher risk
venom phospholipase. Helodermin and helospectin are pep- of negative outcomes from venomous lizard bites.
tides similar to mammalian vasoactive intestinal peptides.
Helothermine is found in the Mexican beaded lizard, causing Prevention and Control. These lizards are federally pro-
hypothermia, lethargy, and rear limb weakness in mice.3,4 tected; therefore, controlling domestic animals is the best
Hyaluronidase is prominent in this venom and very active. prevention.
Hyaluronidase is called the spreading factor because of its
ability to break down connective tissue attachments by PIT VIPERS
cleaving hyaluronic acid, thus allowing the penetration of the
venom components deeper into the victim’s tissues.5 Synonyms. The pit vipers belong to one of three genera:
Crotalus with at least 26 subspecies of rattlesnakes; Sistrurus
Toxicity and Risk Factors. The LD50 in mice ranges from with three subspecies of pygmy rattlesnakes (S. miliaris)
0.4 to 1.4 mg/kg injected subcuticularly and 0.4 to and three subspecies of massassauga (S. catenatus); and
2.7 mg/kg injected intravenously. The minimal toxic dose Agkistrodon with three subspecies of water moccasins
calculated for humans has been estimated at 8 mg of venom or cottonmouths (A. piscivorus) and five subspecies of
(dry weight).6 The venom yield of a Gila monster is 15 to copperheads (A. contortrix).
20 mg dry weight; however, the venom delivery system of
the lizard is poor. The toxic dose for dogs and cats is Source. Identification of pit vipers can be made by their
unknown. I am aware of fatalities in two dogs. characteristic morphologic traits. These snakes have elliptical
pupils, bilateral heat sensing “pits” between the eye and
Clinical Signs. The bite site is extremely painful. Intense pain nostril, a single row of subcaudal scales distal to the anal
usually reaches its peak by one hour after the bite and often plate, triangular shaped heads, and retractable front fangs.
persists 24 hours. There can be significant bleeding from the The rattlesnakes have keratin rattles on the caudal end of
bite wound secondary to multiple lacerations from the sharp their tails; however, they do not always rattle before striking.
teeth, which often break off in the wound. The area around the The pit viper’s heat-sensing pit can sense a temperature
bite site can become edematous. Regional tenderness and change of 0.003° Celsius at a distance of more than 12
lymphadenitis may occur. Hypotension and tachycardia can inches.
occur with resultant weakness. Feline victims can exhibit The majority of snakebites are inflicted by snakes less than
tachypnea, tachycardia, and vomiting, most likely the result of 20 inches in length. The snakes are heavy bodied and
pain. Muscle fasciculations can occur regionally. Tissue necrosis muscular, which allows them to strike up to one half the
is rare, but secondary infection can be a sequela, particularly if length of their body at a speed of 8 feet per second. The
broken teeth are embedded in the wound. pit vipers deliver their venom by rotating the retractable
front fangs downward and stabbing forward. Muscular
Clinical Pathology. Clinical laboratory values are generally contractions of the venom glands then force the venom
within normal limits. Occasionally a stress leukocytosis through the hollow fangs and into the victim. The snake,
develops. through this muscular activity, can control the amount of
Chapter 18 Biotoxins 107

