We suggest the following approach for North American Crotalinae snakebite victims prior to
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© 2021 UpToDate, Inc. and/or its affiliates. All Rights Reserved. definitive hospital care [1]:
Bites by Crotalinae snakes (rattlesnakes, water
moccasins [cottonmouths], or copperheads) in the United
States: Management
Author: Steven A Seifert, MD, FAACT, FACMT
Section Editors: Daniel F Danzl, MD, Stephen J Traub, MD
Deputy Editor: James F Wiley, II, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2021. | This topic last updated: May 25, 2021.
INTRODUCTION
This topic will review the management of poisonous Crotalinae (rattlesnake, water moccasin
[cottonmouth], or copperhead) snakebites. The clinical manifestations, evaluation, and
diagnosis of these snakebites; evaluation and management of bites by coral snakes; and
snakebites outside the United States are discussed separately:
● (See "Bites by Crotalinae snakes (rattlesnakes, water moccasins [cottonmouths], or
copperheads) in the United States: Clinical manifestations, evaluation, and diagnosis".)
● (See "Evaluation and management of coral snakebites".)
● (See "Snakebites worldwide: Clinical manifestations and diagnosis" and "Snakebites
worldwide: Management".)
FIRST AID
The appropriate first aid for snakebites is controversial, and management strategies are
primarily based on case series and clinical experience [1]. Numerous field measures have been
advocated, but none have been shown to improve outcome [2].
● Remove the patient from the snake's territory and keep him or her warm, at rest, and calm.
● Remove any rings, watches, or constrictive clothing from the affected extremity.
● Immobilize the injured body part in a functional position at the level of the heart initially [1].
Further actions should be guided by an experienced clinician. Decisions regarding
dependency or elevation of the bitten part must balance a potential increase in local injury
with that for increased systemic venom absorption. Placing the extremity below the level of
the heart may lead to increased tissue damage in some patients but may be appropriate in
patients who have systemic effects of envenomation [3]. In contrast, elevation of a swollen
extremity to prevent acute swelling in patients without systemic symptoms may
subsequently increase systemic venom absorption but may be acceptable if the time to
definitive care, including antivenom administration, is short [2].
● Do not apply pressure immobilization, tourniquets, or constrictive dressings. Pressure
immobilization refers to a procedure in which an elastic bandage is applied to the affected
limb with a goal of delaying venom spread through the lymphatics but is not applicable and
not advisable for the initial management of Crotalinae pit viper bites. Although pressure
immobilization is mentioned as a potential first aid therapy for snakebites in the United
States by the American Heart Association [4], no clinical studies in human patients have
demonstrated benefit. Most snakebite experts do not support pressure immobilization for
Crotalinae snakebites because these venoms cause local tissue toxicity, and sequestering
the venom in the affected limb may increase local tissue damage [5-7].
Pressure immobilization may be useful as a first aid procedure for neurotoxic snakebites
and is discussed in greater detail separately. (See "Snakebites worldwide: Management",
section on 'Pressure immobilization'.)
● Cleanse the wound.
● Withhold alcohol and drugs that may confound clinical assessment.
● Avoid potentially harmful therapies.
● Transport the patient in the supine position to the nearest medical facility as quickly as
possible, preferably using emergency medical services.
 ● Attempts to identify the snake should not endanger the patient or rescuer and should
never delay transport to a medical facility. A digital photo taken at a safe distance may be
useful. Snake parts should not be handled directly because the bite reflex may remain
intact in recently killed snakes and result in additional envenomation [3].
Misidentification (particularly in an emergency situation) may have potentially serious
outcomes, and patients with possible envenomation should be observed closely [8]. It may
be difficult to determine whether a snake is venomous or not. Several characteristics have
been proposed but are not a substitute for expert consultation ( figure 1) [3]. Venomous
rattlesnakes have a triangular-shaped head, elliptical pupils, and hollow, retractable fangs.
In contrast, nonvenomous snakes have rounded heads and pupils and lack fangs but may
be very effective mimics of venomous snakes in terms of appearance or behavior.
Methods such as tourniquets, incision and oral suction, mechanical suction devices,
cryotherapy, surgery, and electric shock therapy have no role in snakebite management (
algorithm 1B) [5]. Tourniquets can damage nerves, tendons, and blood vessels; and oral
suction can lead to infection [3,9,10]. Furthermore, attempted venom removal by mechanical
suction is minimal at best. In a study of attempted mock venom extraction with a mechanical
suction device in human volunteers, suction reduced the total body venom burden by only 2
percent [11].
APPROACH TO EMERGENCY DEPARTMENT CARE
Treatment depends upon the degree of toxicity, which is estimated by clinical assessment and
ancillary studies, and guides the use of antivenom ( table 1) [5]. (See "Bites by Crotalinae
snakes (rattlesnakes, water moccasins [cottonmouths], or copperheads) in the United States:
Clinical manifestations, evaluation, and diagnosis", section on 'Evaluation'.)
INITIAL STABILIZATION
Stabilization of patients with Crotalinae snakebites requires rapid assessment and management
of the airway, breathing, and circulation:
● Airway and breathing – In addition to emergency antivenom administration, patients with
airway compromise require endotracheal intubation and mechanical ventilation. Patients
with the following clinical features are at highest risk:
MINOR ENVENOMATION
• Bites to the face or neck – Crotalinae snakebites to the face or neck, or intravascular
envenoming, may result in rapid local tissue swelling with airway obstruction.
• Myokymia (rippling muscle movement of the face and extremities) – Myokymia, a
rare manifestation of rattlesnake envenomation, does not reliably respond to
antivenom administration and may cause airway compromise by interfering with the
patient's ability to swallow [12-15].
• Mojave or Pacific coast rattlesnake bite – Bites by these snakes can cause an
ascending paralysis that can be delayed [16,17]. Although the decision to perform
endotracheal intubation and institute mechanical ventilation should be made on
clinical grounds (including the need for airway protection associated with bulbar palsy),
ancillary studies may provide additional objective information to augment serial clinical
assessment in some patients. Options include:
- Serial measurements of pulmonary function, especially maximal inspiratory
pressure (MIP), maximal expiratory pressure (MEP), and forced vital capacity (FVC)
- Detection of hypercarbia by noninvasive capnography and/or blood gas
measurement
Continuous pulse oximetry is advisable but is insensitive for the detection of
respiratory failure. (See "Tests of respiratory muscle strength", section on
'Interpretation' and "Respiratory muscle weakness due to neuromuscular disease:
Management", section on 'Chronic ventilatory support'.)
● Circulation – Emergency management of shock and coagulopathy followed by timely
antivenom administration to patients with moderate or severe envenomation comprise the
most common actions needed when stabilizing patients with Crotalinae snakebites.
Hypovolemia from hemorrhage secondary to coagulopathy, fluid shift into the bitten limb,
and/or direct venom effects with vasodilation or myocardial depression may cause shock
with hypotension [3]. These patients warrant treatment with rapid infusion of normal saline
or blood (depending upon degree of hemorrhage and to maintain the hematocrit at
acceptable levels) and, if shock is not reversed and central venous pressure is not low,
vasoactive medications, similar to patients with septic shock. (See "Septic shock in children:
Rapid recognition and initial resuscitation (first hour)" and "Evaluation and management of
suspected sepsis and septic shock in adults".)
Patients with minor envenomation have swelling that is localized to the bite site and do not
have systemic signs of envenomation, thrombocytopenia, coagulopathy on laboratory studies
(ie, normal platelet count, prothrombin time [PT], partial thromboplastin time [PTT],
international normalized ratio [INR], fibrinogen, and fibrin degradation products [eg, D-dimer
or fibrin split products]), or bleeding ( table 1). Other than following bites to the face or neck,
these patients should not routinely receive antivenom. Management should focus on pain
control, wound care, immobilization and positioning of the bite site, and close monitoring for
development of moderate or severe envenomation.
Bites to the face or neck — For patients with Crotalinae snakebite sites that present a
significant possibility for airway obstruction from local tissue swelling (eg, bites to the face or
neck), we recommend antivenom administration even in the absence of systemic symptoms.
Patients with bites in these locations can have rapid onset of critical airway compromise from
local swelling alone. (See 'Antivenom therapy' below.)
Pain control — Patients with mild to moderate pain may receive oral analgesia with
acetaminophen. Patients with rattlesnake or water moccasin snakebites whose clinical course
suggests that the risk of coagulopathy or thrombocytopenia is low and patients with
copperhead bites and minimal coagulopathy may receive nonsteroidal antiinflammatory
medications (eg, ibuprofen) [18,19]. Severe pain warrants treatment with intravenous (IV) opioid
medications (eg, fentanyl or morphine).
Wound management — Wound management includes cleansing the skin surface around the
bite site with an iodine-containing or other antiseptic solution such as chlorhexidine, removal of
any visible foreign bodies, and administration of tetanus prophylaxis according to the
recommended immunization schedule ( table 2). The leading edge of swelling and
tenderness should be marked and reassessed every 15 to 30 minutes. (See "Tetanus-diphtheria
toxoid vaccination in adults".)
Superficial debridement of hemorrhagic bullae at the bedside to permit recognition of
underlying necrosis and to help decide further intervention has been proposed [20]. However,
we do not endorse this approach because there are insufficient data demonstrating benefit or
evaluating the risks, such as infection, of unroofing intact bullae.
Antibiotic prophylaxis is not indicated. Although snakebites may result in the inoculation of
bacteria, infection is rare. A retrospective analysis of over 2500 rattlesnake bites reported to a
regional poison control center found an infection rate of at most 1 percent based, in most
cases, on clinical appearance [21]. These results may overestimate the frequency of infection in
snakebites because inflammation from venom effects may track up lymphatic channels and
mimic cellulitis. Thus, only patients with established infections or heavily contaminated wounds
should receive antibiotics [3]. Empiric treatment should cover Salmonella species and common
human organisms (eg, Staphylococcus aureus and group A streptococcus) until wound culture
