Wednesday, September 10, 2008

Venomous Snakebite

Venomous Snakebite


Venomous snakes (Fig. 1) of the world belong to the families Viperidae (subfamily Viperinae: Old World vipers; subfamily Crotalinae: New World and Asian pit vipers), Elapidae (including cobras, kraits, coral snakes, and all Australian venomous snakes), Hydrophiidae (sea snakes), Atractaspididae (burrowing asps), and Colubridae (a large family, of which most species are nonvenomous and only a few are dangerously toxic to humans). Bite rates are highest in temperate and tropical regions where the population subsists by manual agriculture. Estimates indicate >5 million bites annually by venomous snakes worldwide, with >125,000 deaths.

Figure 1. Types of highly venomous snakes. (A).The Viperidae, (B). The Elapidae, (C). Hydrophiidae (D). Atractaspididae

Snake Anatomy/Identification

The typical snake-venom apparatus consists of bilateral venom glands located below and behind the eye and connected by ducts to hollow, anterior maxillary teeth. In viperids (vipers and pit vipers), these teeth are long mobile fangs that retract against the roof of the mouth when the animal is at rest. In elapids and sea snakes, the fangs are smaller and are relatively fixed in an erect position. In ~20% of pit viper bites and higher percentages of other snakebites (e.g., up to 75% for sea snakes), no venom is released ("dry" bites). Significant envenomation probably occurs in ~50% of all venomous snakebites.

Differentiation of venomous from nonvenomous snake species can be difficult. Viperids are characterized by somewhat triangular heads (a feature shared with many harmless snakes); elliptical pupils (also seen in some nonvenomous snakes, such as boas and pythons); enlarged maxillary fangs; and, in pit vipers, paired heat-sensing pits (foveal organs) on each side of the head. The New World rattlesnakes generally have a series of interlocking keratin plates (the rattle) on the tip of the tail; the rattle is used to warn potentially threatening intruders. Color pattern is notoriously misleading in identifying most venomous snakes. Many harmless snakes have color patterns that closely mimic venomous snakes found in the same region.

Venoms and Clinical Manifestations

Snake venoms are complex mixtures of enzymes, low-molecular-weight polypeptides, glycoproteins, and metal ions. Among the deleterious components are hemorrhagins that promote vascular leakage and cause both local and systemic bleeding. Proteolytic enzymes cause local tissue necrosis, affect the coagulation pathway at various steps, and impair organ function. Myocardial depressant factors reduce cardiac output, and neurotoxins act either pre- or postsynaptically to inhibit peripheral nerve impulses. Most snake venoms have multisystem effects in their victims.

Envenomations by most viperids and some elapids with necrotizing venoms typically cause progressive local swelling, pain, ecchymosis (Fig. 2), and (over a period of hours or days) hemorrhagic bullae and serum-filled vesicles. In serious bites, tissue loss can be significant (Fig. 3). Systemic findings can include changes in taste, mouth numbness, muscle fasciculations, tachycardia or bradycardia, hypotension, pulmonary edema, hemorrhage (from essentially any anatomic site), and renal dysfunction. Envenomations by neurotoxic elapids such as kraits (Bungarus spp.), many Australian elapids [e.g., death adders (Atractaspis spp.) and tiger snakes (Notechis spp.)], some cobras (Naja spp.), and some viperids [e.g., the South American rattlesnake (Crotalus durissus) and some Indian Russell's vipers (Daboia russelii)] cause neurologic dysfunction. Early findings may consist of cranial nerve weakness (e.g., manifested by ptosis) and altered mental status. Severe poisoning may result in paralysis, including the muscles of respiration, and lead to death due to respiratory failure and aspiration. After elapid bites, the time of onset of venom intoxication varies from minutes to hours depending on the species involved, the anatomic location of the bite, and the amount of venom injected. Sea snake envenomation usually causes local pain (variable), myalgias, rhabdomyolysis, and neurotoxicity; these manifestations are occasionally delayed for hours.

Figure 2. Northern Pacific rattlesnake (Crotalus oreganus oreganus) envenomations. Top: Moderately severe envenomation. Note edema and early ecchymosis 2 h after a bite to the finger. Bottom: Severe envenomation. Note extensive ecchymosis 5 days after a bite to the ankle.

Figure3. Early stages of severe, full-thickness necrosis 5 days after a Russell's viper (Daboia russelii) bite in southwestern India


Field Management

The most important aspect of prehospital care of a victim bitten by a venomous snake is rapid delivery to a medical facility equipped to provide supportive care (airway, breathing, and circulation) and antivenom administration. Most first aid recommendations made in the past are of little benefit, and some can actually worsen outcome. It is reasonable to apply a splint to the bitten extremity in order to lessen bleeding and discomfort and, if possible, to keep the extremity at approximately heart level. In developing regions, indigenous people should be encouraged to seek care quickly at health care facilities equipped with antivenoms as opposed to consulting traditional healers.