venom it injects. A “dry” bite in which no venom is injected of venom-induced thrombocytopenia in humans not
occurs in approximately 25% of strikes.1,2 receiving antivenin is approximately 80 hours.
Every state in the United States, except Hawaii, Maine, and
Alaska, is home to at least one species of pit viper. Approx- Mechanism of Action. The primary purpose of pit viper
imately 8000 pit viper bites occur annually in people in the venom is to immobilize prey and predigest victim’s tissues.
United States. Most of the bites (5000) are inflicted by The enzymatic fraction of the venom breaks down connective
copperheads, which live in close association to human tissue.2-4 Hyaluronidase is called the spreading factor
habitation throughout the southeastern United States. The because it cleaves hyaluronic acid in collagen, allowing rapid
venom potency of copperheads is less than that of the rattle- penetration of the other venom components into the victim’s
snakes.1 The water moccasins (cottonmouths), also south- tissues.3 Myotoxins destroy muscle tissue, sometimes
eastern inhabitants, are pugnacious and have a reputation incurring permanent damage.6 The lower weight myotoxins
for being somewhat territorial and aggressive. act by opening sodium channels through the muscle cellular
Pit viper bites account for 99% of all the snakebites to membrane with the resultant destruction of the muscle cell.5
animals in North America. The true incidence of venomous Phospholipase A can cause the rupture of myofibrils by
snakebites is unknown, but I estimate that approximately inducing hypercontraction of the plasma membrane.5
150,000 cats and dogs are bitten annually in the United The venoms often contain multiple hemorrhagic toxins
States. The incidence in livestock has not been estimated. that affect the coagulation ability of the victim in many ways.
Bites are more common in hotter summer months when the Both hypercoagulation and hypocoagulation are possible,
snakes are more active and venom yields are increased. depending on the venom involved.8 Additionally, some
venoms do not specifically affect clotting but induce
Toxicokinetics. The venom contains multiple toxins that hyperfibrinolysis and dissolve clots as they form. True
act on the victim’s various tissues and are metabolized with disseminated intravascular coagulation is possible but rare.20
their metabolites interacting with each other. The net effect is Some venoms, such as those of the western diamondback
a complex toxic stew, varying with each envenomation. rattlesnake younger than the age of 30 days, usually
Toxicokinetics of individual venom fractions have not been completely defibrinate their human victims.
fully elucidated. More than 50 venom components have Cardiotoxic components have been identified as myo-
been identified and any single venom contains a mini- cardial depressor factors in the venom of western and
mum of 10 (Table 18-3). The venoms contain several non- eastern diamondback venom.12 Hypotension nonresponsive
enzymatic polypeptides, the “killing fractions,” which are to intravenous fluid therapy is manifest in only the most
up to 50 times more toxic than the crude venom. severe envenomations.
These fractions are some of the first regenerated after Venom kallikrein-like activity and metalloproteinase (with
envenomation. zinc cofactor) induce marked local pain, tissue necrosis, and
Rattlesnake venom fractions have been identified in the significant systemic hypotension.13-15 A combination of the
victim’s circulation for weeks after envenomation. The nadir aforementioned venom factors and cardiovascular active

TABLE 18-3 Partial List of North American Pit Viper Venom Fractions
Classification Venom Fractions

Enzymes Proteinases, collagenase, proteolytic trypsinlike enzyme, arginine ester hydrolase, and hyaluronadases.2–4

Myotoxins Phospholipase A2, phospholipase B, phosphodiesterase, and L-amino acid oxidase. Also the low-molecular-weight
proteins crotamine and myotoxin a.5–7

Hemorrhagic/coagulation Fibrinogenases, plasminogen activators, platelet aggregators/inhibitors, thrombinlike venom enzymes, and protein C
activator.5,8

Neurotoxins Generally presynaptic: phospholipase A2, and Mojave toxin.9–11

Cardiotoxins Myocardial depressant factor.12

Cardiovascular Kallikrein-like activity and metalloproteinase with zinc cofactor.13–15

Lipids Caprylic, capric, lauric, linoleic, myristic, oleic, palmitic, palmitoleic, stearic, and arachidonic acids.16