results are available. (See "Cellulitis and skin abscess in adults: Treatment" and "Suspected
Staphylococcus aureus and streptococcal skin and soft tissue infections in children >28 days:
Evaluation and management" and "Nontyphoidal Salmonella bacteremia", section on
'Treatment'.)
Immobilization and positioning — Proper immobilization and positioning for snakebites to
the distal extremities consists of placement of a well-padded splint (preformed, plaster, or
fiberglass) that is gently secured to the extremity with a gauze or elastic wrap applied to avoid
excessive pressure or restriction of circulation. In facilities where antivenom is immediately
available, we advise elevation of the extremity to reduce acute swelling. If antivenom is not
immediately available, similar to first aid guidance, positioning should be determined based
upon the presence or absence of systemic symptoms in consultation with a snakebite expert.
(See 'First aid' above.)
Impaired limb function — Because complete recovery is expected with supportive care alone
in patients with minor Crotalinae envenomation that does not progress, expert guidelines
recommend that antivenom therapy in patients with bites to a limb be reserved for those who
have more than minimal envenomation that is progressing [5,22-26]. Patients with confirmed
copperhead bites appear to be at a lower risk for systemic toxicity and progressive swelling but
may have impairment of function due to swelling and pain in the involved extremity long
enough to cause significant short-term morbidity (eg, inability to work or attend school). In one
study, the duration of this impairment was a median of three weeks with a range of three days
to four months [22].
Some experts have suggested that FabAV may provide short-term benefit to patients with mild
copperhead envenomation with acceptable risk, primarily minor adverse effects and increased
cost of care. However, more data are needed to identify which patients are most likely to benefit
and to establish if antivenom improves function enough to offset the potential risk of serious
adverse effects, such as anaphylaxis, when only local venom effects are present. As an example,
in one small trial of 74 patients with copperhead bites, treatment with polyvalent Crotalinae
ovine immune Fab (FabAV, CroFab) modestly improved limb function and reduced use of opioid
pain medication at two weeks but did not shorten the time to full recovery compared with
placebo [22]. Although the benefit regarding local venom effects in rattlesnake envenomations
has not been studied, there is no reason to believe that similar benefits would not apply to
these cases as well. Patients who received FabAV had more minor adverse events (eg, pruritus,
urticaria, nausea, dizziness, or fever) but no severe effects.
Observation and monitoring — Patients with possible Crotalinae envenomation who initially
have mild or no toxicity on clinical assessment and normal baseline testing should be observed
for progression of local and systemic toxicity. If the patient appears well and repeat laboratory
tests (ie, platelet count, PT, PTT, INR, and fibrinogen) remain normal at 8 to 12 hours, and the
one-time measure of fibrin degradation products (ie, D-dimer or fibrin split products) is not
elevated, it is likely that no significant envenomation has occurred, and the patient may be
discharged as long as pain is controlled. A longer period of observation up to 24 hours may be
necessary for children, older adults, and patients with significant comorbidities, poor social
supports, some symptoms of envenomation, and bites involving the lower limbs or face/neck.
A somewhat longer period of observation (12 to 24 hours) is also necessary for asymptomatic
patients with suspected Mojave or Pacific coast rattlesnake bites because neurotoxicity (eg,
ascending paralysis) may be delayed, though myokymia is usually an early effect of low
molecular weight venom toxins [16]. Monitoring for complications of paralysis should also be
performed. (See 'Initial stabilization' above.)
Patients with rapidly progressive swelling or abnormal coagulation testing during the
observation period have moderate to severe envenomation and should receive antivenom as
described below. They also warrant assessment for rhabdomyolysis. (See 'Antivenom therapy'
below and 'Supportive care' below.)
Discharge instructions — Patients who do not receive antivenom should be instructed to seek
medical care for increased swelling not relieved by elevation, signs of coagulopathy (eg, easy
bruising, petechiae, bleeding from gums or hematochezia), signs of infection (eg, fever or pus
drainage), tissue necrosis, pain not controlled by oral analgesia, or any other acutely concerning
changes in signs or symptoms ( algorithm 1B).
MODERATE TO SEVERE ENVENOMATION
Patients with moderate to severe Crotalinae envenomation have marked swelling, systemic
findings of envenomation, abnormal coagulation testing, and/or bleeding ( table 1). In
addition to treatment of local effects, treatment with Crotalinae antivenom is recommended (
algorithm 1A). (See 'Antivenom therapy' below.)
Antivenom therapy
Initial treatment — Consultation with a medical toxicologist or other physician with
expertise and prior experience treating venomous snakebites is strongly encouraged before
initiating antivenom therapy. Emergency consultation with a medical toxicologist in the United
States is available at 1-800-222-1222. Regional poison control centers can also assist with
locating and facilitating transport of antivenom to the treating facility.
For patients with moderate to severe toxicity after bites by Crotalinae snakes ( table 1), we
recommend antivenom therapy ( table 3). Antivenom is most effective when given within six
hours of the snakebite. Crotalidae Polyvalent-immune Fab (ovine), brand name CroFab (FabAV)
[5,27-38] and Crotalidae Immune F(ab')2 (equine), brand name Anavip (Fab2AV) [39,40] are each
approved for North American Crotalinae snakebites and have similar efficacy as described
below. (See 'Efficacy' below.)
For patients exhibiting neurotoxicity (muscle fasciculation and/or motor weakness) after a
North American rattlesnake bite, FabAV may be preferred. FabAV is raised, in part, against the
venom of the Mojave rattlesnake (C. scutulatus) and may have greater benefit for the
neurotoxicity of Mojave factor in envenomations by Mojave rattlesnakes and Southern Pacific
rattlesnakes (Crotalus oreganus helleri). However, the response of neurotoxicity to FabAV has
been variable [41-43]. Patients with airway compromise or depressed respirations warrant
emergency endotracheal intubation and mechanical ventilation.
Evidence is lacking regarding the efficacy of Fab2AV for neurotoxicity.
● Relative contraindications – For patients receiving FabAV (CroFab), relative
contraindications include allergy to papain, papaya, or FabAV during prior administration.
Relative contraindications for the use of Fab2AV include patients with known allergies to
horse protein or who have had an allergic reaction to prior therapy with Fab2AV antivenom.
When relative contraindications are present, antivenom should only be administered when
the benefits outweigh the risks [38]. These patients require pretreatment for anaphylaxis
and adjustment of the rate of infusion as described separately. (See 'Treatment of acute
antivenom reactions' below.)
Pregnancy is not a contraindication to antivenom administration; indirect experience with
other antivenoms suggests that potential adverse effects to the fetus following pregnancy
are primarily related to venom effects on the mother. Although acute antivenom reactions
may occur in the mother, antivenom plus any required anaphylaxis management is likely
the best approach to improved fetal outcome [38,40,44]. Case reports have also
documented delivery of healthy newborns soon after FabAV antivenom therapy [45-47].
 ● Dose and administration — The table summarizes dosing, reconstitution, and
administration for Crotalidae Polyvalent-immune Fab (ovine), brand name CroFab (FabAV)
and Crotalidae Immune F(ab')2 (equine), brand name Anavip (Fab2AV) ( table 3) and is
based upon the manufacturer’s instructions [33,43]. Snakes inject the same quantity of
venom into children and adults. Thus, the dosage of antivenom is not dependent upon age
or weight but does vary with the severity of envenomation; specifically, higher doses of
antivenom are needed for patients with hypotension or serious active bleeding [5].
Antivenom therapy with FabAV or Fab2AV may be associated with potentially severe allergic
reactions, but the risk appears to be low (<1 percent) [39]. Nevertheless, antivenom should
only be administered in a continuously monitored emergency or intensive care unit setting.
Epinephrine ([concentration 1 mg/mL] 0.3 to 0.5 mg intramuscularly [IM] in the
anterolateral thigh and [concentration 0.1 mg/mL] for continuous intravenous [IV]
infusion), diphenhydramine or similar antihistamine, IV corticosteroids, and inhaled
albuterol should all be immediately available. (See 'Treatment of acute antivenom reactions'
below.)
Signs and symptoms of response — The response to antivenom determines whether or not
further and/or increasing doses are required ( table 3 and algorithm 1A). Signs of response
include [12]:
● Improvement in vital signs, including decrease in tachycardia, tachypnea, and hypotension.
● Improvement in other systemic findings such as vomiting, diarrhea, pain, oral paresthesias,
or altered mental status.
● Lack of progression of tissue swelling and ecchymosis adjacent to the bite site.
● Partial or complete reversal of hematologic toxicity based upon repeated laboratory studies
performed one hour after each dose of antivenom. Studies should include a complete
blood count, prothrombin time (PT), partial thromboplastin time (PTT), international
normalized ratio (INR), fibrinogen, and fibrin degradation products (eg, D-dimer or fibrin
split products).
Treatment of acute antivenom reactions — Based upon the comparative trial between
FabAV and Fab2AV, the rate of acute serum reaction and serum sickness for patients receiving
either FabAV or Fab2AV is approximately 2 to 3 percent [39,48]. Patients who handle Crotalinae
snakes or have previously received Crotalinae antivenom (or, for Fab2AV antivenom, other
equine antivenoms) may be predisposed to acute allergic reactions.
In patients who experience signs of acute hypersensitivity (eg, anaphylactic shock,
oropharyngeal swelling, bronchospasm, or urticaria) or nonimmunologic acute reactions (eg,
nausea, vomiting, arthralgia, headache), the clinician should immediately stop antivenom
infusion. Patients with signs suggestive of anaphylaxis should receive emergency treatment as
outlined in the rapid overview for adults ( table 4) or children ( table 5). (See "Anaphylaxis:
Emergency treatment", section on 'Immediate management'.)
Consultation with a medical toxicologist experienced in the management of Crotalinae
snakebites is strongly encouraged for these patients. Further management depends upon the
nature of the reaction [12]:
● Acute hypersensitivity – Once anaphylaxis is controlled, a decision regarding restarting
the antivenom infusion should be based on a risk-to-benefit analysis. Clinicians may choose
to proceed with antivenom administration in patients who manifest serious systemic
toxicity despite the presence of allergy. If resumption of antivenom therapy is chosen, then
