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The Use of Rattlesnake (Crotaline) Antivenom

By David A. Tanen, MD

Introduction

Research on inducing immunity through the use of vaccines in the early 20th century led to the first rattlesnake antivenoms. There are currently two antivenom products marketed for the treatment of rattlesnake envenomations in North America. Antivenin Crotalidae Polyvalent was first introduced in 1953 by Wyeth Laboratories and was derived by inoculating horses with the venom from 4 different pit vipers: North American Eastern and Western Diamondback rattlesnakes (Crotalus adamenteus and C atrox, respectively), South American tropical rattlesnake (C durissus terrificus) and the fer-de-lance (Bothrops atrox). This product is no longer being manufactured in the United States. In 2000, the FDA approved Crotalidae Polyvalent Immune Fab (Ovine); (CroFab, Protherics, Inc, Nashville, TN) which is derived in sheep from the venom from 4 North American crotaline snakes in its production: the Eastern and Western Diamondback rattlesnake, Mojave rattlesnake (C. scutulatus scutulatus) and the cotton mouth (Agkistrodon piscivorus). Full antibodies are then processed with papain to yield a Fab fragment product. Both antivenoms appear to be efficacious in the treatment of rattlesnake envenomations.

Case presentation

A 16-year-old boy was collecting firewood when he was bitten on the calf of his right leg by a large rattlesnake. He informed his camp councilors, who splinted the extremity and transported him to the hospital. He presented to the emergency department complaining of considerable pain and swelling to his right ankle and leg. He had one episode of emesis and noted a metallic taste in his mouth. Vital signs revealed a temperature of 37oC, blood pressure of 130/70 mm Hg, heart rate of 120 bpm and respiratory rate of 20/minute. Physical examination revealed a single puncture wound presumed to be a fang mark on the medial aspect of his distal calf with surrounding ecchymosis and swelling extending through the ankle and proximally up to his knee. There was also significant tenderness in his groin on the right side. Laboratory analysis demonstrated: a normal WBC, hemoglobin and hematocrit, but no fibrinogen, an elevated PT/INR and a decreased platelet count. The patient initially received 6 vials of CroFab antivenom intravenously. One hour following treatment with antivenom, he was noted to have progressive swelling and another 4 vials were infused. Eight hours post envenomation, the swelling appeared to have halted and his coagulopathy and thrombocytopenia were improving. He was observed for 24 hours with noticeable improvement in his swelling. On hospital day 2 he developed a hemorrhagic bleb near the bite that was debrided at the bedside. The following day, he was discharged with oral pain medication and follow up scheduled in two days with his primary care physician.

Questions

  1. What are the indications for antivenom therapy in rattlesnake envenomation?
  2. How much antivenom is necessary to gain control of the envenomation?
  3. What are the potential adverse effects of crotaline antivenom?

Epidemiology

Thousands of persons are reportedly bitten by pit vipers in the US each year, however, about 25% are considered non-envenomating or “dry bites” in which toxicity does not develop. In the vast majority of bites, evidence of envenomation does occur and is manifest by pain and progressive swelling. Patients are predominantly male and bitten on an extremity. Snakebites also occur most commonly during the summer months when both snakes and humans are active in outdoor habitats. Although fatal rattlesnake envenomations are rare, significant morbidity is common and may lead to digit or limb dysfunction or loss.

Pathophysiology

Venom comprises a complex mixture of enzymes, metalloproteinases and other compounds that are designed to immobilize, kill and begin digestion of prey. Swelling and ecchymosis result from hemorrhagic toxins that increase the permeability of capillary endothelial cells, allowing extravasation of blood and fluid into surrounding tissues. Coagulopathy is multi-factorial but is at least partially related to the depletion of fibrinogen and the inhibition of clotting factors. Thrombocytopenia is also common, although the mechanism remains unclear. Crotaline antivenoms are polyvalent antibodies (whole or Fab fragments) that bind and inactivate venom parts. Depending on the make-up of the particular venom, along with the binding affinity of the antivenom to the venom components, the results of therapy may vary.

Whole IgG-derived antivenom, such as the older Wyeth product, are thought to be slowly deposited on endothelial cells after infusion and eventually eliminated by macrophages, resulting in prolonged elimination times in the body. The smaller Fab fragments of CroFab are removed by the kidneys. Circulating Fab fragments of CroFab generally drop to low levels within about 24 hours of infusion. The volume of distribution throughout the body of the Fab fragments is greater than the larger whole IgG.

