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UNITED STATES SNAKES CROTALINAE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) This management encompasses Crotalidae species indigenous to the United States.
    B) Please refer to LATIN AMERICAN SNAKES CROTALINAE for information on species indigenous to Mexico and Central and South America.

Specific Substances

    1) Varies See Geographical Location section for more information
    2) Snake Bite Crotalidae
    3) Snake Venom Poisoning, Crotalidae
    4) Snake Venom Poisoning, United States
    5) Snakes, Crotalinae
    6) Rattlesnake (Crotalus)
    7) Rattlesnake antivenom

Available Forms Sources

    A) SOURCES
    1) RELIGIOUS CEREMONIES
    a) SNAKE HANDLERS: In rural Appalachia, a small and rare sect of fundamentalist Christians practices "snake handling" during religious ceremonies in which a snake can be passed amongst the congregation or select members of that church. It is not unusual for a bitten individual to refuse all medical treatment based on their beliefs, and several deaths have been reported. Snakes endemic to this region include: timber rattlesnake, the eastern diamondback rattlesnake, and copperheads.
    1) Three members of 3 different churches in Kentucky died after refusing medical care following rattlesnake envenomation (1 case by a black timber rattlesnake, 2 cases by an unknown rattlesnake). All three individuals were attending religious services when the snake bite occurred, and then were taken to a private residence and died within 16 to 52 hours. Postmortem findings were consistent with envenomation in all cases (Hunsaker et al, 2005).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) BACKGROUND (Classification of species): This topic includes the North American species of Crotalus (rattlesnakes), Agkistrodon (copperhead and cottonmouth snakes) and Sistrurus (Massassauga and pigmy rattlesnakes), which inhabit every state except Maine, Hawaii, and Alaska. Generally, they are found in the wild, although many snakes are kept in captivity in the home, zoos, as part of illicit snake trade, and in some regions of the country for religious ceremonies.
    B) TOXICOLOGY: The venom is a complex mixture of molecules ranging from individual metal ions to complex proteins. The components of the venom can cause local injury (tissue necrosis, vascular damage), coagulopathies (hemolysis, coagulation and fibrinolysis), and systemic effects (myocardial and neuromuscular dysfunction) depending on the specific snake venom. A bite deposits venom intradermally, subcutaneously, less often intramuscularly, or rarely directly into the blood vessel. Venom can alter blood vessel permeability, thereby allowing plasma and red cells to leak into tissues resulting in edema and ecchymosis. The most common effects of Crotalinae venom are hypofibrinogenemia and thrombocytopenia.
    C) EPIDEMIOLOGY: The most common bites are due to copperhead snakes, however most deaths are caused by Eastern and Western diamondback rattlesnakes. Although bites from Crotaline snakes are common in the US, deaths are rare. The majority of Crotaline bites are associated with either mild or moderate outcomes and 25% result in dry bites (no envenomation).
    D) WITH POISONING/EXPOSURE
    1) CLINICAL EFFECTS: The clinical manifestations of an envenomation can be classified in three ways: local, systemic and coagulation abnormalities. The absence of all of the manifestations for a period of 12 hours following a bite indicates a dry bite (no envenomation). A slowly progressing initial presentation is not predictive of a benign or an uneventful course.
    a) LOCAL: Typically includes the presence of one or more fang marks (occasionally only scratches or a small laceration may be present), pain and progressive edema extending from the bite site. Swelling usually appears within minutes after the bite, but may not appear for several hours. In severe cases, edema may progress to involve the entire limb. Edema may continue to progress for several days. Other manifestations include ecchymosis at the site that may progress to involve the limb and hemorrhagic blebs. Although uncommon, compartment syndrome may develop.
    b) COAGULATION: Common effect, but frank bleeding is rare following crotalinae snakebites. Both platelets and the coagulation cascade may be affected; some patients will have abnormalities in only one of these systems. It may develop within minutes to hours. Thrombocytopenia is more common with rattlesnakes.
    c) SYSTEMIC: Early systemic effects of crotaline snakes include: nausea, vomiting, numbness, or tingling of the tongue and mouth, and diarrhea. Symptoms can progress to dizziness, tachycardia, fasciculations, weakness, hypotension, airway compromise, rhabdomyolysis with hyperkalemia, and hemoconcentration.
    2) NO EFFECT: Fang marks present without other symptoms.
    3) MINIMAL: Minor local effects only, without progression of swelling, coagulation, or systemic effects.
    4) MODERATE: Progression of swelling beyond the bite site, moderate coagulation abnormalities, or systemic effects.
    5) SEVERE: Marked progression of the local effects (with blisters, bruising, and necrosis), severe coagulopathy, and systemic effects (tachycardia, hypotension, fasciculations, weakness).
    0.2.3) VITAL SIGNS
    A) Hypotension and shock may develop rapidly in severe envenomation. Severe swelling may cause intravascular volume depletion, particularly in children.
    B) Sudden death following envenomation has occurred.
    0.2.4) HEENT
    A) Facial, lip and tongue swelling may develop after envenomation to an extremity and may cause airway compromise. Coagulopathy may result in epistaxis or bleeding gums. The patient may report unusual tastes and increased or decreased salivation.
    0.2.5) CARDIOVASCULAR
    A) Severe envenomations may result in hypotension and shock.
    0.2.6) RESPIRATORY
    A) Acute respiratory failure and acute lung injury are unusual occurrences seen with severe envenomation.
    0.2.7) NEUROLOGIC
    A) Effects on mental status range from excitation and confusion to obtundation and coma. Mental status is often obscured by concurrent alcohol intoxication. Fasciculation may develop in the tongue, bitten extremity or in severe cases may become generalized. Paresthesias of the face, tongue or extremities are common. Cranial nerve dysfunction and generalized muscle weakness have been reported with Mojave rattlesnake and C. durissus envenomation but are not common.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting and diarrhea may develop early in severe envenomation. Gastrointestinal hemorrhage may develop in patients with coagulopathy or thrombocytopenia.
    0.2.10) GENITOURINARY
    A) Acute renal failure is uncommon, but may develop secondary to prolonged hypotension or rhabdomyolysis. Hematuria may develop in patients with coagulopathy or thrombocytopenia.
    0.2.13) HEMATOLOGIC
    A) Thrombocytopenia, increased INR, prolonged PTT, decreased fibrinogen and/or elevated fibrin split products, usually without evidence of hemolysis may develop. Gastrointestinal bleeding, hematuria, bleeding from gingivae or venipuncture sites, and widespread ecchymosis may develop in severe cases.
    B) Coagulation abnormalities associated with crotaline envenomation are usually reversed by antivenom, but are resistant to correction with blood products.
    C) Clinically significant consequences of crotaline snake venom-induced coagulopathy are extremely uncommon.
    0.2.14) DERMATOLOGIC
    A) Local dermatologic manifestations include fang marks, erythema, ecchymosis, lymphangitis, bleb formation and tissue necrosis. Ecchymosis, petechiae and purpura remote from the envenomation site may develop in patients with significant thrombocytopenia or coagulopathy.
    0.2.15) MUSCULOSKELETAL
    A) Rhabdomyolysis may develop. True compartment syndrome is not common, even in cases with severe swelling. Permanent sequelae of envenomation may include weakness, pain, anesthesia, decreased range of motion, and scarring from surgical procedures.
    0.2.20) REPRODUCTIVE
    A) There are few published reports of envenomation in pregnant women.