Although mechanical suction has been recommended in the field management of venomous snakebite for many years, there is now evidence that this intervention is of no benefit and can actually be deleterious in terms of local tissue damage.

Techniques or devices used for centuries in an effort to limit venom spread remain controversial. Lympho-occlusive bandages or tourniquets may limit spread only at the cost of greater local tissue damage, particularly with necrotic venoms. Because tourniquets lead to higher rates of amputation and loss of function, they absolutely should not be used. Elapid venoms that are primarily neurotoxic and have no significant local tissue effects may be localized by pressure-immobilization, in which the entire limb is immediately wrapped with a bandage (e.g., crepe or elastic) and then splinted. The wrap pressure must reach ~40–70 mmHg to be effective. Furthermore, if more than a few minutes from medical care, the victim must be carried out from the scene of the bite. Otherwise, muscular pumping will promote venom dispersal, even in bites to the upper extremities. In short, pressure-immobilization should be used only in cases where the offending snake is reliably identified and has a primarily neurotoxic venom, the rescuer is skilled in pressure-wrap application, and the victim can be carried to medical care—an uncommon combination of conditions. Besides tourniquets, other forbidden measures include incising or cooling the bite site, giving the victim alcoholic beverages, and applying electric shocks. The best first aid advice, as coined by Dr. Ian Simpson of the World Health Organization's Snakebite Treatment Group, is to "do it 'RIGHT'": reassure the victim, immobilize the extremity, get to the hospital, and inform the physician of telltale symptoms and signs.

Hospital Management

In the hospital, the victim should be closely monitored (vital signs, cardiac rhythm, oxygen saturation, urine output) while a history is quickly obtained and a rapid, thorough physical examination is performed. Victims of neurotoxic envenomation should be watched carefully for evidence of difficulty swallowing or respiratory insufficiency, which should prompt definitive securing of the airway by endotracheal intubation. To provide objective evidence of the progression of envenomation, the level of swelling in a bitten extremity should be marked and limb circumferences measured in several locations every 15 min until swelling has stabilized. Large-bore IV access in unaffected extremities should be established. Early hypotension is due to pooling of blood in the pulmonary and splanchnic vascular beds. Later, hemolysis and loss of intravascular volume into soft tissues may play important roles. Fluid resuscitation with isotonic saline should be initiated for clinical shock. If the blood pressure response to administration of crystalloid (20–40 mL/kg) is inadequate, a trial of 5% albumin (10–20 mL/kg) is prudent. If tissue perfusion fails to respond to volume resuscitation and antivenom infusion (see below), vasopressors (e.g., dopamine) can be added. Invasive hemodynamic monitoring (central venous and/or pulmonary arterial pressures) can be helpful in such cases, although obtaining access is risky if coagulopathy has developed.

Blood should be drawn for typing and cross-matching and for laboratory evaluation as soon as possible. Important studies include a complete blood count (to evaluate degree of hemorrhage or hemolysis and effects on platelet count), studies of renal and hepatic function, coagulation studies (to identify consumptive coagulopathy), and testing of urine for blood or myoglobin. In developing regions, the 20-min whole-blood clotting test (WBCT) can be used to diagnose coagulopathy reliably. A few milliliters of fresh blood are placed in a new, plain glass receptacle (e.g., test tube) and left undisturbed for 20 min. The tube is then tipped once to 45° to determine whether a clot has formed. If not, coagulopathy is diagnosed. In severe envenomations or with significant comorbidity, arterial blood gas studies, electrocardiography, and chest radiography may be helpful. Any arterial puncture in the setting of coagulopathy, however, requires great caution and must be performed at an anatomic site amenable to direct-pressure tamponade. After antivenom therapy (see below), laboratory values should be rechecked every 6 h until clinical stability is achieved.

The key to management of venomous snakebite is the administration of specific antivenom. Circulating venom components bind quickly with heterologous antibodies produced in animals immunized with the venom in question (or a very closely related venom). Antivenoms may be monospecific (for a particular snake species) or polyspecific (covering several medically important species in the region) but rarely offer cross-protection against snake species other than those used in their production unless the species are known to have homologous venoms. In the United States, assistance in finding antivenom can be obtained 24 h a day from regional poison control centers.