Nucleosides/nucleotides NAD nucleotidase17

Organic acids Citrate18

Cations Zinc17,19
108 PART THREE Classes of Toxicants

components, including those that markedly affect clotting, Toxicity and Risk Factors. The toxicity and risk factors
are responsible for the primary systemic pathophysiologic depend on the snake and the victim. The snake factors
clinical manifestation of hypotension. All these components include species of snake, size of the snake, time of year,
can combine to produce a profound hypotension. For exam- attitude of snake (affecting volume of venom injected, e.g.,
ple, a 2-cm increase in the circumferential measurement of defensive vs. offensive strike), age of the snake, and time
the swelling in an envenomated human thigh can remove up since last bite (quantity of venom fractions reconstituted).
to one third of the body’s circulating fluid volume and Victim-related factors are species (natural immunity), size,
thereby compound the hypotensive event. Differing amounts bite site, time elapsed from bite to medical care, amount
of metalloproteinase inhibitors are the primary reason for of physical activity after the bite, preexisting medical
varying mammalian resistance to pit viper venoms.21 conditions, and medications.
The nonenzymatic polypeptides in the venom include the Studies over the years have given a wide range of LD50s
“killing fraction,” which is more than 50 times more toxic and venom yields that highlight the individual variations
than the crude venom. The lipid fraction in cobra venoms in these levels regardless of snake species. Therefore,
potentiates the toxicity by a factor of 50%; however, their Table 18-5 is primarily useful for comparisons of toxicity
impact in pit viper venoms has not been totally elucidated.16 between species. How dangerous a particular species is
Some pit viper venoms include potent presynaptic relates not only to the toxicity of the venom but also the total
neurotoxins, whereas other pit vipers only have neurotoxic venom yield available. The analysis is additionally affected by
venoms (Table 18-4).9-11 These toxins act triphasically by both the circumstances of the bite situation (offensive vs.
binding to the presynaptic nerve membrane, inhibiting defensive) and the proclivity of that particular snake species
neurotransmitter release. Then phospholipase increases the to bite and inject venom. Some snake species (e.g., eastern
release of neurotransmitter and a final block occurs when and western diamondback rattlesnakes) are aggressive and
the transmitter is depleted.5 strike readily, whereas other species (e.g., speckled
In general, three venom types in North American rattlesnake) are docile and need a higher level of stimulation
rattlesnakes have been defined. The classic diamondback to be induced to bite and envenomate.
rattlesnake venom causes marked tissue destruction, coag-
ulopathy, and hypotension. Mojave A rattlesnake venom Clinical Signs. The initial clinical sign is usually marked
causes virtually no tissue destruction or coagulation defects, regional swelling resulting from increased vascular perme-
but it induces a severe neurotoxicosis. The third venom class ability. Ecchymosis and petechiation may become evident,
is an intergrade found in multiple species of rattlesnakes that and discoloration of the skin often occurs within hours of the
have interbred, resulting in venoms that contain both the bite if coagulation factors are affected. The intensity of pain
neurotoxins and the classic venom components (e.g., Mojave at the bite site is significant and the onset of pain is almost
A/B and tiger rattlesnakes). immediate.
Venomous snakebite is not always easy to diagnose,
TABLE 18-4 Rattlesnake Species with Neurotoxic Venom particularly when swelling and a heavy haircoat obscure
puncture wounds. Clipping the hair in the region of an
Latin Name Common Name unknown swelling often helps in locating the bite site.
Usually, painful, bleeding puncture wounds can be found
Crotalus horridius atricaudatus Canebreak rattlesnake
consistent with a pit viper bite. Single or multiple punctures
may be present from an individual bite or the victim may
Crotalus lepidus klauberi Banded rock rattlesnake
have received multiple bites.
The severity of the envenomation cannot be judged solely
Crotalus mitchellii mitchellii San Lucan speckled rattlesnake
by assessing the local tissue response. Life-threatening enveno-
mations with severe systemic manifestations can occur with
Crotalus tigris Tiger rattlesnake
little to no local tissue pathology. As a general rule, the severity
of systemic clinical signs is most severe with the rattlesnakes,
Crotalus vegrandis Uracoan rattlesnake
followed by water moccasins and copperheads. In species with
only neurotoxic venom, the signs may be limited to puncture
Crotalus durissus durissus Central American rattlesnake
wounds and neurologic deficits.
Crotalus durissus terrificus South American rattlesnake
TABLE 18-5 Approximate LD50 and Venom Yields of Selected North
Crotalus viridis abyssus Grand Canyon rattlesnake American Pit Vipers
Snake LD50 Venom Yield (mg)
Crotalus viridis concolor Midget faded rattlesnake
Eastern diamondback (C. adamanteus) 1.68 590
Crotalus scutulatus scutulatus (A) Mojave A rattlesnake Western diamondback (C. atrox) 2.18 500
Timber rattlesnake (C. horridus) 2.69 140
Crotalus scutulatus salvini Huamantlan rattlesnake Copperhead (A. contortrix) 10.92 60
Cottonmouth (A. piscivorus) 4.17 130
Sistrurus catenatus catenatus Eastern massasauga Mojave A rattlesnake (C. scutulatus) 0.23 113
Data from reference 22.
Chapter 18 Biotoxins 109