the patient should receive pretreatment to blunt the allergic response (eg, IV
diphenhydramine 1.25 mg/kg, maximum single dose 100 mg and/or IV methylprednisolone
2 mg/kg, maximum single dose 125 mg), and the clinician should ensure preparation and
immediate availability of epinephrine (0.3 to 0.5 mg IM to the anterolateral thigh, 1:1000
preparation or continuous IV infusion of 1:10,000 epinephrine 0.1 to 1 microgram per
minute, titrated to effect) before administration of any antivenom. Antivenom should be
administered at a lower infusion rate (eg, 25 mL/hour or slower).
● Acute reactions without hypersensitivity – Because acute reactions are often
nonimmunologic in nature, the antivenom infusion may be resumed cautiously and
completed at a lower infusion rate (eg, 25 mL/hour).
If signs or symptoms of anaphylaxis or hypersensitivity reactions occur again, antivenom
administration should be discontinued immediately, appropriate therapy instituted, and the
need for further antivenom treatment re-evaluated.
Prevention of recurrent toxicity (FabAV) — To prevent recurrent toxicity marked by
subsequent worsening of local (eg, swelling) or systemic (eg, deterioration in the coagulation
parameters following initial normalization) effects after initial improvement, we suggest that
patients with Crotalinae snakebites and moderate to severe envenomation who have
undergone FabAV administration receive scheduled doses of antivenom (two vials every six
hours for three doses) ( table 1 and algorithm 1A and algorithm 1B) [5,33,38].
Alternatively, if medical toxicology oversight and resources allow, the clinician may choose to
perform careful clinical assessment of the bite site and measurement of coagulation studies
every six hours to determine the need for additional antivenom [49].
Among patients with coagulopathy who receive FabAV, the risk of recurrent toxicity is
approximately 30 to 50 percent depending upon the geographic region, snake species involved,
and other factors. Recurrent toxicity may be apparent within 24 hours but can also occur or
persist beyond 14 days after initial control with antivenom [39]. This risk is increased in patients
with abnormal coagulation within the first 12 hours after FabAV administration [50]. Additional
markers for recurrent coagulopathy include [51]:
● Abnormalities within 48 hours of a snakebite in platelet count, PT, PTT, INR, D-dimer,
fibrinogen, or fibrin split products
or
● A rise of ≥20 percent in platelet count within four hours of FabAV administration, regardless
of initial platelet count.
Individuals with any of these markers are at particular risk for recurrent coagulopathy.
However, late, new-onset hematologic abnormalities may develop even without these indicators
[52]. Thus, all patients warrant serial coagulation profiles after antivenom therapy at two to
three days and again at five to seven days, with additional monitoring as indicated by
abnormalities or trends.
This approach is based upon evidence that suggests that scheduled doses of FabAV appear to
prevent recurrent toxicity. For example, in an open-label, multicenter trial of 31 patients who
received an initial dose of FabAV with control of toxicity, the 15 patients who received scheduled
treatment of approximately 2 g (two vials) every six hours for three doses did not experience
recurrence, while 8 of 16 patients in the group who only received further antivenom if recurrent
symptoms developed required no further antivenom therapy [33]. Post-hoc analysis indicated
that scheduled maintenance dosing also reduced the incidence of coagulation abnormalities at
follow-up compared with as-needed dosing [38].
Some experts suggest that, in settings where close monitoring of local swelling and
coagulation parameters can occur, as-needed dosing of FabAV antivenom may be more
appropriate than scheduled dosing. For example, in a retrospective observational study of
310 adults that compared hospital length of stay and total vials used between patients
treated with an as-needed versus a scheduled maintenance antivenom regimen, the as-
needed group received fewer vials overall (8 versus 16 vials) and had a shorter hospital
length of stay (27 versus 34 hours) [49]. The duration of follow-up was insufficient to
determine if recurrence of hematologic abnormalities occurred after discharge. However,
patients were admitted to a toxicology service managed by full-time toxicology faculty
practicing at the bedside and covered by 24-hour onsite medical toxicology fellows. The
immediate availability of physicians with a high level of snakebite expertise likely optimized
timely detection of local recurrence and hastened administration of antivenom when
necessary. From a practical standpoint, this degree of monitoring is not available at most
hospitals where snakebite victims are managed. In those settings, a delay in recognition of
and response to recurrence of local venom effects could result in increased local tissue
injury, and scheduled maintenance dosing of FabAV is preferred.
Identification and treatment of recurrent toxicity — Recurrent toxicity refers to
subsequent worsening of local (eg, swelling), or systemic (eg, deterioration in the coagulation
parameters following initial normalization) effects despite initial control with antivenom.
Recurrent toxicity may occur after administration of either FabAV or Fab2AV. For FabAV,
recurrence may be evident as soon as 24 hours after initial treatment and is common enough
to warrant routine maintenance doses during the first day of treatment ( table 3) [5]. For
Fab2AV, recurrent toxicity is less likely than with FabAV but may be seen several days after
administration. Thus, all patients who receive antivenom warrant monitoring (physical
assessment and laboratory studies) for recurrent toxicity [33]. (See 'Prevention of recurrent
toxicity (FabAV)' above.)
For patients with recurrent toxicity, treatment varies according to the antivenom that was
initially administered:
● FabAV (Crofab) – Redosing of FabAV after the initial phase of treatment and maintenance
antivenom therapy is indicated for patients who have bleeding or any one of the following
findings suggestive of ongoing venom effects:
• Plasma fibrinogen <50 mcg/mL
• Platelet count <25,000/mL
• INR >3.0
• Activated PTT >50 seconds
• Multiple defects in coagulation parameters
• Comorbid conditions or behaviors that increase hemorrhagic risk
In patients who have persistent or recurrent toxicity, these findings may be seen up to
several weeks after envenomation. Retreatment should be performed in consultation with
a medical toxicologist or other physician with expertise in managing Crotalinae snakebites.
An initial bolus dose of two vials is a reasonable starting point, with additional doses
titrated to the neutralization of ongoing venom effects [50]. For patients in whom recurrent
 toxicity is severe or difficult to control, a continuous infusion of FabAV may be a more
efficient way to maintain a continuously protective, circulating concentration of antivenom.
In some instances, total reversal of coagulopathy with FabAV is not possible, and the
clinician may choose improvement in coagulation parameters towards normal as an
acceptable outcome in patients who have no significant bleeding [35].
● Fab2AV (Anavip) – Recurrent coagulopathy can occur with Fab2AV, presents the same
bleeding risks when present, and is not predictable. For these reasons, all patients who
receive Fab2AV should have reassessment of their coagulation status within five days after
antivenom administration.
No routine maintenance doses are recommended after control has been achieved with
Fab2AV. However, an additional four vials may be given for recurrent toxicity identified at
follow-up [40].
Efficacy — Crotalidae Polyvalent-immune Fab (ovine), brand name CroFab (FabAV); and
Crotalidae Immune F(ab')2 (equine), brand name Anavip (Fab2AV) are the two antivenoms
available for bites by Crotalinae snakes in North America:
● FabAV (CroFab) – FabAV consists of the purified Fab fragments of sheep immunoglobulin
(IgG) raised against the venom of four snakes: Crotalus atrox (western diamondback
rattlesnake), Crotalus adamanteus (eastern diamondback rattlesnake), Crotalus scutulatus
(Mojave rattlesnake), and Agkistrodon piscivorus (cottonmouth or water moccasin)
[29,50,53]. When infused, these Fab fragments bind venom in the intravascular space and
are renally excreted. The larger volume of distribution, compared with IgG and Fab2AV,
results in more rapid decline in circulating antivenom levels.
Because approximately 50 percent of patients in the first phase of the clinical trial
developed recurrence of local venom effects, routine maintenance doses in the first 18
hours are recommended for control of local effects. The half-life of FabAV is approximately
15 hours and shorter than Crotalinae venom substances, which may be detected for more
than two weeks post-envenomation. Thus, recurrent toxicity is possible despite initial
control of systemic effects and may necessitate repeated FabAV administration. FabAV
appears most effective when given within six hours of envenomation [30].
● Fab2AV (Anavip) – Fab2AV consists of the purified F(ab')2 fragments of equine IgG raised
against the venom of Bothrops asper and Crotalus durissus [39,54]. When infused, these
F(ab')2 fragments bind venom in the intravascular space. Because of the smaller volume of
distribution compared with FabAV, circulating antivenom concentrations do not decline as
rapidly, and routine maintenance doses in the first 18 hours following initial control are not
required. Although no studies have specifically looked at the effectiveness of Fab2AV and
time to treatment, it had similar effectiveness to FabAV when given in the same timeframe
[39].
Because the molecular weight of Fab2AV is above the threshold for renal clearance, these
fragments are not cleared renally and have a longer half-life (133 hours) than FabAV [40].
Thus, recurrent hematologic toxicities occur at a lower rate than with FabAV [34].
Based upon small trials and observational studies, the majority of envenomated patients
achieve control of toxicity (local swelling and systemic effects) after initial administration of one
or two loading doses of either FabAV [32-35,37,55] or Fab2AV [39,56], with some patients
requiring additional doses. There is an approximately 2 to 3 percent risk of adverse immune
reactions or type 1 (acute) and type 3 (delayed, "serum sickness") hypersensitivity; almost all of
these are typically minor [39]. Evidence is limited regarding the comparative effectiveness of
FabAV versus Fab2AV:
● FabAV – Among patients receiving FabAV, initial control appears less likely in patients with
severe envenomation compared with patients with moderate envenomation [35,39]. For
patients receiving FabAV, thrombocytopenia and/or neurologic effects on presentation
have been associated with difficulty achieving initial control [32]. In addition, FabAV
antivenom did not reverse the thrombocytopenia following a reported timber rattlesnake
envenomation [57].
● Fab2AV – Fab2AV appears to have similar initial therapeutic benefit and risk profile as
FabAV . For example, in a trial of over 110 children and adults with Crotalinae
envenomation, Fab2AV was found to have comparable efficacy as FabAV in terms of initial
control of hematological effects of rattlesnake envenomation. Individuals receiving Fab2AV
also did not require maintenance dosing for continued control of local envenomation