Laboratory Monitoring

    A) Obtain a complete blood count (follow hemoglobin, hematocrit, and platelets), and coagulation profile (ie, INR, PT, and fibrinogen). Repeat these labs after each course of antivenom and every 4-6 hours after initial control has been established.
    B) Monitor potassium, renal function, and creatine kinase (CK); repeat periodically, as necessary.
    C) Monitor for systemic signs of envenomation such as hypotension, refractory vomiting, diarrhea, bleeding from areas other than the bite site, angioedema, neurologic effects.
    D) Monitor for local tissue injury including swelling, tenderness, erythema, ecchymosis or bleb formation. Mark the leading edge of tenderness and edema every 15 to 30 minutes to evaluate for progression.
    E) Measure compartment pressures if compartment syndrome is a concern.

Treatment Overview

    0.4.7) BITES/STINGS
    A) MANAGEMENT OF NO EFFECT TO MILD TOXICITY
    1) No antivenom is required. Local wound care and tetanus prophylaxis. Patients should be observed for 8 to 12 hours to be certain that delayed effects do not develop.
    B) MANAGEMENT OF MODERATE TO SEVERE TOXICITY
    1) Antivenom is recommended. Other recommended procedures/treatments: tetanus prophylaxis, local wound care, IV fluids, cardiac monitoring, analgesia, and follow laboratory values. Patients may need aggressive resuscitation including endotracheal intubation, IV fluids, and vasopressors if they manifest severe envenomation. If patients have severe swelling and compartment syndrome is a clinical concern, monitor compartment pressures. Initial treatment is antivenom. Fasciotomy is only indicated if elevated compartment pressures do not respond to antivenom.
    C) MONITORING OF PATIENT
    1) Monitor for local tissue injury (pain, swelling, erythema, ecchymosis, blebs) and systemic effects (hypotension, persistent vomiting, diarrhea, angioedema, neurologic effects). Mark the leading edge of the edema or pain and the limb circumference at arrival, then every 15 to 30 minutes to assess for progression of envenomation. If the patient arrives with a tourniquet or constricting bands applied to the bitten limb, release the bands ONLY when the patient is placed on a monitor, IV line is established, and antivenom is available. The affected limb should be elevated above the heart level once the patient arrives to the ED to observe for possible progression of envenomation while the patient is still in the ED, and to decrease the chance for dependent edema. It also provides more of a chance to neutralize the venom with the circulating antivenom.
    D) DECONTAMINATION
    1) PREHOSPITAL: Apply dressing if bleeding. Immobilize the affected limb at or below the level of the heart. Transport to the nearest facility with experience in treating snakebites.
    E) AIRWAY MANAGEMENT
    1) Airway compromise is unusual, but early intubation is recommended if signs of airway obstruction starts to develop to avoid a difficult intubation.
    F) ANTIDOTE
    1) INDICATIONS
    a) CroFab is effective in the treatment of almost all types of crotaline snakebites.
    b) Primary indications: progressive local, systemic or coagulation effects.
    2) DOSING
    a) Admit patient to critical care area; follow CroFab treatment guidelines.
    b) Reconstitute each vial of CroFab(R) with 18 mL of 0.9% saline and mix by continuous manual inversion until no solid particles are visible.
    c) DOSE: The initial dose of CroFab diluted in 250 mL of saline should be infused IV over 60 minutes; start the infusion slowly over the first 10 minutes at a rate of 25 to 50 mL/hr and observe for any allergic reactions. If no reactions occur, the infusion may be increased to a rate of 250 mL/hr until the infusion is complete. The reconstituted product should be used within 4 hours. The patient should be observed for up to 1 hour after the infusion is complete to determine if envenomation control has been achieved (ie, complete arrest of local symptoms, normal coagulation tests and systemic signs are normal). If control is NOT achieved after the first dose, give an additional dose of 4 to 6 vials until initial control of the envenomation syndrome is achieved.
    d) MAINTENANCE THERAPY: After initial control, additional doses (2 vials/dose) of CroFab(R) every 6 hrs for up to 18 hrs (3 doses) are recommended. Optimal dosing following the 18-hour scheduled dose has not been determined by the manufacturer.
    e) Observe for signs of acute allergic reaction during the infusion.
    f) Recurrence of local, systemic, and coagulation effects may develop after initial control has been established and patients need to be observed for signs of recurrence.
    3) AVAILABILITY
    a) Crotalidae Polyvalent Immune Fab (ovine) CroFab(R) distributed by BTG International, Inc., West Conshohocken, PA (1-877-852-8542). For medical information about CroFab(R) Crotalidae Polyvalent Immune Fab (Ovine) or to report an adverse event, please contact 1-877-377-3784.
    G) ALLERGIC REACTION
    1) MILD TO MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    H) PATIENT DISPOSITION
    1) HOME MANAGEMENT: All patients need to be referred to a health care facility, if they have been bitten by a crotaline snake.
    2) OBSERVATION CRITERIA: Patients who present with fang marks only should be observed for at least 8 to 12 hours, then discharged if no signs or symptoms. If they present with mild envenomation, admit the patient for at least 12 to 24 hours to a monitored bed. During the observation period the patient should be followed for progression of local signs every 15 to 30 minutes, coagulation abnormalities (every 4 to 6 hours), and systemic effects.
    3) ADMISSION CRITERIA: All patients who present with moderate to severe envenomation should be admitted for antivenom therapy and observation.
    4) DISCHARGE CRITERIA: Patients can be discharged once they complete the maintenance antivenom doses, lab values are normal or have a definite trend towards normal, and there is no evidence of recurrence. Early post discharge physiotherapy referral, and 2-4 days after discharge outpatient follow-up (for laboratory testing) should be arranged.
    5) CONSULT CRITERIA: Consult a poison center or medical toxicologist if the presentation is unclear, severe envenomation, no response to antivenom, or to locate the nearest facility that stocks the appropriate antivenom.
    I) PITFALLS
    1) Use of antibiotics without evidence of infection.
    2) Assuming that minimal or slowly progressing swelling is predictive of a good outcome.
    3) Routine fasciotomy for all snake bites who present with severe swelling (severe swelling is common, whereas, true compartment syndrome is rare).
    4) Failure to refer the patient for early physiotherapy.
    5) Assuming that the absence of clear fang marks precludes the possibility of envenomation.
    J) DIFFERENTIAL DIAGNOSIS
    1) Other snake species bite.
    2) Stings and envenomation by insects and arthropods such as scorpions and spiders.
    3) Coagulopathy from sepsis, cancer, or other poisoning.

Range Of Toxicity

    A) The LD50 of any particular venom varies substantially between species. About 25% of bites result in no envenomation, most others are of mild to moderate severity. Death is unusual.