Bite site has a significant part to play in the severity of a In horses, the bites most frequently occur on the nose,
given bite, primarily because of regional differences in and marked tissue necrosis is possible. Cattle are often bitten
systemic venom uptake. Most bites in dogs are to the head on the muzzle or tongue. Tissue necrosis and secondary
or front legs. As local swelling increases, alterations in infection is a major problem in large animals that have not
regional vascular supply begin to slow venom uptake. had a bite identified until several days after envenomation.
Swelling from bites to a horse’s muzzle can occlude the One study implies persistent cardiac damage in prairie
nares and the victim can die of the subsequent anoxia. rattlesnake (C. viridis viridis) envenomated horses.29
Envenomations to the body wall allow venom to be
absorbed more rapidly. Bites to the tongue are equivalent to Diagnostic Testing. A non-EDTA blood smear or one drop
intravascular envenomations, usually resulting in rapid and of blood mixed with a drop of saline should be examined
devastating results. microscopically, looking for evidence of echinocytosis, which
Onset of significant clinical signs may be delayed for has been reported in many pit viper envenomations during
several hours. This phenomenon cannot be overemphasized. the first 12 hours.30 The presence of echinocytosis greatly
One report of a human victim describes resolution of mild increases the probability that the victim has been en-
swelling over 3 hours, at which time he was discharged. venomated.31 However, a negative test does not preclude
The patient returned to the emergency department 12 hours envenomation.
later with severe pain, swelling, and a marked coagulopathy.23
Traditionally, 40% of severe human envenomations are Treatment. Many first aid measures have been advocated
graded as mild to nonenvenomating at some point in the for early field treatment of pit viper bites, but none have
envenomation syndrome.24 Twenty-five percent of all rattle- proven to lessen mortality or morbidity.32 In particular, cold
snake bites are nonenvenomating, and another 20% are packs, ice, tourniquets, incision and suction, electroshock,
mild envenomations.1,25 and alcohol are to be avoided. Additionally, a significant
Marked hypotension often develops early, but can be period of time can be consumed trying to use question-
delayed. Swelling is progressive for up to 36 hours after able first aid measures when time would be better spent
envenomation. Additional clinical signs can include tachy- transporting the victim to a veterinary facility where specific
cardia, shallow respirations, lethargy, nausea, obtundation, medical therapy can be instituted. The key principle in first
muscle fasciculations, increased salivation, and enlarged, aid is to do no additional harm. Therefore, the victim should
painful regional lymph nodes. be kept calm, the bitten extremity should be maintained
below heart level if possible, and the victim should be rapidly
Clinical Pathology. Initial diagnostic testing should transported to a veterinary facility.
include a baseline complete blood count with serum Circumferential measurements above, below, and at the
chemistries to identify not only the possible effects of the bite site should be measured hourly for the first 6 hours and
venom but also highlight any underlying disease processes in then as indicated. This allows the clinician to objectively
the patient. Repeated laboratory testing at 6, 12, and monitor regional swelling and the progression of the
24 hours is recommended. Early high elevations of creatine envenomation locally. Temperature, respiration rate, pulse,
phosphokinase (more than 1000 on entry) can be an indi- and blood pressure should be monitored hourly for the first
cator of severe envenomation. few hours after admission and then as dictated by the
Coagulation parameters including activated partial throm- progression or resolution of the envenomation.
boplastin time, prothrombin time, fibrinogen, fibrin split The use of a severity score system is helpful in monitoring
products, and platelet counts should be monitored at base- the severity of the snakebite, the progression of the
line, 6, 12, and 24 hours or as indicated by the progression envenomation, and the success of the treatment (Box 18-1).
of the envenomation syndrome. This system has been validated in the human model and has
Urinalysis should be performed to examine for signs of been used successfully in veterinary cases to allow an
hematuria or rhabdomyolysis. This should be repeated at 6 objective systemic evaluation of the patient.33 I am aware of
and 12 hours, or more often if the case dictates. several fatal envenomations that had entry severity scores as
low as 2. Therefore, it is important to view these enveno-
Lesions. The characteristics of the local lesions depend on mations as a progressive syndrome. In general, severity score
several factors, such as the species of snake, amount of sheets should be completed at baseline (entry) and at 6, 12,
venom injected, bite site, and time to medical care. Water and 24 hours after hospital admission.
moccasin bites create significant tissue necrosis. On the General medical management of pit viper envenomations
other hand, multiple species of rattlesnakes have sub- should combat specific venom-induced pathophysiology.
populations that have a neurotoxin (Mojave A) in their Therefore, intravenous crystalloid fluid therapy should be
venom, which results in only a local lesion from the puncture started to combat the third spacing of fluids and the
wounds.26-28 resultant hypovolemic crisis.34 The primary cause of death is
Tissue necrosis and sloughing in the region of the bite site cardiovascular collapse resulting from hypovolemic shock.
can be severe, particularly in areas with minimal muscle Broad-spectrum antibiotics are not routinely recom-
mass such as over the carpus. Systemic lesions often revolve mended in human snakebite victims. However, I recommend
around the primary shock organ of the victim species. Feline their use in veterinary patients, particularly in species highly
patients can have severe pulmonary hemorrhage. In dogs, susceptible to clostridial infections. One should avoid
the hepatosplenic vascular bed is primarily affected. selecting antibiotics that may negatively affect renal function.
110 PART THREE Classes of Toxicants