effects, had a lower incidence of late coagulopathy (5 to 10 percent for Fab2AV versus 30
percent for FabAV [absolute risk reduction 0.20, 95% CI 0.01-0.37]), and had similar rates of
type 1 and type 3 hypersensitivity reactions (2 to 3 percent) [39]. In an observational study
of 37 patients with rattlesnake envenomation from the New Mexico regional poison control
center, both Fab2AV and FabAV achieved initial control of local effects and managed initial
coagulopathy without rescue therapy [56]. In a subsequent analysis of 72 patients from the
same regional poison control center that included patients from this study, late
coagulopathy was significantly more likely in patients treated with FabAV (22 percent [46
patients]) compared with Fab2AV (4 percent [26 patients]) [58].
Prior to the availability of antivenoms active against Crotalinae snakebites and the widespread
availability of emergency departments and critical care units, snakebite mortality ranged from 5
to 36 percent in the United States [27,31,59]. After the introduction of Antivenin Crotalidae
Polyvalent (ACP; Wyeth) in the 1950s and the development of widespread availability of
emergency and critical care medicine starting in the 1960s, deaths from snakebites dropped to
less than 1 percent. For example, analysis of 23,676 venomous snake exposures from 2001 to
2005 reported to the American Association of Poison Control Centers database found a fatality
rate of 0.06 percent [60]. Similarly, no fatalities occurred in a United States registry study of 442
native pit viper snakebites occurring from 2013 to 2015 [61]. Thus, the availability of antivenom
for most native Crotalinae snakebites combined with other trends in emergency and critical
care capability has been associated with a marked and sustained decrease in snakebite
mortality in the United States.
Additional observational experience suggests that untreated Crotalinae envenomation is rarely
fatal in regions where copperhead bites predominate but can be life or limb threatening. For
example, an observational study of 81 adult and pediatric patients who were managed without
antivenom therapy after snakebite (45 copperhead, 12 water moccasin [cottonmouth], 10
rattlesnake, and 14 unknown) reported no fatalities or long-term morbidity [62]. However,
significant acute toxicity did occur, including coagulopathy (15 patients), skin necrosis (8
patients), respiratory distress requiring endotracheal intubation (3 patients), hypotension (2
patients), and cardiac arrhythmia (2 patients).
Supportive care — Antivenom administration is the mainstay for treatment of moderate to
severe envenomation by North American Crotalinae snakes.
In addition, the clinician should provide pain control and monitor for and be ready to manage
hypotension, thrombocytopenia, coagulopathy, rhabdomyolysis, elevated tissue and/or
compartment pressures, and, rarely, respiratory failure (following a Mojave or southern Pacific
rattlesnake bite).
Pain control — Although evidence is limited, patients with rattlesnake or water moccasin
snakebites whose clinical course suggests that the risk of coagulopathy or thrombocytopenia is
low or patients with copperhead bites and minimal coagulopathy may receive initial analgesia
for mild to moderate pain with acetaminophen or nonsteroidal antiinflammatory medications
(eg, ibuprofen) [18,19]. Severe pain after snakebite frequently warrants treatment with opioid
medications (eg, fentanyl or morphine).
Coagulopathy and thrombocytopenia — The coagulopathy associated with Crotalinae
envenomation is due to thrombin-like glycoproteins within the venom as well as
thrombocytopenia [63]. This pathophysiology is in contrast to true disseminated intravascular
coagulation (DIC), where fibrinolysis is activated by increased levels of endogenous thrombin.
Thus, antivenom administration, and not coagulation factor replacement, is the primary
treatment for Crotalinae-induced coagulopathy. (See 'Antivenom therapy' above.)
In patients with recurrent coagulopathy despite initial control with FabAV, hematologic
abnormalities may persist for more than two weeks [50]. Recurrent toxicity appears to be less
common after successful treatment with Fab2AV but still warrants monitoring (See
'Identification and treatment of recurrent toxicity' above.)
Transfused platelets and coagulation factors in fresh frozen plasma are inactivated by
Crotalinae venom and should be avoided in patients with Crotalinae-induced coagulopathy
unless the patient has significant bleeding that is uncontrolled by high-dose antivenom
administration ( algorithm 1B) [63]. Whenever blood or blood products are given to replenish
platelets or clotting factors (fibrinogen or factors in the cascade), it should be given with
additional antivenom to prevent rapid depletion of those components.
Because Crotalinae-induced coagulopathy arises from thrombin-like substances in the venom
that are not inhibited by antithrombin III, heparin is also ineffective [63,64].
Rhabdomyolysis — Rhabdomyolysis (creatine phosphokinase [CK] ≥1,000 IU/L) with
potential for renal failure has been described in approximately 5 percent of patients bitten by
rattlesnakes or water moccasins (cottonmouths) but is rare after copperhead bites [61]. The
classic triad consists of pigmented granular casts in the urine, a red to brown color of the urine
supernatant, and a marked elevation in the plasma level of CK. Primary treatment goals consist
of fluid repletion and evaluation for significant electrolyte abnormalities (hyperkalemia,
hyperphosphatemia, hypocalcemia). (See "Clinical features and diagnosis of heme pigment-
induced acute kidney injury", section on 'Clinical manifestations' and "Prevention and treatment
of heme pigment-induced acute kidney injury".)
Elevated tissue pressures — Elevated tissue pressures may complicate Crotalinae bites. Any
dressing, constriction band, splint, cast, or other restrictive covering should be removed. Venom
is usually introduced into the subcutaneous tissues, and most, if not all, edema occurs in this
space. Tissue pressures may increase because of the massive amounts of subcutaneous tissue
fluid and because the skin has limits to its elasticity. Swelling, pain, and paresthesias may occur
in patients after Crotalinae snakebite, but true elevation in compartment pressure is
uncommon. Antivenom administration is the primary treatment in this situation; surgical
intervention based on clinical findings alone is inappropriate ( algorithm 1B).
Generally, increased compartment pressures result from this extrinsic pressure and can be States for exotic, non-United States snakebites, even in the setting of initially normal clinical
reduced with the administration of adequate amounts of antivenom and elevation. After appearance. (See "Snakebites worldwide: Clinical manifestations and diagnosis".)
antivenom administration, elevation results in the drainage of subcutaneous edema and
At discharge, patients who have received antivenom should also receive the following
contributes to the reduction of the source of increased tissue pressure. (See 'Immobilization
instructions ( algorithm 1B) and be scheduled for recommended follow-up:
and positioning' above.)
● Seek care if they develop symptoms of serum sickness (fever, rash, muscle pain, arthralgia,
Compartment syndrome — True compartment syndrome with documented elevations of
or arthritis).
muscle compartment pressure is uncommon after Crotalinae snakebites, and fasciotomy is
rarely indicated. For example, among 442 patients with snakebite from the North American ● If they had coagulopathy during their care or were victims of a rattlesnake envenomation,
Snakebite Registry, only eight (2 percent) had clinical findings concerning for compartment they should avoid contact sports, surgery, or dental work for two weeks.
syndrome and only two (0.5 percent) had elevated intracompartmental pressure documented,
although six received fasciotomy [61]. ● Patients bitten by a rattlesnake or water moccasin (cottonmouth) should also have PT,
fibrinogen, hemoglobin, and platelets measured two to three days and five to seven days
Bites to a muscle that is very close to the skin (eg, anterior tibial, hand, or foot compartments) after the bite.
have a higher potential for compartment syndrome. For these patients, antivenom and
elevation may still reduce compartment pressures by the reduction of extrinsic pressure, but
persistent intracompartmental pressures may remain high. The indications for fasciotomy in SERUM SICKNESS
this context are unclear. An animal model of direct compartmental injection of venom
Serum sickness occurs in about 2 to 3 percent of patients receiving either FabAV or Fab2AV. The
demonstrated improved outcomes with antivenom alone versus antivenom plus immediate
evaluation and management of serum sickness is discussed separately. (See "Serum sickness
fasciotomy, but application to human bites is uncertain [65]. If there is a concern for clinically
and serum sickness-like reactions".)
significant increased tissue or compartment pressures, direct measurement with an
appropriate device should be performed to guide additional management with antivenom and
elevation [66,67] (see "Acute compartment syndrome of the extremities", section on OUTCOMES
'Measurement of compartment pressures'). Further management should be guided by a
medical toxicologist and surgeon with extensive experience caring for victims with snakebite. Most victims of venomous North American snakebites fully recover. Morbidity is uncommon
and associated with bites to the face or upper extremity [63]. Loss of range of motion is most
Full recovery has been described with nonsurgical management of acute compartment
common. Other permanent sequelae include weakness, pain, abnormal sensation (paresthesia,
syndrome in the hand (compartment pressure of 55 mmHg) in a patient with a rattlesnake bite
hypesthesia, anesthesia), or skin discoloration.
to the thenar eminence [68]. The patient received large amounts of polyvalent Crotalinae
antivenom (46 vials total) and 20 g of IV mannitol. Tissue necrosis occurs frequently and may require operative debridement. For example, in a
prospective cohort of rattlesnake envenomation, tissue necrosis was seen in 40 percent of
Neurotoxicity — Neurotoxicity, such as ascending paralysis, may rarely occur after bites by
upper extremity envenomations, despite antivenom administration [20]. Signs on presentation
North American rattlesnakes (eg, Mojave,Pacific coast, or timber rattlesnakes). Although
associated with increased risk of necrosis included cyanosis and ecchymosis. In addition,
antivenom is recommended, it may not reliably reverse neurotoxicity. Patients with airway
patients with social or regular ethanol use were more likely to develop necrosis, and regular
compromise or depressed respirations warrant emergency endotracheal intubation and
cocaine use was associated with an increased risk of surgical debridement.
mechanical ventilation. (See 'Initial stabilization' above and 'Initial treatment' above.)
Death following Crotalinae snakebite is unusual (<1 percent of all bites) [60,61]. Mortality is
Disposition — All patients who require treatment with antivenom require hospital admission
associated with rattlesnake bites, proximal bite sites (eg, face, neck, trunk), no antivenom
for further observation and supportive care. Hospitalization is also warranted in the United
therapy or inadequate antivenom dosing, or inadequate fluid resuscitation of shock [63].

SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Envenomation by
snakes, arthropods (spiders and scorpions), and marine animals".)
SUMMARY AND RECOMMENDATIONS
● First aid measures for patients with Crotalinae (rattlesnake, water moccasin [cottonmouth],
or copperhead) bites consist of moving the patient away from the snake, keeping the
patient calm and at rest, immobilizing the affected extremity initially at the level of the
heart, and rapid transport to definitive care. For patients with bites by Crotalinae snakes,
we discourage the use of pressure immobilization. (See 'First aid' above.)
● Treatment of patients with minor envenomation consists of pain control, local wound
management, tetanus immunization when indicated, immobilization, and, in facilities with
immediately available antivenom, elevation of the affected extremity. Because complete
recovery is expected with supportive care alone in patients with minor Crotalinae
envenomation that does not progress, expert guidelines recommend that antivenom
therapy be reserved for patients with bites to the face or neck or who have more than
minimal and progressing snakebite envenomation. (See 'Minor envenomation' above.)
● For patients with minor Crotalinae envenomation, we suggest close observation (eg,
continuous monitoring with frequent vital signs and repeated assessment of degree of
swelling and tenderness) for 12 to 24 hours to ensure that progression of toxicity, as
indicated by worsening local or systemic effects, does not occur ( table 1 and
algorithm 1A). Coagulation studies should be repeated at four to six hours after the bite
and, if all results are normal, once more prior to discharge. A period of observation of 24
hours is indicated for asymptomatic patients with suspected Mojave or Southern Pacific
rattlesnake bites because neurotoxicity (ascending paralysis) may be delayed. (See
'Observation and monitoring' above.)
● For patients with North American Crotalinae bites and moderate to severe envenomation (
table 1 and algorithm 1A), we recommend antivenom therapy (Grade 1A). Crotalidae
Polyvalent-immune Fab (ovine), brand name CroFab (FabAV) and Crotalidae Immune F(ab')2
(equine), brand name Anavip (Fab2AV) have similar efficacy ( table 3) for initial control of
toxic effects; FabAV requires scheduled doses to prevent recurrent toxicity and is associated
with a higher risk for delayed coagulopathy. For patients exhibiting neurotoxicity (muscle
fasciculation and/or motor weakness) after a North American rattlesnake bite, FabAV may
be preferred. Antivenom therapy is most effective when given within six hours of
envenomation. (See 'Initial treatment' above.)
● For patients with Crotalinae snakebite sites that present a significant possibility for airway
obstruction from local tissue swelling (eg, bites to the face or neck), we recommend
antivenom administration even in the absence of systemic symptoms (Grade 1C). (See
'Bites to the face or neck' above.)
● The clinician should immediately stop antivenom infusion in patients who experience signs
of acute hypersensitivity (eg, anaphylactic shock, oropharyngeal swelling, bronchospasm,
urticaria) attributable to antivenom. These patients should receive treatment for
anaphylaxis as outlined in the rapid overviews for anaphylaxis in adults ( table 4) and in
children ( table 5). Cautious resumption of antivenom administration in consultation with
a medical toxicologist or other physician with expertise in Crotalinae snakebite treatment
may be appropriate in patients in whom the benefit of antivenom therapy outweighs the
risk of continued exposure. (See 'Treatment of acute antivenom reactions' above.)
● The response to antivenom determines whether or not further and/or increasing doses are
required. Control of envenomation is supported by improvement in physical signs (reversal
or improvement of tachycardia, hypotension, and local tissue swelling) and reversal or
improvement in thrombocytopenia and/or coagulopathy. (See 'Signs and symptoms of
response' above.)
● For patients who have received FabAV (CroFab), we suggest scheduled doses of FabAV (
algorithm 1A-B and table 3) (Grade 2C). Patients who receive Fab2AV (Anavip) do not
require scheduled antivenom doses but should undergo follow-up testing for recurrent
toxicity. (See 'Prevention of recurrent toxicity (FabAV)' above and 'Identification and
treatment of recurrent toxicity' above.)
● Antivenom administration is the mainstay for treatment of moderate to severe
envenomation by North American Crotalinae snakes. Patients with moderate to severe
envenomation and airway compromise require endotracheal intubation and mechanical
ventilation. Those at highest risk include patients with (see 'Initial stabilization' above):
• Bites to the face or neck
• Myokymia (rippling muscle movement of the face and extremities) and inability to
swallow
• Bites by neurotoxic snakes (Mojave, Pacific coast, or timber rattlesnake)
 ● Hypovolemia from hemorrhage secondary to coagulopathy, fluid shift into the bitten limb, GRAPHICS
and/or direct venom effects with vasodilation or myocardial depression may cause shock
with hypotension [3]. These patients warrant treatment with rapid infusion of normal saline Comparison of native venomous snakes (pit vipers) and
or blood (depending upon degree of hemorrhage and to maintain the hematocrit at nonvenomous snakes in the United States
acceptable levels) and, if shock is not reversed and central venous pressure is not low,
vasoactive medications, similar to patients with septic shock. (See 'Initial stabilization'
above.)