Clinical Effects

Summary Of Exposure

    A) BACKGROUND (Classification of species): This topic includes the North American species of Crotalus (rattlesnakes), Agkistrodon (copperhead and cottonmouth snakes) and Sistrurus (Massassauga and pigmy rattlesnakes), which inhabit every state except Maine, Hawaii, and Alaska. Generally, they are found in the wild, although many snakes are kept in captivity in the home, zoos, as part of illicit snake trade, and in some regions of the country for religious ceremonies.
    B) TOXICOLOGY: The venom is a complex mixture of molecules ranging from individual metal ions to complex proteins. The components of the venom can cause local injury (tissue necrosis, vascular damage), coagulopathies (hemolysis, coagulation and fibrinolysis), and systemic effects (myocardial and neuromuscular dysfunction) depending on the specific snake venom. A bite deposits venom intradermally, subcutaneously, less often intramuscularly, or rarely directly into the blood vessel. Venom can alter blood vessel permeability, thereby allowing plasma and red cells to leak into tissues resulting in edema and ecchymosis. The most common effects of Crotalinae venom are hypofibrinogenemia and thrombocytopenia.
    C) EPIDEMIOLOGY: The most common bites are due to copperhead snakes, however most deaths are caused by Eastern and Western diamondback rattlesnakes. Although bites from Crotaline snakes are common in the US, deaths are rare. The majority of Crotaline bites are associated with either mild or moderate outcomes and 25% result in dry bites (no envenomation).
    D) WITH POISONING/EXPOSURE
    1) CLINICAL EFFECTS: The clinical manifestations of an envenomation can be classified in three ways: local, systemic and coagulation abnormalities. The absence of all of the manifestations for a period of 12 hours following a bite indicates a dry bite (no envenomation). A slowly progressing initial presentation is not predictive of a benign or an uneventful course.
    a) LOCAL: Typically includes the presence of one or more fang marks (occasionally only scratches or a small laceration may be present), pain and progressive edema extending from the bite site. Swelling usually appears within minutes after the bite, but may not appear for several hours. In severe cases, edema may progress to involve the entire limb. Edema may continue to progress for several days. Other manifestations include ecchymosis at the site that may progress to involve the limb and hemorrhagic blebs. Although uncommon, compartment syndrome may develop.
    b) COAGULATION: Common effect, but frank bleeding is rare following crotalinae snakebites. Both platelets and the coagulation cascade may be affected; some patients will have abnormalities in only one of these systems. It may develop within minutes to hours. Thrombocytopenia is more common with rattlesnakes.
    c) SYSTEMIC: Early systemic effects of crotaline snakes include: nausea, vomiting, numbness, or tingling of the tongue and mouth, and diarrhea. Symptoms can progress to dizziness, tachycardia, fasciculations, weakness, hypotension, airway compromise, rhabdomyolysis with hyperkalemia, and hemoconcentration.
    2) NO EFFECT: Fang marks present without other symptoms.
    3) MINIMAL: Minor local effects only, without progression of swelling, coagulation, or systemic effects.
    4) MODERATE: Progression of swelling beyond the bite site, moderate coagulation abnormalities, or systemic effects.
    5) SEVERE: Marked progression of the local effects (with blisters, bruising, and necrosis), severe coagulopathy, and systemic effects (tachycardia, hypotension, fasciculations, weakness).

Vital Signs

    3.3.1) SUMMARY
    A) Hypotension and shock may develop rapidly in severe envenomation. Severe swelling may cause intravascular volume depletion, particularly in children.
    B) Sudden death following envenomation has occurred.
    3.3.4) BLOOD PRESSURE
    A) HYPOTENSION and shock may develop rapidly in severe envenomation (Morgan et al, 2006; Hardy, 1986; Curry & Kunkel, 1985; Kitchens et al, 1987; Lewis & Portera, 1994; Bush & Jansen, 1995).
    1) Severe swelling may cause intravascular volume depletion, particularly in children.

Heent

    3.4.1) SUMMARY
    A) Facial, lip and tongue swelling may develop after envenomation to an extremity and may cause airway compromise. Coagulopathy may result in epistaxis or bleeding gums. The patient may report unusual tastes and increased or decreased salivation.
    3.4.2) HEAD
    A) FACIAL SWELLING: Facial and oral swelling have been reported in patients with severe envenomation involving an extremity (Russell, 1980; Davidson, 1988; Hinze et al, 2001).
    B) TONGUE and submandibular swelling has been reported following a direct envenomation to the tongue. The patient recovered following 40 vials of antivenom, with no complications and no evidence of glossal sloughing (Tanen et al, 2001).
    3.4.3) EYES
    A) CASE REPORT: Ocular exposure to C. atrox venom through spitting, a method of defense of certain rattlesnakes, produced conjunctival injection, with a few areas of corneal de-epithelialization, in one patient. No conjunctival edema was reported. Effects were transient, resolving within 24 hours, no systemic or hemotoxic manifestations developed (Ness et al, 2000).
    B) CASE REPORT: A 23-year-old man was bitten on his right eye by his pet North Pacific rattlesnake (Crotalus oreganus) and was somnolent upon arrival to the ED. He was intubated to protect his airway. His initial exam revealed bilateral periorbital swelling and ecchymosis, right greater than left. Edema of the face and neck were present. The right globe was proptotic with chemosis and diffuse subconjunctival hemorrhage. Intraocular pressure was 18 mmHg with a positive Seidel test. Laboratory studies included an INR of 1.1 and hyperkalemia. The patient was treated with 4 vials of Crotalidae Polyvalent Immune Fab shortly after arrival (approximately 11 hours after envenomation). He was transferred to a tertiary treatment center and received 18 additional vials of antivenin. His coagulation studies gradually improved; however, serial evaluations determined that the right eye was permanently damaged. He was successfully extubated on day 4 and was discharged the following day (Fernandez et al, 2015).
    3.4.5) NOSE
    A) EPISTAXIS may develop in patients with coagulopathy (Morgan et al, 2006; Curry & Kunkel, 1985; Burgess & Dart, 1991; Cruz & Alvarez, 1994).
    3.4.6) THROAT
    A) SUMMARY: Edema of the lips or tongue may develop and cause airway compromise (Hinze et al, 2001). Bleeding from gums may develop secondary to coagulopathy. The patient may report unusual tastes and increased or decreased salivation.
    B) AIRWAY COMPROMISE: Swelling of the lips and tongue have been reported after extremity envenomation (Hinze et al, 2001; Davidson, 1988).
    1) CASE REPORT/ADULT: Life-threatening airway obstruction developed in an adult male who sustained a bite to the tongue from a C. atrox (Gerkin et al, 1987). Another adult sustained a timber rattlesnake bite to the thumb with rapidly developing airway edema and obstruction (Hinze et al, 2001).
    C) GINGIVAL BLEEDING: Bleeding from the gums may develop secondary to coagulopathy.
    D) UNUSUAL TASTES often described as metallic, may be reported (Russell, 1980; Jansen et al, 1992).
    E) SALIVATION may be increased or decreased (Russell, 1980).

Cardiovascular

    3.5.1) SUMMARY
    A) Severe envenomations may result in hypotension and shock.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Hypotension and shock may develop rapidly in severe envenomation, particularly an intravenous envenomation (Morgan et al, 2006; Hardy, 1986; Curry & Kunkel, 1985; Kitchens et al, 1987; Lewis & Portera, 1994; Bush & Jansen, 1995; Tanen et al, 2001; Pearson et al, 2001; Hinze et al, 2001).
    a) CASE REPORT: A 14-year-old boy intentionally injected himself with the venom of a presumed Crotalus atrox snake and his blood pressure could not be determined on admission. Three hours after aggressive therapy including 7 L of fluid and pressors, his blood pressure was 111/51 mm Hg with a heart rate of 78 beats/min (Morgan et al, 2006).
    2) Severe swelling may cause intravascular volume depletion, particularly in children.