Indications for antivenom administration in victims of viperid bites include any evidence of systemic envenomation (systemic symptoms or signs; laboratory abnormalities) and (possibly) significant, progressive local findings (e.g., soft tissue swelling crossing a joint or involving more than half the bitten limb in the absence of a tourniquet). Care must be used in determining the significance of isolated soft-tissue swelling as, in many countries, the saliva of some relatively harmless snakes causes mild edema at the bite site. In such bites, antivenoms are unhelpful and unnecessary.

In the developing world (e.g., much of Asia and Africa), elapid bites are generally treated similarly to viperid bites. Systemic symptoms such as ptosis, other manifestations of cranial nerve impairment, or respiratory compromise constitute grounds for antivenom administration. Decisions about antivenom administration to victims with isolated local signs or symptoms are based on the criteria listed above for viperid bites.

Production of the only antivenom currently available in the United States for coral snake bites has been discontinued, and remaining stocks will be exhausted or will expire shortly. Until a suitable substitute is produced or imported, physicians caring for victims of Micrurus bites may have to rely on sound supportive care, especially airway management and respiratory support.

The package insert for the selected antivenom can be consulted regarding species covered, method of administration, starting dose, and need (if any) for re-dosing. The information in antivenom package inserts, however, is not always accurate and reliable. Whenever possible, it is advisable for treating physicians to seek advice from experts in snakebite management regarding indications for and dosing of antivenom. For viperid bites, antivenom administration should generally be continued as needed until the victim shows definite improvement (e.g., stabilized vital signs, reduced pain, restored coagulation). Neurotoxicity from elapid bites may be harder to reverse with antivenom. Once neurotoxicity is established and endotracheal intubation is required, further doses of antivenom are unlikely to be beneficial. In such cases, the victim must be maintained on mechanical ventilation until recovery occurs, which may take days to weeks.

The newest available antivenom in the United States (CroFab; Fougera, Melville, NY) is an ovine, Fab fragment antivenom that covers systemic venom effects of all North American pit viper species and carries a low risk of allergic sequelae. Table 1 compares the two antivenoms recently available for the treatment of pit viper bites in the United States. The manufacturer of Antivenin (Crotalidae) Polyvalent has recently discontinued its production, leaving CroFab as the current drug of choice for the management of indigenous pit viper envenomations in the United States. Use of any heterologous serum product carries a risk of anaphylactoid reactions and delayed-hypersensitivity reactions (serum sickness). Skin testing for potential allergy is insensitive and nonspecific and should be omitted. Worldwide, the quality and availability of antivenoms are highly variable. In many developing countries, antivenom resources are scarce, contributing to high morbidity and mortality rates in these regions. The rates of acute anaphylactoid reactions to some of these products exceed 50%. If the risk of allergic reaction is significant, pretreatment with appropriate loading doses of IV antihistamines (e.g., diphenhydramine, 1 mg/kg to a maximum of 100 mg; and cimetidine, 5–10 mg/kg to a maximum of 300 mg) may be considered. In some regions, a prophylactic SC or IM dose of epinephrine is given in an effort to reduce the risk of reaction. Further research is necessary to determine whether any pretreatment measures are truly beneficial. Modest expansion of the patient's intravascular volume with crystalloids could blunt an acute adverse reaction.

Table 1 Comparison of Antivenoms Recently Available for Treatment of Pit Viper Bites in the United States

Antivenin (Crotalidae) Polyvalenta


Available since






Snakes used in manufacture

Crotalus adamanteus

C. adamanteus

C. atrox

C. atrox

C. durissus terrificus

C. scutulatus

Bothrops atrox

Agkistrodon piscivorus

Snakes covered

All North, Central, and South American and some Asian pit vipers

All North American pit vipers (and possibly other Latin American pit vipers)


IgG, equine albumin

Fab fragments

Skin testing recommended by manufacturer



Pretreatment with antihistamines recommended



Dosing (for North American pit viper bites only)c

Dry bite




0 or 5 vials

4 vials


10 vials

4–6 vials


15–20 vials

6 vials

Repeat dosing

As needed

Repeat starting dose if patient fails to stabilize. After stabilization, give 2 vials q6h for 3 more doses. (Alternatively, re-dose on an as-needed basis with close observation for recurrence of abnormalities.)

Volume of diluent

1000 mLd

250 mL

Administer over

2 h

1 h

Incidence of anaphylactic/-oid reaction



Incidence of delayed serum sickness



aWyeth-Ayerst Laboratories, Philadelphia, PA.

bFougera, Melville, NY.

cDegrees of envenomation: mild = progressive local findings (no systemic findings and normal laboratory tests); moderate = local findings plus either mild systemic findings or mild laboratory abnormalities; and severe = local findings plus either severe systemic findings or severe laboratory abnormalities.

dReduce for children and for patients with congestive heart failure.

eSome reactions have been severe, and some have been fatal.

fTo date, all reactions have been relatively mild.

gIncidence is higher with larger doses.