Coagulopathies generally respond well to intravenous

BOX
SNAKEBITE SEVERITY SCORE antivenin administration. Resolution followed by recurrence
18-1 of thrombocytopenia may occur in up to 30% of severely
Pulmonary System thrombocytopenic patients.35 However, the recurrent throm-
0 Signs within normal limits bocytopenia is usually less severe than the baseline level and
1 Minimal: slight dyspnea may not require additional antivenin administration.
2 Moderate: respiratory compromise, tachypnea, use of Topical application of dimethyl sulfoxide (DMSO) to the
accessory muscles bite site in envenomated horses increases the speed of
3 Severe: cyanosis, air hunger, extreme tachypnea, respiratory venom uptake systemically and is not recommended.
insufficiency or respiratory arrest from any cause Corticosteroids should not be used and have no place in the
treatment of venomous snakebites (Glen J: Veterans Admin-
Cardiovascular System istration Medical Center Venom Research Laboratories, per-
0 Signs within normal limits sonal communication, 1990).36-51 Some studies revealed
1 Minimal: tachycardia, general weakness, benign dysrhythmia, increases in mortality with the use of corticosteroids.52,53 They
hypertension can be used in the treatment of allergic reactions to antivenin if
2 Moderate: tachycardia, hypotension (but tarsal pulse still it occurs.
palpable) Administration of diphenhydramine (10 to 25 mg SC or
3 Severe: extreme tachycardia, hypotension (nonpalpable tarsal IV) aids in calming fractious or painful animals and may be
pulse or systolic blood pressure <80 mm Hg), malignant used to pretreat the patient against possible allergic
dysrhythmia or cardiac arrest reactions to antivenin. However, antihistamines have no
direct effect against the snake venom or its action.
Local Wound
The only proven treatment against pit viper envenomation
0 Signs within normal limits
is intravenous administration of antivenin, which stops
1 Minimal: pain, swelling, ecchymosis, erythema limited to bite
progression of swelling, reverses coagulopathy, reverses
site
thrombocytopenia, and improves muscle strength in patients
2 Moderate: pain, swelling, ecchymosis, erythema involves less
with weakness and paralysis.54-60 Thrombocytopenia induced
than half of extremity and may be spreading slowly
by Crotalus horridus horridus venom may not reliably
3 Severe: pain, swelling, ecchymosis, erythema involves most or
respond to antivenin because of the presence of a novel
all of one extremity and is spreading rapidly
platelet-aggregating protein in the venom.
4 Very severe: pain, swelling, ecchymosis, erythema extends
Two antivenins are available in North America for use against
beyond affected extremity, or significant tissue slough
pit viper venoms. The only licensed veterinary antivenin product
Gastrointestinal System is produced and distributed by Fort Dodge Laboratories, Ames,
0 Signs within normal limits Iowa (Antivenin [Crotalidae] Polyvalent—equine origin). Approx-
1 Minimal: abdominal pain, tenesmus imately 50% of the total protein in each vial is equine albumin
2 Moderate: vomiting, diarrhea and severe allergic reactions are possible; however, true
3 Severe: repetitive vomiting, diarrhea, or hematemesis anaphylaxis occurs in less than 1% of all patients receiving this
product. The immunizing snake venoms present in this anti-
Hematologic System venin are eastern diamondback rattlesnake (C. adamanteus),
0 Signs within normal limits western diamondback rattlesnake (C. atrox), fer-de-lance (Bo-
1 Minimal: coagulation parameters slightly abnormal, PT <20 sec, throps atrox), and the South American rattlesnake (C. durissus
PTT <50 sec, platelets 100,000-150,000/mm3 terifficus). This antivenin is the least effective against Southern
2 Moderate: coagulation parameters abnormal, PT 20-50 sec, Pacific rattlesnake (Crotalus viridis helleri) venom.
PTT 50-75 sec, platelets 50,000-100,000/mm3 The other antivenin available in the United States is
3 Severe: coagulation parameters abnormal, PT 50-100 sec, manufactured by Protherics, Nashville, Tennessee (CroFab
PTT 75-100 sec, platelets 20,000-50,000/mm3 [Crotalidae polyvalent immune Fab] ovine origin). This product
4 Very severe: coagulation parameters markedly abnormal with is currently approved by the Food and Drug Administration for
bleeding present or the threat of spontaneous bleeding, human use and is in the final stage of U.S. Department of
including PT unmeasurable, PTT unmeasurable, platelets Agriculture approval for the veterinary market. The immunizing
< 20,000/mm3. snakes are all indigenous to North America: eastern and
western diamondback rattlesnakes (C. adamanteus and C.
Central Nervous System
atrox, respectively), water moccasin (A. piscivorus), and Mojave
0 Signs within normal limits
A rattlesnake (C. scutulatus scutulatus). Because the purifi-
1 Minimal: apprehension
cation process removes extraneous protein and the Fc antibody
2 Moderate: chills, weakness, faintness, ataxia
fragments, the risk of anaphylaxis or serious allergic reactions is
3 Severe: lethargy, seizures, coma
minimized (although not completely removed). Large-scale
Total Score Possible 0 to 20
clinical trials of CroFab have been completed in dogs with
results comparable to those obtained in human snakebite
Hypoalbuminemia can be treated with plasma infusion; victims. This antivenin has proven its effectiveness against a
however, coagulopathies are particularly difficult to treat with wide range of pit viper venoms and is capable of binding
blood products that are rapidly consumed by the venom. Southern Pacific rattlesnake (C. viridis helleri) venom.60
Chapter 18 Biotoxins 111