Respiratory

    3.6.1) SUMMARY
    A) Acute respiratory failure and acute lung injury are unusual occurrences seen with severe envenomation.
    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH POISONING/EXPOSURE
    a) Respiratory failure or compromise (airway obstruction or bronchospasm) are unusual occurrences seen with severe envenomation (Brooks et al, 2001; Hardy, 1986). In a case series of 289 envenomated patients, only 2 required intubation as a result of the envenomation (Brooks et al, 2001).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Acute lung injury is a rare occurrence seen with severe envenomation (Hardy, 1986; Curry & Kunkel, 1985; Bush & Jansen, 1995).
    C) EDEMA OF LARYNX
    1) WITH POISONING/EXPOSURE
    a) Airway occlusion may develop secondary to rapid swelling in patients with facial bites (Richardson et al, 2005; Lewis & Portera, 1994).
    D) RESPIRATORY OBSTRUCTION
    1) WITH POISONING/EXPOSURE
    a) A case of timber rattlesnake snakebite-induced, rapidly developing upper airway edema, resulting in airway obstruction and requiring emergency cricothyrotomy was reported. The patient was envenomated in the thumb by the severed snake head. The authors suspect the upper airway edema, a local manifestation, was the result of a severe systemic envenomation as opposed to an anaphylactoid reaction based on radioallergosorbent testing and no prior history of exposure to snake venom (Hinze et al, 2001).
    b) CASE REPORT: After she was envenomated by a Southern Pacific rattlesnake (Crotalus viridis helleri) above the right upper lip, a 14-month-old toddler developed stridor and significant facial and oropharyngeal edema, requiring orotracheal intubation. She recovered after receiving a total of 16 vials of FabAV (Richardson et al, 2005).

Neurologic

    3.7.1) SUMMARY
    A) Effects on mental status range from excitation and confusion to obtundation and coma. Mental status is often obscured by concurrent alcohol intoxication. Fasciculation may develop in the tongue, bitten extremity or in severe cases may become generalized. Paresthesias of the face, tongue or extremities are common. Cranial nerve dysfunction and generalized muscle weakness have been reported with Mojave rattlesnake and C. durissus envenomation but are not common.
    3.7.2) CLINICAL EFFECTS
    A) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Generally mental status is normal. Patients with severe envenomation may develop confusion, obtundation or coma (Curry & Kunkel, 1985; Davidson, 1988; Buntain, 1983; Cruz & Alvarez, 1994; Ekenback et al, 1985; Bush & Jansen, 1995).
    B) SPASMODIC MOVEMENT
    1) WITH POISONING/EXPOSURE
    a) Fasciculations may develop in the tongue, face or bitten extremity; in severe cases fasciculations may be generalized (Russell, 1980; Davidson, 1988; Wingert & Chan, 1988; Brick et al, 1987; Buntain, 1983; Clark et al, 1997).
    b) CASE REPORTS: Wallace et al (1997) reported 2 cases of Southwestern rattle- snake envenomations resulting in myokymia involving the face, arms, and legs in one case and peripheral and perioral myokymia in the other case. Both patients showed marked improvement following administration of polyvalent crotaline antivenom (Wallace et al, 1997).
    C) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) Paresthesias of the face, tongue, or extremities are commonly reported (Wingert & Chan, 1988; Clark et al, 1997).
    D) NEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) Cranial nerve dysfunction manifested as ptosis, diplopia, facial muscle paresis, ophthalmoplegia, difficulty swallowing and handling secretions, and difficulty speaking have been reported following Mojave envenomation, but is not common (Jansen et al, 1992).
    E) MUSCLE WEAKNESS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT/CHILD: Generalized muscle weakness and decreased respiratory effort required intubation developed in an 11-year-old girl 30 hours after Mojave envenomation despite administration of 30 vials of antivenom (Jansen et al, 1992).
    b) CASE REPORT/CHILD: A 7-year-old boy developed generalized weakness and lower extremity tetany associated with a low ionized serum calcium 24 hours after severe crotaline envenomation (Bush & Jansen, 1995). Weakness and tetany persisted for 4 days despite treatment of hypocalcemia.

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting and diarrhea may develop early in severe envenomation. Gastrointestinal hemorrhage may develop in patients with coagulopathy or thrombocytopenia.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea is fairly common after envenomation (Norris, 2005; Russell, 1980) (Burch, 1988) (Lopoo et al, 1998). Vomiting and diarrhea occur less frequently and may suggest more severe envenomation (Davidson, 1988; Curry & Kunkel, 1985; Bush & Jansen, 1995).
    B) GASTROINTESTINAL HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) Gastrointestinal hemorrhage may develop in patients with severe coagulopathy or thrombocytopenia (Morgan et al, 2006; Curry & Kunkel, 1985; Hardy, 1986; Burgess & Dart, 1991).

Genitourinary

    3.10.1) SUMMARY
    A) Acute renal failure is uncommon, but may develop secondary to prolonged hypotension or rhabdomyolysis. Hematuria may develop in patients with coagulopathy or thrombocytopenia.
    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Acute renal failure is an uncommon complication that may develop secondary to rhabdomyolysis or prolonged hypotension (Curry & Kunkel, 1985; Hardy, 1986; Ahlstrom et al, 1991; Jansen et al, 1992; Cruz & Alvarez, 1994).
    B) BLOOD IN URINE
    1) WITH POISONING/EXPOSURE
    a) Hematuria may develop in patients with coagulopathy or thrombocytopenia (Tallon et al, 1981; Curry & Kunkel, 1985; Davidson, 1988; Burgess & Dart, 1991; Cruz & Alvarez, 1994) .

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) Metabolic acidosis may develop in patients with hypotension after severe envenomation (Bush & Jansen, 1995).