Pretreatment is not recommended by the manufacturer of CroFab. Epinephrine should, however, always be immediately available, and the antivenom dose to be administered should be diluted in an appropriate volume of crystalloid according to the package insert. Antivenom should be given only by the IV route, and the infusion should be started slowly, with the physician at the bedside during the initial period to intervene immediately at the first signs of any acute reaction. The rate of infusion can be increased gradually in the absence of a reaction until the full starting dose has been administered (over a total period of ~1 h). Further antivenom may be necessary if the patient's clinical condition fails to stabilize or worsens. After stabilization, additional doses of CroFab are often recommended as the small-molecular-weight Fab fragments are rapidly cleared from the circulation. Larger, whole IgG or F(ab)2 antivenoms have longer half-lives that eliminate the need for re-dosing after initial stabilization unless definitive symptoms of envenomation reappear.

If the patient develops an acute reaction to antivenom, the infusion should be temporarily stopped and the reaction immediately treated with IM epinephrine and IV antihistamine and steroids (Chap. 311). If the severity of envenomation warrants additional antivenom, the dose should be further diluted in isotonic saline and restarted as soon as possible. Rarely, in recalcitrant cases, a concomitant IV infusion of epinephrine may be required to hold allergic sequelae at bay while further antivenom is administered. The patient must be very closely monitored, preferably in an intensive care setting, during such therapy.

Blood products are rarely necessary in the management of the envenomated patient. The venoms of many snake species can cause a drop in platelet count or hematocrit and depletion of coagulation factors. Nevertheless, these components usually rebound within hours after administration of adequate antivenom. If the need for blood products is thought to be great (e.g., for a dangerously low platelet count in a hemorrhaging patient), these products still should be given only after adequate antivenom administration to avoid adding fuel to ongoing consumptive coagulopathy.

Rhabdomyolysis and hemolysis should be managed in standard fashion. Victims who develop acute renal failure should be evaluated by a nephrologist and referred for dialysis (peritoneal or hemodialysis) as needed. Such renal failure, usually due to acute tubular necrosis, is frequently reversible. If bilateral cortical necrosis occurs, however, the prognosis for renal recovery is more grim, and long-term dialysis with possible renal transplantation may be necessary.

Acetylcholinesterase inhibitors (e.g., edrophonium and neostigmine) may promote neurologic improvement in patients bitten by snakes with postsynaptic neurotoxins. Victims with objective evidence of neurologic dysfunction after snakebite should receive a trial of acetylcholinesterase inhibitors as outlined in Table 2. If they respond, additional doses of long-acting neostigmine can be continued as needed. Special vigilance is required to prevent aspiration if repetitive dosing of neostigmine is used in an attempt to obviate endotracheal intubation.

Table 2 Use of Acetylcholinesterase Inhibitors in Neurotoxic Snake Envenomation

1. Patients with clear, objective evidence of neurotoxicity after snakebite (e.g., ptosis or inability to maintain upward gaze) should receive a trial of edrophonium (if available) or neostigmine.

a. Pretreat with atropine: 0.6 mg IV (children, 0.02 mg/kg; minimum of 0.1 mg)

b. Follow with:

Edrophonium: 10 mg IV (children, 0.25 mg/kg)


Neostigmine: 1.5–2.0 mg IM (children, 0.025–0.08 mg/kg)

2. If objective improvement is evident at 5 min, continue neostigmine at a dose of 0.5 mg (children, 0.01 mg/kg) every 30 min as needed, with continued administration of atropine by continuous infusion of 0.6 mg over 8 h (children, 0.02 mg/kg over 8 h).

3. Maintain vigilance regarding aspiration risk, and secure the airway with endotracheal intubation as needed.

Care of the bite wound includes application of a dry sterile dressing and splinting of the extremity with padding between the digits. Once the administration of an indicated antivenom has been initiated, the extremity should be elevated above heart level to relieve edema. Tetanus immunization should be updated as appropriate. Prophylactic antibiotics are generally unnecessary after bites by North American snakes, as the incidence of secondary infection is low. Antibiotics can be considered, however, if misguided first-aid efforts have included incisions or mouth suction. In some regions of the world, secondary bacterial infection is more common and the consequences are dire. In these regions, prophylactic antibiotics (e.g., cephalosporins) are commonly used.