● In addition, the clinician should provide pain control and monitor for and be ready to
manage thrombocytopenia, coagulopathy, rhabdomyolysis, and elevated tissue and/or
compartment pressures. (See 'Supportive care' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Allen Cheng, MB, BS,
FRACP, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 121865 Version 8.0

Reproduced with permission from: Hodge III D. Bites and Stings. In: Textbook of Pediatric Emergency Medicine,
6th edition, Fleisher GR, Ludwig S (Eds), Lippincott Williams & Wilkins, Philadelphia, 2010. Copyright © 2010
Lippincott Williams & Wilkins.

Graphic 73865 Version 11.0

Management of North American Crotalinae* snakebite: Indications for
referral, maintenance therapy (CroFab antivenom), follow-up, and
treatments to avoid
* Includes rattlesnakes, copperheads, and cottonmouths (water moccasins).
Reproduced with permission from: Lavonas EJ, Ruha AM, Banner W, et al. Unified treatment algorithm for the
management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop. BMC
Emerg Med 2011; 11:2. Copyright © 2011.

Graphic 63835 Version 8.0

Consultation with a medical toxicologist is recommended prior to additional

antivenom administration unless the physician has experience with snakebite
treatment. Phone consultation with a medical toxicologist is available through a
United States regional poison control center by calling 1-800-222-1222 .
All treatment recommendations in this worksheet refer to Crotalinae polyvalent
immune Fab (ovine) (CroFab).
This worksheet represents general advice from a panel of United States snakebite experts
convened in May, 2010. No guideline can anticipate all clinical situations. Other valid
approaches exist, and deviations from this worksheet based on individual patient needs,
local resources, local treatment guidelines, and patient preferences are expected. This
document is not intended to represent a standard of care. For more information,
please see the following article.
Clinical classification of United States Crotalinae* envenomation to guide
antivenom administration
Category Tissue effect
Minimal Swelling, pain, and
ecchymosis adjacent to the
bite site
Moderate Swelling, pain, and
ecchymosis less than full
extremity or less than 50 cm
if bite on head, neck, or
trunk
Severe Swelling, pain, ecchymosis
involving more than the
entire extremity; greater
than 50 cm if bite on head,
neck, or trunk; threatens the
airway; OR signs of
compartment syndrome
FabAV: polyvalent Crotalidae ovine immune Fab (Crofab, Protherics); BP: blood pressure.
* Includes bites by rattlesnakes, water moccasins (cottonmouths), and copperheads.
¶ Coagulation parameters include platelet count, prothrombin time (PT), partial thromboplastin time
(PTT), international normalized ratio (INR), fibrinogen, and fibrin degradation products (eg, D-dimer or
fibrin split products [FSP]).
Data from: Goto, CS, Feng, SY. Crotalidae polyvalent immune fab for the treatment of pediatric crotaline envenomation. Pediatr
Emerg Care 2009; 25:273.
Graphic 53948 Version 7.0
Wound management and tetanus prophylaxis
Clean and minor wound All other wounds¶
Previous doses
Systemic signs and Coagulopathy and
of tetanus Tetanus toxoid- Human tetanus Tetanus toxoid- Human tetanus
symptoms bleeding containing immune containing immune
toxoid*
None Normal coagulation vaccineΔ globulin vaccineΔ globulin◊
parameters¶ ; no bleeding
<3 doses or Yes§ No Yes§ Yes
unknown
Present but not life- Abnormal coagulation
≥3 doses Only if last dose No Only if last dose No
threatening (eg, nausea, parameters¶ ; no bleeding or
given ≥10 years given ≥5 years
vomiting, diarrhea, oral minor hematuria, gum
ago ago¥
paresthesia, unusual tastes, bleeding, and/or epistaxis
tachycardia, tachypnea, mild
Appropriate tetanus prophylaxis should be administered as soon as possible following a wound but
hypotension [eg, systolic BP
should be given even to patients who present late for medical attention. This is because the incubation
>90 mmHg in an adult or
period is quite variable; most cases occur within 8 days, but the incubation period can be as short as 3
>5th percentile for age in
days or as long as 21 days. For patients who have been vaccinated against tetanus previously but who
children])
are not up to date, there is likely to be little benefit in administering human tetanus immune globulin
Present and life-threatening Markedly abnormal more than 1 week or so after the injury. However, for patients thought to be completely unvaccinated,
(eg, respiratory insufficiency, coagulation parameters¶ human tetanus immune globulin should be given up to 21 days following the injury; Td or Tdap should
marked tachycardia for age with serious bleeding be given concurrently to such patients.
with severe hypotension,
obtundation, seizures)
DT: diphtheria-tetanus toxoids adsorbed; DTP/DTwP: diphtheria-tetanus whole-cell pertussis; DTaP:
diphtheria-tetanus-acellular pertussis; Td: tetanus-diphtheria toxoids absorbed; Tdap: booster tetanus
toxoid-reduced diphtheria toxoid-acellular pertussis; TT: tetanus toxoid.
* Tetanus toxoid may have been administered as DT, DTP/DTwP (no longer available in the United States),
DTaP, Td, Tdap, or TT (no longer available in the United States).
¶ Such as, but not limited to, wounds contaminated with dirt, feces, soil, or saliva; puncture wounds;
avulsions; or wounds resulting from missiles, crushing, burns, or frostbite.
Δ The preferred vaccine preparation depends upon the age and vaccination history of the patient:
<7 years: DTaP.
Underimmunized children ≥7 and <11 years who have not received Tdap previously: Tdap.
Children who receive Tdap at age 7 through 9 years should receive another dose of Tdap at age 11
through 12 years.
≥11 years: A single dose of Tdap is preferred to Td for all individuals in this age group who have
not previously received Tdap; otherwise, Td or Tdap can be administered without preference.
Pregnant women should receive Tdap during each pregnancy.
◊ 250 units intramuscularly at a different site than tetanus toxoid; intravenous immune globulin should
be administered if human tetanus immune globulin is not available. Persons with HIV infection or severe
immunodeficiency who have contaminated wounds should also receive human tetanus immune
globulin, regardless of their history of tetanus immunization.
§ The vaccine series should be continued through completion as necessary.
¥ Booster doses given more frequently than every 5 years are not needed and can increase adverse
effects. Hospital management of Crotalinae* snake bite when using Crotalid
ae Polyvalent-immune Fab (ovine), (CroFab) antivenom
References:

1. Liang JL, Tiwari T, Moro P, et al. Prevention of Pertussis, Tetanus, and Diphtheria with Vaccines in the United States:
Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2018; 67:1.
2. Havers FP, Moro PL, Hunter P, et al. Use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines:
Updated recommendations of the Advisory Committee on Immunization Practices - United States, 2019. MMWR Morb
Mortal Wkly Rep 2020; 69:77.

Graphic 61087 Version 34.0

 Consultation with a medical toxicologist is recommended prior to antivenom
administration unless the physician has experience with snakebite treatment.
Phone consultation with a medical toxicologist is available through a United
States regional poison control center by calling 1-800-222-1222 .
All treatment recommendations in this algorithm refer to Crotalinae polyvalent
immune Fab (ovine) (CroFab). For management recommendations when using
Crotalidae Immune (F(ab')2 (Equine), Anavip antivenom to treat Crotalinae snake bites,
refer to UpToDate topics on the management of bites by Crotalinae snakes
(rattlesnakes, water moccasin [cottonmouth], or copperhead).
This worksheet represents general advice from a panel of United States snakebite
experts convened in May, 2010. No algorithm can anticipate all clinical situations. Other
valid approaches exist, and deviations from this worksheet based on individual patient
needs, local resources, local treatment guidelines, and patient preferences are
expected. This document is not intended to represent a standard of care. For more
information, please see the following article.
For additional guidance on use of D-dimer results prior to antivenom and platelet
response after antivenom to predict the risk of recurrent toxicity, refer to UpToDate
topics on management of bites by Crotalinae snakes (rattlesnake, water moccasin
[cottonmouth], or copperhead).

* Includes rattlesnakes, copperheads, and cottonmouths (water moccasins).

¶ For maintenance antivenom therapy guidance, refer to UpToDate content on

management of Crotalinae snakebites in the United States.

Reproduced with permission from: Lavonas EJ, Ruha AM, Banner W, et al. Unified treatment algorithm for the
management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop.
BMC Emerg Med 2011; 11:2. Copyright © 2011.

Graphic 72265 Version 13.0

Antivenoms for bites by rattlesnakes, water moccasins (cottonmouths), and * For indications regarding when to administer antivenom, refer to UpToDate topics on management of
copperheads in North America*[1-5] Crotalinae snakebites in the United States.

Antivenom
 
Polyvalent Crotalinae ovine Crotalidae immune equine
immune Fab (FabAV, CroFab) F(ab')2 (Fab2AV, Anavip)
¶ When precautions are present, antivenom should only be administered when the benefit outweighs
the risk. These patients warrant pretreatment for anaphylaxis and adjustment of the rate of infusion.
Refer to UpToDate content on treatment of acute allergic reactions to Crotalinae snake antivenom.
Δ Dose is the same for children and adults. Reconstitution depends upon the antivenom used: 

Approved indication(s)
Precautions¶
Initial dose (same for pediatric
Moderate or severe
and adult patients)Δ
Once either FabAV or Fab2AV is reconstituted, combine contents of all vials and further dilute to a total of
Rattlesnakes, water moccasins
(cottonmouths), and
copperheads
Known allergy to papain, papaya,
or FabAV during prior
administration
Moderate envenomation:
For both antivenoms, do not use if otherwise discolored or turbid.
4 to 6 vials; repeat dose if initial
control of local and systemic
venom effects not achieved
Severe envenomation:
Rattlesnakes, water moccasins
(cottonmouths), and
copperheads
Known allergy to horse protein or
Fab2AV during prior
administration
envenomation:
10 vials; repeat dose if initial
control of local and systemic
venom effects not achieved
For FabAV (CroFab), the manufacturer suggests the modified method for reconstitution: inject 18
mL sterile normal saline into the vial and manually invert about 2 times per second (do not shake)
until completely dissolved by visual inspection. The resulting antivenom should appear weakly
yellow and opalescent. Typical reconstitution time is 3 minutes.
For Fab2AV (Anavip), reconstitute each vial of lyophilized power with 10 mL of sterile normal saline
and mix with continuous, gentle swirling. Typical reconstitution time is less than 1 minute per vial.
The resultant material is yellow/green and opalescent.
250 mL sterile normal saline. Infuse within 4 hours of preparation: administer the antivenom as an
intravenous infusion at an initial rate of 25 to 50 mL/hour for the first 10 minutes. If tolerated, increase
the rate to finish the infusion over 1 hour.

Routine maintenance doses
8 to 12 vials; repeat with higher
number of vials if insufficient
response
Call physician expert if initial
control not achieved after 2
loading doses
2 vials every 6 hours for 3 doses
Call physician expert if initial
control not achieved after 2
loading doses
Not recommended; may give 4
additional vials for recurrent local
or systemic effects
If signs of adverse effects (eg, urticaria, lip or tongue swelling, difficulty breathing, or hypotension)
develop, immediately stop the infusion. Refer to UpToDate content on treatment of acute
hypersensitivity caused by North American Crotalinae snake antivenom for further recommendations.
◊ Coagulation testing should include complete blood count with a focus on the platelet count,
prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR),
plasma fibrinogen, and either D-dimer or fibrin split products. Fibrin degradation testing should occur at
least 4 hours after envenomation, which is usually after antivenom is given; antivenom therapy does not
affect the results of these tests. Refer to UpToDate topics on treatment of recurrent coagulopathy after
management of Crotalinae snakebite.