Hematologic

    3.13.1) SUMMARY
    A) Thrombocytopenia, increased INR, prolonged PTT, decreased fibrinogen and/or elevated fibrin split products, usually without evidence of hemolysis may develop. Gastrointestinal bleeding, hematuria, bleeding from gingivae or venipuncture sites, and widespread ecchymosis may develop in severe cases.
    B) Coagulation abnormalities associated with crotaline envenomation are usually reversed by antivenom, but are resistant to correction with blood products.
    C) Clinically significant consequences of crotaline snake venom-induced coagulopathy are extremely uncommon.
    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) Profound thrombocytopenia may develop, with platelet counts below 10,000 (Morgan et al, 2006; Odeleye et al, 2004; Camilleri et al, 2005; Tallon et al, 1981; Furlow & Brennan, 1985; Riffer et al, 1987; Burgess & Dart, 1991; Bond & Burkhart, 1997; Rao et al, 1998). In a series of 14 patients, with severe thrombocytopenia, improvement of thrombocytopenia was noted immediately after antivenom administration (Bush et al, 2000).
    b) Thrombocytopenia may persist or recur despite antivenom administration and platelet transfusion, especially after timber rattlesnake envenomation (Richardson et al, 2005; Camilleri et al, 2005; Rao et al, 1998; Bond & Burkhart, 1997).
    c) CASE REPORT: A 46-year-old man developed recurrent venom-induced thrombocytopenia after envenomation by a Southern Pacific Rattlesnake (sp. Crotalus Helleri). The patient was in a remote area and it took 9 hours for the patient to receive 3 repeated doses of 4 vials of CroFab(TM) (total 12 vials) for markedly increased swelling; a total of 20 vials were given within 24 hours. No further antivenom was administered. The patient had an initial platelet count of 46,000 followed by a platelet count of 233,000 after the first 8 vials of antivenom. By day 5, it had decreased to 40,000 and on day 7 it was 11,000, and the patient received a platelet transfusion. The patient was discharged on day 9 for rehabilitative care (Wasserberger et al, 2006).
    d) CASE REPORT: A 30-year-old man developed pain, swelling, ecchymosis, nausea, and mild anemia and thrombocytopenia (platelets, nadir 117,000/mcL 60 hours post envenomation) after being bitten on the dorsal aspect of his nondominant, left thumb by a mottled rock rattlesnake (Crotalus lepidus lepidus). He refused antivenom administration. Following supportive therapy, he was discharged on the 5th hospital day (Norris, 2005).
    B) ANEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 30-year-old man developed pain, swelling, ecchymosis, nausea, and mild anemia (hematocrit 36.3% 84 hours post envenomation) and thrombocytopenia after being bitten on the dorsal aspect of his nondominant, left thumb by a mottled rock rattlesnake (Crotalus lepidus lepidus). He refused antivenom administration. Following supportive therapy, he was discharged on the 5th hospital day. The author suggested that the mild anemia was likely due to cellular sequestration in the soft tissues of his upper extremity (extensive ecchymosis) (Norris, 2005).
    C) PROTHROMBIN TIME LOW
    1) WITH POISONING/EXPOSURE
    a) INCREASED INR and PROLONGED PTT: Markedly increased INR and prolonged PT/PTT may develop (Morgan et al, 2006; Camilleri et al, 2005; Curry & Kunkel, 1985; Davidson, 1988; Burgess & Dart, 1991; Guisto, 1995; Rao et al, 1998; Tanen et al, 2001). Prothrombin times generally return to normal following administration of antivenom.
    D) DECREASED FIBRINOGEN
    1) WITH POISONING/EXPOSURE
    a) DECREASED FIBRINOGEN INCREASED FIBRIN SPLIT PRODUCTS: Markedly decreased fibrinogen (undetectable) and/or increased fibrin split products may develop after crotaline envenomation (Camilleri et al, 2005; Budzynski et al, 1984; Crane & Irwin, 1985; Guisto, 1995). Decreased fibrinogen and/or increased fibrin split products can develop in the absence of other coagulation abnormalities (Burgess & Dart, 1991; Rao et al, 1998).
    E) BLOOD COAGULATION DISORDER
    1) WITH POISONING/EXPOSURE
    a) SUMMARY
    1) The coagulation abnormalities associated with crotaline envenomation may be resistant to correction with blood products (Morgan et al, 2006; Camilleri et al, 2005; Budzynski et al, 1984; Burgess & Dart, 1991; Bond & Burkhart, 1997). Coagulopathy is one of the most common presenting findings following major envenomation (60% of patients in one study and 62.5% in another study of envenomated children) (Tanen et al, 2001a; Tanen et al, 2001; Lopoo et al, 1998). Prolonged or recurrent coagulopathy can occur. Close monitoring of hematologic parameters should be ongoing for the first 2 weeks after snakebite (Boyer et al, 1999).
    b) RECURRENT OR LATE COAGULOPATHIES
    1) MECHANISM: The mechanism of late (prolonged) coagulopathies following rattlesnake envenomation in the US is not fully understood but it may be due to a mismatch of venom and antivenom or the presence of a venom depot at the bite site. Outpatient monitoring is suggested until complete resolution or to detect a delayed coagulopathy (Karpen et al, 2015).
    2) CASE SERIES: In a retrospective chart review of patients with a rattlesnake exposure during a 2-year period, 315 exposures were identified and a total of 120 patients had complete follow-up data and were included in the analysis. Fifty-nine (49%) patients developed an initial coagulopathy and 61 (51%) patients did not develop a coagulopathy. A total of 63 (53%) patients developed a late coagulopathy, described as "delayed" (no initial coagulopathy) or "recurrent" (initial coagulopathy occurred after completion of antivenom therapy). Nineteen (31%) patients developed a delayed coagulopathy. Many patients (n=44; 75%) developed a recurrent coagulopathy after having an initial coagulopathy and were 2.3 times more likely to develop a coagulopathy compared to those without an initial coagulopathy following envenomation. Repeat antivenom therapy was needed in 17 (14%) patients. Serious bleeding was not reported in any patient (Karpen et al, 2015).
    3) CASE REPORT: A 53-year-old woman was bitten on the ankle by a rattlesnake and developed localized swelling and pain. She was initially treated with 6 vials of antivenom but her coagulation studies worsened along with increased swelling and was given further antivenom (2 subsequent 6 vial doses). On day 3, she was discharged to home with a platelet count of 86, INR 0.95 and fibrinogen of 232. Once she returned home she reported oozing at the bite site. On follow-up day 6, her platelet count was 49 and she was given 4 vials of antivenom and readmitted to the hospital and treated with 2 more 4-vial doses of antivenom. On day 8 of exposure, she was discharged to home with a platelet count of 100, PT 11.3, INR 1, PTT 28.7 and fibrinogen 127. On day 16, outpatient coagulation studies (platelet 203, PT 55.8, INR 5 and undetectable fibrinogen) were once again elevated requiring readmission and she was given 10 vials of antivenom. Following discharge, outpatient labs were followed for over 2 months with a gradual decline in platelet count. A hematology evaluation did not find any other cause for thrombocytopenia and the events were consistent with envenomation. The last labs collected on day 80 were as follows: platelet count 111, PT 10;7, INR 1, PTT 25.9 and fibrinogen 246. The patient was lost to follow-up (Hurst et al, 2015).
    F) HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) Hematuria, gastrointestinal bleeding, epistaxis, ecchymosis, and bleeding from gingivae or venipuncture sites may develop in patients with severe coagulation anomalies or thrombocytopenia (Morgan et al, 2006; Curry & Kunkel, 1985; Davidson, 1988; Burgess & Dart, 1991).
    G) HEMOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Clinically significant intravascular hemolysis, a rare complication of crotaline envenomations, has been reported without any significant coagulopathy (Gibly et al, 1997).