Most snake envenomations involve subcutaneous deposition of venom. On occasion, however, venom can be injected more deeply into muscle compartments. If swelling in the bitten extremity raises concern that subfascial muscle edema may be impeding tissue perfusion (muscle-compartment syndrome), intracompartmental pressures (ICPs) should be checked by any minimally invasive technique—e.g., wick catheter or ICP monitor (Stryker Instruments, Kalamazoo, MI). If any ICP is high (>30–40 mmHg), the extremity should be kept elevated while further antivenom is given. A dose of IV mannitol (1 g/kg) can be given in an effort to reduce muscle edema if the patient's hemodynamic status is stable. If, after 1 h of such therapy, the ICP remains elevated, a surgical consultation for possible fasciotomy should be obtained. While evidence from studies of animals suggests that fasciotomy may actually worsen myonecrosis, compartmental decompression is still required to preserve nerve function. Fortunately, the incidence of muscle-compartment syndrome is very low following snakebite.

Wound care in the days after the bite may require careful aseptic debridement of clearly necrotic tissue once coagulation has been restored. Intact serum-filled vesicles or hemorrhagic blebs should be left undisturbed. If ruptured, they should be debrided with sterile technique.

Physical therapy should be started when pain allows in order to return the victim to a functional state. The incidence of long-term loss of function (e.g., reduced range of motion, impaired sensory function) is unclear but is probably quite high (>30%), particularly after viperid bites.

Any patient with signs of venom poisoning should be observed in the hospital for at least 24 h. In North America, a patient with an apparently "dry" viperid bite should be watched for at least 8 h before discharge, as significant toxicity occasionally develops after a delay of several hours. The onset of systemic symptoms is commonly delayed for a number of hours after bites by several of the elapids (including coral snakes), some non–North American viperids [e.g., the hump-nosed pit viper (Hypnale hypnale)], and sea snakes. Patients bitten by these reptiles should be observed in the hospital for at least 24 h. Unstable patients should be admitted to a monitored setting.

At discharge, victims of venomous snakebite should be warned about signs and symptoms of wound infection and serum sickness as well as other potential long-term sequelae, such as pituitary insufficiency in Russell's viper (D. russelii) bites. If the victim had evidence of coagulopathy early on, this abnormality can recur during the first 2–3 weeks after the bite. Such victims should be warned to avoid elective surgery or activities posing a high risk of trauma during this period. Outpatient analgesic treatment and physical therapy should be continued.

In the event of serum sickness (fever, chills, urticaria, myalgias, arthralgias, and possibly renal or neurologic dysfunction developing 1–2 weeks after antivenom administration), the victim should be treated with systemic glucocorticoids (e.g., oral prednisone, 1–2 mg/kg daily) until all findings resolve, at which point the dose is tapered over 1–2 weeks. Oral antihistamines (e.g., diphenhydramine in standard doses) provide additional relief of symptoms.

Morbidity and Mortality

The overall mortality rates for venomous snakebite are low in areas with rapid access to medical care and appropriate antivenoms. In the United States, for example, the mortality rate is <1% for victims who receive antivenom. Eastern and western diamondback rattlesnakes (Crotalus adamanteus and C. atrox, respectively) are responsible for the few snakebite deaths occurring in the United States. Snakes responsible for large numbers of deaths in other regions include cobras (Naja spp.), carpet and saw-scaled vipers (Echis spp.), Russell's vipers (D. russelii), large African vipers (Bitis spp.), lancehead pit vipers (Bothrops spp.), and tropical rattlesnakes (C. durissus).

The incidence of morbidity—defined as permanent functional loss in a bitten extremity—is difficult to estimate but is substantial. Morbidity may be due to muscle, nerve, or vascular injury or to scar contracture. In the United States, such loss tends to be more common and severe after rattlesnake bites than after bites by copperheads (Agkistrodon contortrix) or water moccasins (A. piscivorus).


beauty said...

Really I appreciate the effort you made to share the knowledge. The topic here I found was really effective to the topic which I was researching for a long time.

anoida said...

Your blog always create some informational and amazing things, which add in my knowledge

and experience.But I am a bit confuse. Thanks for sharing.Waiting for next post..

arman said...

Well I am quite satisfied with that opinion given in your site. I think it must be implacable in real life.

dpk said...

You write, "Most snake envenomations involve subcutaneous deposition of venom. On occasion, however, venom can be injected more deeply into muscle compartments."

I suspected this to be the case, however, I am looking for a study that can confirm this finding. Could you direct me to one?


Biosyn said...

Helpful Information
We provide
Peptide Synthesis,
Custom Peptide Synthesis,
Peptide Synthesis Services,
Peptide Synthesis Company at