Reassessment of coagulation Yes Yes

status at 2 to 3 days and 5 to 7
days after antivenom
administration?◊
Consultation with a medical toxicologist or other physician with expertise and prior experience
treating venomous snake bites is strongly encouraged before initiating antivenom therapy for
bites by Crotalinae snakes found in North America (rattlesnakes, water moccasins [cottonmouths],
and copperheads). Emergency consultation with a medical toxicologist in the United States is
available at 1-800-222-1222 . Antivenom administration is associated with potentially severe allergic
reactions; it should only occur in a continuously monitored emergency or intensive care unit setting.
During administration, the physician should ensure the immediate availability of epinephrine
([concentration 1 mg/mL] 0.3 to 0.5 mg intramuscularly in the anterolateral thigh, [concentration 0.1
mg/mL] prepared for continuous intravenous infusion), diphenhydramine or similar antihistamine,
intravenous corticosteroids, and inhaled albuterol during antivenom administration.
References:
1. Lavonas EJ, Ruha AM, Banner W, et al. Unified treatment algorithm for the management of crotaline snakebite in the
United States: Results of an evidence-informed consensus workshop. BMC Emerg Med 2011; 11:2.
2. Bush SP, Ruha AM, Seifert SA, et al. Comparison of F(ab')2 versus Fab antivenom for pit viper envenomation: A prospective,
blinded, multicenter, randomized clinical trial. Clin Toxicol (Phila) 2015; 53:37.
3. Highlights of prescribing information. ANAVIP. Crotalidae Immune F(ab')2 (Equine). Available at:
https://www.fda.gov/media/92139/download (Accessed on June 10, 2019).
4. CroFab: Dosing and administration. Available at: https://www.crofab.com/Treatment-With-CroFab/Dosing-and-
administration (Accessed August 5, 2019).
5. Gerring D, King TR, Branton R. Validating a faster method for reconstitution of Crotalidae Polyvalent Immune Fab (ovine).
Toxicon 2013; 69:42.
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Rapid overview: Emergency management of anaphylaxis in adults
Diagnosis is made clinically:
The most common signs and symptoms are cutaneous (eg, sudden onset of generalized urticaria,
angioedema, flushing, pruritus). However, 10 to 20% of patients have no skin findings.
Danger signs: Rapid progression of symptoms, respiratory distress (eg, stridor, wheezing, dyspnea,
increased work of breathing, persistent cough, cyanosis), vomiting, abdominal pain, hypotension,
dysrhythmia, chest pain, collapse.
Acute management:
The first and most important treatment in anaphylaxis is epinephrine. There are NO absolute
contraindications to epinephrine in the setting of anaphylaxis.
Airway: Immediate intubation if evidence of impending airway obstruction from angioedema. Delay may
lead to complete obstruction. Intubation can be difficult and should be performed by the most
experienced clinician available. Cricothyrotomy may be necessary.
Promptly and simultaneously, give:
IM epinephrine (1 mg/mL preparation): Give epinephrine 0.3 to 0.5 mg intramuscularly, preferably in
the mid-outer thigh. Can repeat every 5 to 15 minutes (or more frequently), as needed. If epinephrine is
injected promptly IM, most patients respond to one, two, or at most, three doses. If symptoms are not
responding to epinephrine injections, prepare IV epinephrine for infusion.
continuously according to blood pressure, cardiac rate and function, and oxygenation.
Vasopressors¶ : Some patients may require a second vasopressor (in addition to epinephrine). All
vasopressors should be given by infusion pump, with the doses titrated continuously according to blood
pressure and cardiac rate/function and oxygenation monitored by pulse oximetry.
Glucagon: Patients on beta-blockers may not respond to epinephrine and can be given glucagon 1 to 5
mg IV over 5 minutes, followed by infusion of 5 to 15 mcg/minute. Rapid administration of glucagon can
cause vomiting.
Instructions on how to prepare and administer epinephrine for IV continuous infusions are available as
separate tables in UpToDate.
IM: intramuscular; IV: intravenous.
* These medications should not be used as initial or sole treatment.
¶ All patients receiving an infusion of epinephrine and another vasopressor require continuous
noninvasive monitoring of blood pressure, heart rate and function, and oxygen saturation.
Δ For example, the initial infusion rate for a 70 kg patient would be 7 mcg/minute. This is consistent with
the recommended range for non-weight-based dosing for adults, which is 2 to 10 mcg/minute. Non-
weight-based dosing can be used if the patient's weight is not known and cannot be estimated.
Adapted from: Simons FER. Anaphylaxis. J Allergy Clin Immunol 2010; 125:S161.

Place patient in recumbent position, if tolerated, and elevate lower extremities. Graphic 58346 Version 32.0

Oxygen: Give 8 to 10 L/minute via facemask or up to 100% oxygen, as needed.

Normal saline rapid bolus: Treat hypotension with rapid infusion of 1 to 2 liters IV. Repeat, as needed.
Massive fluid shifts with severe loss of intravascular volume can occur.

Albuterol (salbutamol): For bronchospasm resistant to IM epinephrine, give 2.5 to 5 mg in 3 mL saline

via nebulizer, or 2 to 3 puffs by metered dose inhaler. Repeat, as needed. 

Adjunctive therapies:
H1 antihistamine*: Consider giving cetirizine 10 mg IV (given over 2 minutes) or diphenhydramine 25
to 50 mg IV (given over 5 minutes) - for relief of urticaria and itching only.

H2 antihistamine*: Consider giving famotidine 20 mg IV (given over 2 minutes).

Glucocorticoid*: Consider giving methylprednisolone 125 mg IV.

Monitoring: Continuous noninvasive hemodynamic monitoring and pulse oximetry monitoring should
be performed. Urine output should be monitored in patients receiving IV fluid resuscitation for severe
hypotension or shock.

Treatment of refractory symptoms:

Epinephrine infusion¶ : For patients with inadequate response to IM epinephrine and IV saline, give
epinephrine continuous infusion, beginning at 0.1 mcg/kg/minute by infusion pumpΔ . Titrate the dose

Rapid overview: Emergency management of anaphylaxis in infants and
children*
Diagnosis is made clinically:
The most common signs and symptoms are cutaneous (eg, sudden onset of generalized urticaria,
angioedema, flushing, pruritus). However, 10 to 20% of patients have no skin findings.
Danger signs: Rapid progression of symptoms, evidence of respiratory distress (eg, stridor,
wheezing, dyspnea, increased work of breathing, retractions, persistent cough, cyanosis), signs
of poor perfusion, abdominal pain, vomiting, dysrhythmia, hypotension, collapse.
Acute management:
The first and most important therapy in anaphylaxis is epinephrine. There are NO absolute
contraindications to epinephrine in the setting of anaphylaxis.
Airway: Immediate intubation if evidence of impending airway obstruction from angioedema. Delay
may lead to complete obstruction. Intubation can be difficult and should be performed by the most
experienced clinician available. Cricothyrotomy may be necessary.
Epinephrine infusion¶ : In patients with inadequate response to IM epinephrine and IV saline, give
epinephrine continuous infusion at 0.1 to 1 mcg/kg/minute, titrated to effect.
Vasopressors¶ : Patients may require large amounts of IV crystalloid to maintain blood pressure. Some
patients may require a second vasopressor (in addition to epinephrine). All vasopressors should be
given by infusion pump, with the doses titrated continuously according to blood pressure and cardiac
rate/function monitored continuously and oxygenation monitored by pulse oximetry.
IM: intramuscular; IV: intravenous.
* A child is defined as a prepubertal patient weighing less than 40 kg.
¶ All patients receiving an infusion of epinephrine and/or another vasopressor require continuous
noninvasive monitoring of blood pressure, heart rate and function, and oxygen saturation. We suggest
that pediatric centers provide instructions for preparation of standard concentrations and also provide
charts for established infusion rate for epinephrine and other vasopressors in infants and children.
Graphic 74242 Version 36.0

IM epinephrine (1 mg/mL preparation): Epinephrine 0.01 mg/kg should be injected intramuscularly in

the mid-outer thigh. For large children (>50 kg), the maximum is 0.5 mg per dose. If there is no
response or the response is inadequate, the injection can be repeated in 5 to 15 minutes (or more
frequently). If epinephrine is injected promptly IM, patients respond to one, two, or at most, three
injections. If signs of poor perfusion are present or symptoms are not responding to epinephrine
injections, prepare IV epinephrine for infusion (see below).

Place patient in recumbent position, if tolerated, and elevate lower extremities.

Oxygen: Give 8 to 10 L/minute via facemask or up to 100% oxygen, as needed.

Normal saline rapid bolus: Treat poor perfusion with rapid infusion of 20 mL/kg. Re-evaluate and
repeat fluid boluses (20 mL/kg), as needed. Massive fluid shifts with severe loss of intravascular volume
can occur. Monitor urine output.

Albuterol: For bronchospasm resistant to IM epinephrine, give albuterol 0.15 mg/kg (minimum dose:
2.5 mg) in 3 mL saline inhaled via nebulizer. Repeat, as needed.

H1 antihistamine: Consider giving diphenhydramine 1 mg/kg (max 50 mg IV, over 5 minutes) or

cetirizine (children aged 6 months to 5 years can receive 2.5 mg IV, those 6 to 11 years of age can
receive 5 or 10 mg IV, over 2 minutes).

H2 antihistamine: Consider giving famotidine 0.25 mg/kg (max 20 mg) IV, over at least 2 minutes.

Glucocorticoid: Consider giving methylprednisolone 1 mg/kg (max 125 mg) IV.

Monitoring: Continuous noninvasive hemodynamic monitoring and pulse oximetry monitoring should
be performed. Urine output should be monitored in patients receiving IV fluid resuscitation for severe
hypotension or shock.

Treatment of refractory symptoms:

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