Dermatologic

    3.14.1) SUMMARY
    A) Local dermatologic manifestations include fang marks, erythema, ecchymosis, lymphangitis, bleb formation and tissue necrosis. Ecchymosis, petechiae and purpura remote from the envenomation site may develop in patients with significant thrombocytopenia or coagulopathy.
    3.14.2) CLINICAL EFFECTS
    A) DISORDER OF SKIN
    1) FANG MARKS are usually visible and may be a single puncture wound or several (Russell, 1980). The site of envenomation may also appear like a scratch or laceration. In a case series of 178 envenomations, 93% were reported to have fang marks (Thorson et al, 2003).
    B) PAIN
    1) PAIN usually develops soon after the bite, and is out of proportion to that produced by a simple traumatic puncture. Without therapy, it generally increases during the first several hours, and is accentuated by swelling (Camilleri et al, 2005; Dart et al, 1996; Dart et al, 1992).
    a) It is most severe after bites by the Eastern and Western diamondbacks. In bites by some species, particularly the Mojave rattlesnake, pain may be minimal. Pain was reported in 93% of 178 cases of copperhead envenomation (Thorson et al, 2003).
    b) INTRAVENOUS INJECTION: Severe pain was reported in a 14-year-old boy who intentionally injected himself with the venom of a presumed Crotalus atrox (Morgan et al, 2006).
    2) LONG-TERM EFFECTS
    a) In a prospective study of patients (n=128) reporting a snakebite to a regional poison center in the southeastern United States, a standardized questionnaire was administered following hospital discharge. Of those cases 16 (12.5%) were lost to follow-up, 31 (24.2%) reported no progression of symptoms and the remaining 81 (63.3%; 51 admitted to the hospital and 30 were evaluated and treated in the ED only) patients were queried about symptoms. A total of 64 (79%) patients reported continued pain and edema at the site of the bite for an average of 16.4 and 15.6 days, respectively. A mean score of 4.8 to 5 on a pain scale of 1 to 10 was reported by patients. The number of patients reporting pain after hospital discharge for weeks 1, 2, 3 , and 4 were 79%, 59%, 36%, and 20%, respectively (Spiller & Bosse, 2003).
    C) PURPURA
    1) Ecchymosis in the area of envenomation is common (Camilleri et al, 2005; Richardson et al, 2005; Russell, 1980). Ecchymosis, petechiae and purpura in areas remote from the envenomation site may develop in patients with significant coagulopathy or thrombocytopenia (Furlow & Brennan, 1985).
    2) CASE REPORT: Roberts & Greenberg (1997) reported an unusual case of ascending hemorrhagic signs, probably related to lymphatic drainage of venom and venom-induced bleeding, following a copperhead bite to the toe. A hemorrhagic blister at the bite site occurred within minutes. An ecchymotic area developed and spread up his leg over a 5 day period (Roberts & Greenberg, 1997).
    D) CYANOSIS OF SKIN
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 14-year-old boy intentionally injected himself with the venom of a presumed Crotalus atrox snake and his hands and feet were markedly cyanotic on admission along with swelling of the lips and tongue. Following aggressive care the patient made a complete recovery (Morgan et al, 2006).
    E) LYMPHANGITIS
    1) Erythema and lymphangitis in the area of envenomation are common. Local lymph nodes may be enlarged and tender (Russell, 1980). These findings are common and do not usually indicate infection.
    F) BITE - WOUND
    1) Hemorrhagic blebs may appear at the site of envenomation, usually requiring several days to develop (Russell, 1980). Blebs may be more common with upper extremity envenomations than with lower extremity envenomations (Tanen et al, 2001a). The most common local manifestations in a series of 178 copperhead envenomations included: fang marks (93%), edema (167/178 cases; 94%), ecchymosis (72/136 cases; 53%), erythema (51/137 cases; 37%), bullae (18/137 cases; 13%), and tissue necrosis (11/138 cases; 8%) (Thorson et al, 2003).
    2) In a retrospective review of 92 copperhead snakebites, 33% (n=30) of the cases were documented to have a local severity score of 3 to 4 (clinically significant local effects), with signs of pain requiring parenteral analgesics, ecchymosis, and swelling of over one half of the bitten extremity (Scharman & Noffsinger, 2001).
    3) CASE REPORT: A 12-year-old girl developed mild edema, ecchymosis, and pain after envenomation by a Northern blacktail rattlesnake (Crotalus molossus molossus) on her right foot while walking in her backyard. During the therapy, all laboratory results were normal. Following treatment with 18 vials of CroFab(R), she recovered and was discharged without further sequelae (Yarema & Curry, 2005).
    4) CASE REPORT: A 26-month-old girl (16 kg) developed pain, ecchymosis with swelling and erythema after being bitten on the right hand by a copperhead snake in her backyard. Swelling progressed to the distal humerus, with tense swelling of the hand. Following treatment with 8 vials of CroFab(R) (4 vials in the ED, 2 at 6 hours, and 2 at 12 hours), her symptoms improved significantly and was discharged the following day with some soft swelling to the forearm and minimal pain (Trinh & Hack, 2005).
    5) CASE REPORT: A 30-year-old man developed pain, swelling, ecchymosis, nausea, and mild anemia and thrombocytopenia after being bitten on the dorsal aspect of his non-dominant, left thumb by a mottled rock rattlesnake (Crotalus lepidus lepidus). He also complained of a 'cold water dropping' sensation on his lips and chin. He refused antivenom administration. Following supportive therapy, he was discharged on the 5th hospital day. No long term sequelae were reported (Norris, 2005).
    G) SKIN NECROSIS
    1) Local tissue necrosis may develop at the site of envenomation (Russell, 1980). Several days are usually required to define areas of nonviable tissue.

Musculoskeletal

    3.15.1) SUMMARY
    A) Rhabdomyolysis may develop. True compartment syndrome is not common, even in cases with severe swelling. Permanent sequelae of envenomation may include weakness, pain, anesthesia, decreased range of motion, and scarring from surgical procedures.
    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Slight elevations in CPK commonly develop, and significant rhabdomyolysis may occur with severe envenomation (Wingert & Chan, 1988; Jansen et al, 1992; Ahlstrom et al, 1991; Buntain, 1983) (Azevedo-Marquez et al, 1985) (Bush & Jansen, 1995; Wallace et al, 1997).
    b) Severe rhabdomyolysis can occur in the absence of compartment syndrome, and may be related to a direct toxic effect of venom on muscle (Garfin et al, 1984; Kitchens et al, 1987; Carroll et al, 1997). Rhabdomyolysis is common following a bite by a canebrake rattlesnake.
    B) COMPARTMENT SYNDROME
    1) WITH POISONING/EXPOSURE
    a) True compartment syndrome may develop but is not common even in patients with severe swelling (Roberts et al, 1985; Curry & Kunkel, 1985). Tunget-Johnson et al (1998) reported elevated compartment pressures in a 13-month-old child, with pressures decreasing after additional vials of antivenom were administered, thus avoiding fasciotomy (Tunget-Johnson et al, 1998). In a retrospective study of 233 envenomations, dermotomy/fasciotomy was performed in only 3.4% of patients (Tanen et al, 2001).
    b) Noninvasive vascular studies or intracompartmental pressure monitoring should be employed to evaluate for this complication when it is suspected.
    c) CASE REPORT: Envenomation by Crotalus atrox in the foot of a 59-year-old man resulted in compartment syndrome (increased anterior tibial pressure of 46 mmHg and lateral tibial pressure of 33 mmHg), which developed within 52 hours, after he refused antivenom therapy due to an adverse response to a test dose. Edema had progressed up to his scrotum. After 52 hours, antivenom therapy was started, with marked improvement of symptoms following 15 vials of antivenom (Rosen et al, 2000).
    C) SEQUELA
    1) WITH POISONING/EXPOSURE
    a) Permanent sequelae of envenomation may include weakness, pain, anesthesia, decreased range of motion, and scarring from surgical procedures.
    1) Permanent dysfunction may be more common with upper extremity envenomation, particularly those involving the hand, than with envenomation involving the lower extremities (Dart et al, 1992).
    b) Prolonged limb dysfunction, up to 365 days, has been reported following envenomations of the limbs (Thorson et al, 2003).
    c) CASE SERIES
    1) In a prospective study of patients (total study population = 81) reporting a snakebite to a regional poison center in the southeastern United States, ongoing reduced function and strength were reported for an average of 18.1 and 21.4 days, respectively. Bites occurring in the lower limb, often required some type of accommodation (i.e., modified shoe wear, crutches, or a cane) to ambulate in 78% (n=33) of patients. Of note, 13 (16%) patients reported recurrent symptoms for an average of a month in the affected limb during normal daily activities. Time lost from work was an average of two weeks for 37/42 (88%) patients. Limitations noted in this study included self-reporting via phone interview and the findings were primarily based on copperhead envenomation (Spiller & Bosse, 2003).
    3.15.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) MUSCLE NECROSIS
    a) MAMMALIAN JOINTS: Envenomation of rabbit knee joints resulted in histopathological effects within 20 hours, which included necrosis of muscle and soft tissue, inflammation and hemorrhage of the subsynovium, denuded cartilage surface with 100% proteoglycan loss and increased eosinophil density (Hill et al, 1999).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH POISONING/EXPOSURE
    a) Anaphylactic reactions to crotaline snakebites are rare, but have been reported to occur within minutes of envenomation, usually in patients with a history of previous crotaline envenomation. Reported reactions have included hypotension, diffuse urticaria, dyspnea and bronchospasm, and periorbital edema (Graeme et al, 1997). It can be difficult to distinguish anaphylactoid reactions from severe systemic manifestations of envenomation.
    b) CASE REPORT/INTRAVENOUS INJECTION: Severe swelling of the lips and tongue, along with hypotension, were observed upon admission in a 14-year-old male after intentionally injecting himself with the venom of a presumed Crotalus atrox snake. The patient was immediately intubated and a total of 18 vials of crotalidae polyvalent immune fab and aggressive fluid resuscitation and blood products were given. The patient made a complete recovery (Morgan et al, 2006).
    c) CASE REPORT: Life threatening anaphylaxis (airway compromise and hypotension) has been reported after a first time Crotalinae envenomation (prior history of consuming rattlesnake) in a 26-year-old man. The authors suggested that dermal and oral exposure to snake proteins may predispose to anaphylaxis (Brooks et al, 2001).
    d) CASE REPORT: In one patient, face and neck swelling and dyspnea developed immediately after the pressure band on the arm was removed. The author suggested that venom was accumulated in the lymphatics of the arm with the pressure band. The removal of this pressure band allowed a more concentrated bolus of venom-contained antigens to reach the systemic circulation (Camilleri, 2004). However, another author believed that the above patient may have had respiratory distress from systemic venom effects, rather than an IgE-mediated antigenic process (German, 2005)