Regardless of which antivenin is used, the earlier it is and the murderer. This spider earned its name as a result of
administered, the more effective its action. Epinephrine the female behavior in which she consumes her mate.
should be available and the clinician should be prepared to
respond to an anaphylactic event. More commonly, par- Sources. The characteristic red hourglass-shaped marking
ticularly with the Fort Dodge antivenin, anaphylactoid is found on the ventral abdomen of these spiders. This is not
reactions occur. Discontinuing the infusion of antivenin, to be confused with nonvenomous species that use mimicry
administering diphenhydramine, waiting 5 minutes, and then with an orange or red hourglass on the dorsal aspect of their
restarting the antivenin infusion at a slower rate usually abdomen. The black widow spiders are generally shy and are
solves this complication. Delayed serum sickness can occur found in garages or outside in brush or wood piles. The
in 7 to 10 days, but is rare in dogs and cats. The incidence of spiders generally envenomate if their web or egg sack is
delayed serum sickness is more prevalent in the equine- disturbed. The female of the species causes envenomation
origin, multiple-protein antivenin (Fort Dodge); it was not because the males have small jaws and are unable to
identified in a CroFab antivenin trial of 115 dogs. penetrate the skin.
Infusion of antivenin can be facilitated by mixing each vial
of antivenin with approximately 200 ml of crystalloid fluid Toxicokinetics. The venom of the black widow is potent,
(limited by the victim’s body weight). Infusion rates are much more so than the venomous snakes. It is thought that
much easier to control when mixed in this manner, and the picomolar concentrations of the venom can result in clinical
patient can be monitored for any possible adverse reaction intoxication.1
(e.g., redness of pinna, fluffing of the tail, nausea).
The typical dose of antivenin is a single vial. Critics of Mechanism of Action. The toxin primarily responsible for
antivenin use have claimed that because the dosage clinical signs is generally thought to be α-latrotoxin, which is
required in a human averages 12 vials, that a single vial in a a labile, large (120 to 130 kD) protein neurotoxin. 2 The
dog would be insignificant to the treatment. However, results three-dimensional structure has recently been identified as a
from clinical trials with the CroFab antivenin revealed the tetramer of molecules in the presence of cations (calcium
same 6- and 12-hour severity scores with a single vial as and magnesium).3 The toxin binds to at least two different
their human counterparts averaging 13 vials.61 The difference neuronal receptors: neurexins and CIRL (Ca++-independent
in the effective dosage is due to the natural immunity of receptor for α-latrotoxin) also known as latrophilin.4,5 Binding
various species, all having different levels of antimetallo- of α-latrotoxin to these receptors serves to recruit the
proteinases. For example, wood rats (Neotoma micropus) are toxin to the synapse, specifically the presynaptic neuronal
120 times more refractory to the pit viper venoms than membrane,4 which leads to the release of neurotransmit-
are Balb/C mice.20 Occasionally multiple vials of antivenin ters by calcium-dependent (catecholamines) and calcium-
are required, and repeat administration may be indicated independent (acetylcholine, GABA, glutamate) mechanisms.4
depending on monitoring of deteriorating severity scores, In the presynaptic nerve terminals, the α-latrotoxin per-
clinical signs, or serial laboratory values. forms several functions. Dimers of the toxin form tetramers
Antivenin should only be administered intravenously in the presence of divalent cations with the newly formed
because intramuscular or bite site injection delays uptake of tetramers binding to the CIRL receptor, which is coupled to a
the antivenin by several hours.62 If coagulation parameters G protein. The binding CIRL receptor protein is calcium
continue to deteriorate (even as long as 72 hours after independent and activates phospholipase C, leading to
envenomation), venom components are still active and inositol triphosphate–induced calcium mobilization.1 The α-
antivenin should be administered. Antivenin cannot correct latrotoxin also binds to neurexin receptor proteins when in
necrotic tissue damaged by venom; therefore, early the presence of calcium. The neurexin receptor proteins then
administration is recommended. bind to membrane-bound kinases that are involved in
synaptic vesicle trafficking. Furthermore, the α-latrotoxin
Prognosis. With early medical intervention, most snake- tetramer forms a stable transmembrane pore that allows
bitten dogs and cats survive. Large animals often survive the calcium influx into the presynaptic nerve terminal.1,2 These
initial venom effect; however, by the time they are recog- actions of α-latrotoxin are not exclusive; they all work in
nized as having been envenomated they are at risk of death concert to increase the movement of neurotransmitter-laden
from secondary tissue damage and infection. synaptic vesicles to the membrane for exocytosis.