Reproductive

    3.20.1) SUMMARY
    A) There are few published reports of envenomation in pregnant women.
    3.20.3) EFFECTS IN PREGNANCY
    A) COPPERHEAD ENVENOMATION
    1) CASE REPORT - A 32-year-old woman at 28 5/7 weeks gestation was bitten by a copperhead (Agkistrodon contortrix) on the foot and developed evidence of envenomation with worsening local symptoms and received 5 vials of CroFab(TM). Local effects ceased within 1 to 2 hours and coagulation parameters improved. Ultrasound was normal and correlated with gestational age. The patient was discharged after 24 hours with no symptoms, and at 41 weeks delivered a healthy baby girl. Follow-up at 24 months revealed normal physical and developmental growth in the toddler (Kravitz & Gerardo, 2006).
    2) CASE REPORT - A 28-year-old woman at 26 weeks gestation was bitten on the foot by a small copperhead and developed localized symptoms with no evidence of coagulopathy. Fetal monitoring was normal. Although the patient developed worsening localized swelling, the patient declined antivenom following full consent. By day 3, swelling had begun to decline (which had progressed to the thigh), and the patient recovered uneventfully. At 39 weeks a planned C-section was performed and a healthy infant was delivered (Chang et al, 2006).
    B) STILLBIRTH
    1) CASE REPORT/COPPERHEAD - A 28 weeks pregnant woman sustained a copperhead envenomation complicated by mild hypotension. She developed more severe hypotension (BP 70/0) during antivenom administration and was treated with intravenous epinephrine and isoproterenol (Anon, 1984).
    a) Six weeks following the bite she delivered a still born fetus with evidence of intracranial hemorrhage. It was speculated that decreased uterine blood flow secondary to epinephrine administration may have contributed to the outcome.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Obtain a complete blood count (follow hemoglobin, hematocrit, and platelets), and coagulation profile (ie, INR, PT, and fibrinogen). Repeat these labs after each course of antivenom and every 4-6 hours after initial control has been established.
    B) Monitor potassium, renal function, and creatine kinase (CK); repeat periodically, as necessary.
    C) Monitor for systemic signs of envenomation such as hypotension, refractory vomiting, diarrhea, bleeding from areas other than the bite site, angioedema, neurologic effects.
    D) Monitor for local tissue injury including swelling, tenderness, erythema, ecchymosis or bleb formation. Mark the leading edge of tenderness and edema every 15 to 30 minutes to evaluate for progression.
    E) Measure compartment pressures if compartment syndrome is a concern.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) A complete blood count including platelet count should be ordered and repeated periodically (6 hours or as clinically indicated).
    B) COAGULATION STUDIES
    1) Obtain a coagulation profile (INR or PT, PTT, fibrinogen, fibrin split products) in moderate or severe envenomation. Repeat periodically (every 4 to 6 hours after initial control or as clinically indicated). Because persistent or recurrent coagulopathy may occur, it may be advisable to monitor hematologic parameters for the first 2 weeks after snakebite, particularly after pit viper envenomation (Boyer et al, 1999).
    C) LATE HEMATOLOGIC ABNORMALITIES
    1) A retrospective, observational case series of rattlesnake bites recorded at 2 US poison centers found that envenomated (North American Crotalus or Sistrurus snake) patients with an early onset hypofibrinogenemia, a positive D-dimer, thrombocytopenia, or a 20% increase in platelet count within 4 hours post treatment of antivenom therapy (ie, administration of Crotalidae Polyvalent Immune Fab (CroFab(R)) had a significant likelihood of late hematologic effects. Of 60 cases that met inclusion criteria, 17 (28%) had a hematologic abnormality as a result of envenomation. Eleven of 60 patients developed late hematologic abnormalities 4 or more days post-envenomation. A new onset of hypofibrinogenemia and/or thrombocytopenia occurred in 4 patients. All were associated with early D-dimer elevation and/or platelet rise following CroFab(R) treatment. Monitoring should include platelet counts, post-antivenom platelet trend, fibrinogen, D-dimer, PT/INR, and PTT in the first 36 to 48 hours post-envenomation and for at least 4 days post-envenomation (Seifert et al, 2011).
    D) BLOOD/SERUM CHEMISTRY
    1) Serum electrolytes (including potassium), renal and liver function, and creatinine kinase (CK) levels should be obtained in moderate or severe poisonings. Repeat as clinically indicated.
    E) ACID/BASE
    1) Obtain blood gases or pulse oximetry and repeat as clinically indicated.
    F) BLOOD PRODUCTS
    1) Type and hold blood for cross-matching in cases of severe envenomation.
    G) VENOM CONCENTRATION
    1) Blood venom concentrations can be determined and have correlated with clinical evidence of envenomation, but are not widely available (Seifert et al, 1997).
    H) LABORATORY INTERFERENCE
    1) It has been shown that administration of horse serum-derived Crotalidae antivenin commonly results in a positive direct Coombs antibody test. This should NOT be taken as evidence of likely hemolysis in the absence of other convincing findings (Ruha et al, 2000).
    4.1.3) URINE
    A) URINALYSIS
    1) Perform urinalysis to evaluate for hematuria and proteinuria.
    2) Following envenomation, abnormal urinalysis (presence of cells, blood, glucose, or protein) is common. In a retrospective review, 43% of 41 subjects had abnormalities prior to antivenom therapy, and 80% (33 patients) had abnormal urinalysis at some time during the 2-week period following envenomation.
    a) Abnormal urinalysis was most common with increased bite severity and was more frequent during the first few hours following the bite. Antivenom treatment may be responsible for some of the abnormal urinalyses (Moss et al, 1998).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) In severe poisonings, an electrocardiogram is indicated.
    2) SYSTEMIC SIGNS AND SYMPTOMS
    a) Monitor for systemic signs of envenomation such as hypotension, refractory vomiting, diarrhea, bleeding from areas other than the bite site, angioedema, neurologic effects (Lavonas et al, 2011).
    3) LOCAL TISSUE INJURY
    a) Monitor for local tissue injury including swelling, tenderness, erythema, ecchymosis or bleb formation. Mark the leading edge of tenderness and edema every 15 to 30 minutes to evaluate for progression (Lavonas et al, 2011).
    4) INTRACOMPARTMENTAL PRESSURE MONITORING
    a) Intracompartmental pressure monitoring should be performed in cases of suspected compartment syndrome (Garfin et al, 1984; Roberts et al, 1985; Curry & Kunkel, 1985).
    5) IMMUNOLOGIC TESTING
    a) Immunologic tests for the detection of snake venom in blood, urine and tissue have been developed, but are not commercially available (Minton et al, 1984; Minton, 1987).