Toxicity and Risk Factors. All mammalian species are

susceptible to α-latrotoxin; however, limited literature reports
SPIDERS of clinical envenomation are found in species other than
dogs, cats, and humans. Cats are more sensitive to
envenomation.6
Joseph D. Roder
Clinical Signs. The clinical signs associated with black
BLACK WIDOW widow spider envenomation are generally related to the
nervous or muscular systems. The signs include muscle
Synonyms. The black widow spider (Lactrodectus mactans) fasciculation and rigidity, abdominal pain, ataxia, and flaccid
is also known as the brown widow, the red-legged spider, paralysis. This may progress to an ascending paralysis that
112 PART THREE Classes of Toxicants

involves the muscles of respiration. If the respiratory mus- envenomation, 40 µg of venom-proteins are introduced into
cles are involved, the animal exhibits dyspnea and altered the victim.2
breathing mechanics.
Mechanism of Action. The venom of the brown recluse
Clinical Pathology. Elevation of enzymes indicating skeletal spider is a complex mixture of enzymes. The component of
muscle damage (creatine kinase, aspartate transaminase) the venom most commonly associated with dermal necrosis
may be noted in envenomated animals. is a 32-kD protein, sphingomyelinase.1,3 This component of
the venom interacts with the plasma membrane of a variety
Treatment. Supportive and symptomatic therapy is essential of cells: endothelium, erythrocytes, and platelets. The protein
initially to stabilize the patient. The therapeutic plan should causes a disruption of these membranes with resulting
include respiratory and cardiovascular monitoring as well as microvascular damage and platelet aggregation. Sphingo-
pain management. In humans, pain management is a key myelinase D may also act as a chemotactic factor for neutro-
element in the management of Latrodectus envenomation. phils, resulting in recruitment of inflammatory cells to the
Opioids (fentanyl) or benzodiazepines (diazepam) have wound. The influx of neutrophils with accompanying platelet
been recommended for the control of pain. aggregation results in intravascular coagulation in the capil-
Specific therapy for black widow envenomation includes laries surrounding the wound and leads to dermal necrosis.
calcium gluconate to reverse the signs of muscle fasciculation Additionally, recent in vitro and in vivo studies of the
and weakness. A 10% calcium gluconate solution is given at a venom of Loxosceles intermedia have shown degradation of
dose of 5 to 15 ml for cats and 10 to 30 ml for dogs. basement membrane components, specifically heparan
A specific antidote for black widow evenomation is sulfate proteoglycan and laminin-enactin, of endothelial
available: Antivenin (Latrodectus mactans), Equine Origin, cells.2,4 This action of the venom was noted in the absence of
Merck & Co., Inc. This antivenin may be obtained from most neutrophils and may cause an altered organization and
hospital pharmacies or located through a regional poison adhesion of endothelial cells.2,4 Other components of venom
control center. If the clinician believes the patient’s condition include hyaluronidase for venom spreading, lipase, alkaline
warrants the use of antivenin, generally a single vial is phosphatase, esterases, and proteases.1 In addition to the
required for a cat or dog. An intradermal injection of the components of the venom previously described, the fangs of
antivenin is recommended before administration to deter- the brown spider may introduce clostridial organisms into
mine whether the patient is hypersensitive to the product. the wound.5 There may be some synergistic effect of the
The antivenin is diluted in normal saline (10 to 50 ml) and is venom with the toxins liberated by the growing clostridial
given intravenously over 15 minutes.6 organisms.5

Prognosis. Most animals respond to supportive and symp- Toxicity and Risk Factors. All mammalian species are
tomatic therapy and return to normal within a few days. In susceptible to the venom of brown recluse spiders. Dogs and
severe clinical cases, complete recovery may take weeks. cats are more likely to come into contact with these spiders
and be presented for veterinary care.
BROWN RECLUSE
Clinical Signs. The clinical signs associated with brown
Limited information is available concerning brown recluse recluse envenomation are grouped into local and systemic
envenomation in veterinary patients. Most of the following signs. The local signs relate to the ability of the venom to
information is derived from information and cases of human cause dermal necrosis. In humans, the dermal lesions de-
envenomation. velop within a few hours to several days after envenomation.1
Rabbit models of envenomation and dermal necrosis are the
Synonyms. The brown recluse spider (Loxosceles spp.) is most commonly referenced animal information in the
also known as the brown spider, fiddleback spider, or violin literature.5 No clinical reports of envenomation in veterinary
spider. patients are in the literature. In humans, the progression of
the dermal lesion generally starts with a central blister at the
Sources. Thirteen different species of Loxosceles are found wound site with surrounding edema and erythema. The lesion
in the United States.1 The most commonly reported species progresses to one with a darkened center and the develop-
associated with toxicosis is Loxosceles reclusa.1 The brown ment of a vesicle. The central area of the wound may become
recluse spider is more commonly found in the southern half necrotic with the development of an eschar.6 In humans, sys-
of the United States. These spiders have a characteristic dark temic signs of envenomation are uncommon: hemolysis,
marking of the dorsal aspect of the cephalothorax that nausea, vomiting, fever, and generalized malaise.6
resembles a violin or fiddle. They have long, thin legs
compared to their body and are reclusive as their name Clinical Pathology. A complete blood count and serum
suggests. They are commonly found in corners, closets, or chemistry evaluation may show evidence of a Coombs-
attics, and envenomation generally occurs when the spider is negative hemolytic anemia.
disturbed or threatened.
Treatment. Most human patients envenomated by the
Toxicokinetics. The venom from a single bite is sufficient brown recluse spider do not require treatment.1 Treatment of
to cause intoxication. It has been estimated that during an brown recluse envenomation is controversial in the human
Chapter 18 Biotoxins 113

literature because there is a lack of well-controlled clinical These changes alter the resting membrane potential of
studies of treatment efficacy. Animals with suspected brown excitable cells resulting in a depressed electrical conduction,
recluse bites should be treated conservatively with general which leads to an inhibition of myocardial conduction and
wound care and observed for any generalized symptoms. A function.
broad-spectrum antibiotic may be indicated because bacteria
may be introduced into the wound by the fangs of the Toxicity and Risk Factors. The toxicity of bufotoxin has
spider.5 been reported to be 100 mg of crude toxin for a dog weigh-
No specific antidote for brown recluse envenomation ing 9 to 14 kg.2 Dogs are the most commonly poisoned
exists. Antivenin therapy is experimental and the antivenin is species.1-3 The risk of intoxication is greater during the spring,
not commercially available. summer, and fall at dusk or dawn or after a rainfall.
Anecdotal treatment for human envenomation includes
dapsone, wound excision, and hyperbaric oxygen therapy. Clinical Signs. Hypersalivation, vomiting, and anxiety are
The rationale for dapsone treatment is that it inhibits the common initial signs in dogs after biting a toad. The majority
influx of neutrophils to the site of envenomation. It is of animals in one study presented with neurologic abnor-
recommended that this drug be used within 36 hours of the malities, including convulsions, ataxia, nystagmus, stupor, or
envenomation. The probable delay in presentation of veter- coma.3 The mucous membranes of the oral cavity may be
inary patients as well as the propensity of dapsone to induce hyperemic.3 The onset of clinical signs is rapid and death
methemoglobinemia would reduce the effectiveness of this may occur 15 minutes after the onset of clinical signs.1
possible therapy. Excision of the wound and hyperbaric
oxygen therapy have not been shown to be reliably effective Diagnostic Testing. The diagnosis of toad intoxication
in controlled experimental settings. In addition to being depends on clinical signs and a history of exposure to toads.
unnecessary, aggressive wound excision may prolong the
healing of the necrotic area. Treatment. Initial treatment of toad intoxication should
focus on decontamination of the oral cavity. The dog’s mouth
Prognosis. In human cases of envenomation, uncompli- should be immediately flushed with copious volumes of
cated dermal necrosis is associated with a good prognosis. running water unless the animal is seizing or unconscious. If
The time for complete healing of the necrotic area of skin the animal presents with seizures, diazepam (0.5 mg/kg IV)
depends on the size of the lesion. In humans, the healing may be administered as an anticonvulsant.3 An initial cardiac
time ranges from 1 to 7 weeks. The prognosis becomes examination should include auscultation, determination of
guarded if systemic signs occur. heart rate, and evaluation of perfusion. If the animal has
arrhythmias or signs of shock, it should be monitored by
electrocardiogram. If bradycardia is noted, the animal may be
treated with IV atropine at 0.02 mg/kg.3 Sustained tachy-
TOADS cardia can be treated with beta-antagonists. Atropinization
should be reserved for animals with marked bradycardia and
not used as a symptomatic treatment for hypersalivation. If
Joseph D. Roder
hyperkalemia is present, treat with an infusion of insulin,
glucose, and sodium bicarbonate to drive potassium back
Synonyms. Bufo marinus (cane or marine toad) and Bufo into cells. Administration of calcium is contraindicated in
alvarius (Colorado River toad) are the most toxic toads in animals suffering from bufotoxicosis.
North America. Digoxin-specific Fab-fragment (Digibind) has been suc-
cessfully used experimentally in mice and clinically in
Sources. These toads are primarily located in Florida, humans.4,5 Even though this antidote has been used for
Texas, Colorado, Arizona, and Hawaii. digoxin toxicosis in a dog, it has not been evaluated in
clinical cases of toad intoxication.6
Toxicokinetics. When these toads are mouthed or bitten
by a dog, the parotid glands located on the toad’s dorsum Prognosis. Most animals recover if treated with early
release toxins that are absorbed via the buccal mucous decontamination and appropriate symptomatic therapy.
membranes of the dog.1 The secretions from these glands
may contain a variety of substances including epinephrine,
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