Methods

    A) CHROMATOGRAPHY
    1) The Natural Toxins Research Center at Texas A&M University has cataloged on an Internet database information regarding the venoms of over 250 snakes (11 species and 20 subspecies) with their geographical location data, proteolytic activities, high performance liquid chromatography (HPLC) and electrophoretic titration (ET) profiles. The site may be found at: URL: http://ntri.tamuk.edu/serp/ (Perez et al, 2001).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.6) DISPOSITION/BITE-STING EXPOSURE
    6.3.6.1) ADMISSION CRITERIA/BITE-STING
    A) All patients who present with moderate to severe envenomation should be admitted for antivenom therapy and observation.
    1) Most patients should be observed for 18 to 24 hours following the initial control of envenomation. This includes serial exams every 6 to 8 hours along with serial laboratory evaluation (ie, protime, hemoglobin, platelet count and fibrinogen) at 6 to 12 hours after initial control and before discharge (Lavonas et al, 2011).
    2) Prior to discharge to home, the patient should be instructed about possible signs and symptoms that can occur following envenomation and antivenom therapy (Lavonas et al, 2011):
    a) Patients with evidence of hematologic venom effects during the acute phase of treatment are at greater risk of developing late hematologic venom effects 2 to 7 days after antivenom therapy. Follow-up laboratory testing is recommended 2 to 7 days and 5 to 7 days after discharge. Repeat labs as indicated based on clinical signs and symptoms and laboratory results.
    b) Patients should be instructed about the possible occurrence of serum sickness following discharge and instruction to seek care. Serum sickness is usually mild following Fab antivenom and can be managed with oral antihistamines and corticosteroids.
    6.3.6.2) HOME CRITERIA/BITE-STING
    A) All patients need to be referred to a health care facility, if they have been bitten by a crotaline snake.
    6.3.6.3) CONSULT CRITERIA/BITE-STING
    A) Consult a poison center or medical toxicologist, if the presentation is unclear, severe envenomation, no response to antivenom, or to locate the nearest facility that stocks the appropriate antivenom.
    6.3.6.5) OBSERVATION CRITERIA/BITE-STING
    A) Patients who present with fang marks only should be observed for at least 8 to 12 hours, then discharged if no signs or symptoms. If they present with mild envenomation, admit the patient for at least 12 to 24 hours to a monitored bed. During the observation period the patient should be followed for progression of local signs every 5 to 10 minutes, coagulation abnormalities, and systemic effects.
    1) Observe patient for minimum of 8 to 12 hours in all cases of snake bite (Hurlbut et al, 1988; Guisto, 1995). Reliable patients with no evidence of swelling, coagulopathy, or systemic effects at the end of this time may be discharged with appropriate follow up.

Monitoring

    A) Obtain a complete blood count (follow hemoglobin, hematocrit, and platelets), and coagulation profile (ie, INR, PT, and fibrinogen). Repeat these labs after each course of antivenom and every 4-6 hours after initial control has been established.
    B) Monitor potassium, renal function, and creatine kinase (CK); repeat periodically, as necessary.
    C) Monitor for systemic signs of envenomation such as hypotension, refractory vomiting, diarrhea, bleeding from areas other than the bite site, angioedema, neurologic effects.
    D) Monitor for local tissue injury including swelling, tenderness, erythema, ecchymosis or bleb formation. Mark the leading edge of tenderness and edema every 15 to 30 minutes to evaluate for progression.
    E) Measure compartment pressures if compartment syndrome is a concern.

Abstracts

Case Reports

    A) INTRAVENOUS INJECTION: A 14-year-old boy milked a presumed C. atrox and injected the venom into his antecubital vein. He developed vomiting, confusion, agitation, severe swelling of the lips and tongue, profound hypotension, thrombocytopenia (52,000/mm), and coagulopathy (INR 8.9, PT 98.3 sec). He subsequently developed epistaxis and gastrointestinal bleeding. He was treated with aggressive fluid resuscitation, dopamine, and 18 vials of crotalidae polyvalent immune fab (ovine) as well as 2 units of fresh frozen plasma and 6 units of platelets, and recovered (Morgan et al, 2006).

Range Of Toxicity

Summary

    A) The LD50 of any particular venom varies substantially between species. About 25% of bites result in no envenomation, most others are of mild to moderate severity. Death is unusual.

Pharmacology Toxicology

Toxicologic Mechanism

    A) The common practice of dividing snake venoms into such groups as neurotoxins, hemotoxins, cardiotoxins and the like, has led to much misunderstanding. Chemical, pharmacological and clinical studies have shown these divisions to be both superficial and clinically irrelevant.
    B) Snake venoms are complex mixtures. The effects of various combinations of the venom components, and of metabolites formed by their interactions, can be complicated by the response of the victim. The release of autopharmacological substances by the envenomated patient may complicate the poisoning and make treatment more difficult.
    C) The venoms of pit vipers produce deleterious local tissue effects, changes in blood cells, defects in coagulation, injury to the intimal linings of the vessels and changes in blood vessel resistances. The hematocrit may fall rapidly and platelets may disappear. Pulmonary edema may occur in severe poisoning and bleeding phenomena may occur in the lungs, peritoneum, kidneys and heart. These changes are often accompanied by alterations in cardiac dynamics and renal function.
    D) Most North American venoms produce relatively minor changes in neuromuscular transmission, the notable exception being the venom of the Mojave rattlesnake, which also produces less tissue destruction. The early cardiovascular collapse seen in an occasional patient bitten by a rattlesnake is due to a marked fall in circulating blood volume. Although cardiac dynamics may be disturbed, in most cases the heart changes may be secondary to the decrease in circulating blood volume (Zamuner et al, 2001).

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