Clinical presentation

Envenomated patients commonly present with pain at the site of the bite along with marked tissue edema and evidence of local tissue injury. Over time, the wound site may develop ecchymosis and signs of frank necrosis, especially if located on a digit. In some cases, patients may exhibit hypotension secondary to hypovolemia, severe coagulopathy (hypofibrinogenemia and prolongation of the prothrombin time) and thrombocytopenia, however, cases of spontaneous hemorrhage are uncommon. Even more rarely, anaphylaxis from the bite, disseminated intravascular coagulation, or death may occur. Swelling is sometimes delayed and may be difficult to measure depending on the location. In addition, swelling of the extremity may be so severe that increased compartment pressures have been documented. Unless the bite occurs directly into the muscular compartment, the compartment pressure elevation seen proximally from the site of a rattlesnake bite does not usually lead to compartment syndrome.

In a subset of pit viper bites, most notably from the Mojave rattlesnake, the venom appears to contain a neurotoxin that may present with parathesias and myokymia (fasciculations) at sites distal to the bite. Individual presentations differ among patients because the composition of the venom varies greatly among different snakes and even among envenomations from the same snake. Recognition of these signs and symptoms should prompt the use of antivenom.

Human fatalities following a rattlesnake bite are very rare. It is estimated that 1-2 fatal bites occur in California each year. Life-threatening spontaneous hemorrhage can be seen after a severe rattlesnake bite and include gastrointestinal and intracerebral bleeding. Some of these cases are likely the result of direct intravenous or intra-arterial envenomation, and in these cases, bleeding can occur rapidly following the bite. Anaphylactic and anaphylactoid reactions can also develop after rattlesnake bites and lead to airway compromise and severe hypotension that can be refractory to antivenom. These hypersensitivity reactions can appear in patients without previous snake or snakebite exposures, and may require treatment with epinephrine and other vasopressors along with endotracheal intubation during resuscitation. Bites on or close to the face can produce rapid swelling of the mouth and throat necessitating early airway control.

Diagnosis

Clues that suggest the diagnosis of a significant pit viper envenomation include: pain and puncture wounds at the bite site, progressive swelling and ecchymosis, and laboratory analysis demonstrating coagulopathy and/or thrombocytopenia. As the venom spreads through the lymphatic system, it may produce tender lymphadenopathy in the groin or axilla depending on the extremity affected. Systemic effects may manifest as nausea or vomiting, myokymia, perioral numbness and a metallic taste. Severe envenomations may cause respiratory distress, hypotension, altered mental status and death.

Rarely, compartment syndrome can be seen with a rattlesnake bite. In these rare cases, the bite is almost always deep into a muscular compartment. Since almost all rattlesnake bites can result in pain and swelling of an extremity irrespective of elevated compartment pressures, quantitative measurement of intracompartmental pressure is necessary when considering the diagnosis of compartment syndrome. Aggressive treatment of a bite with antivenom and limb elevation can prevent compartment syndrome in the majority of cases.

Treatment

The mainstay of treatment is the administration of intravenous fluids with isotonic crystalloid to maintain fluid homeostasis. Evidence of progressive swelling or laboratory evidence of coagulopathy (fibrinogen generally less than 100 mg/dL) or thrombocytopenia (platelets less than 90,000/mm3) should prompt antivenom therapy. In animal models and clinical experience, both the Wyeth Antivenin and CroFab are efficacious in the treatment of envenomations from pit vipers. However, CroFab is currently the preferred antivenom due to its low risk of side effects and because of the limited availability of the Wyeth product. The amount of antivenom needed to treat a particular pit viper bite depends on the severity of the envenomation and not on the patient’s weight. Therefore, children and adults generally receive the same amount of antivenom; however the practitioner must carefully consider fluid volumes and rates in small children.

Patients requiring antivenom therapy secondary to the clinical or laboratory findings of progressive swelling, hypotension, coagulopathy or thrombocytopenia should be admitted to a monitored setting (ED or ICU). Opioids such as fentanyl or morphine are commonly administered for pain control. Blood products such as fresh frozen plasma or platelets are generally ineffective in reversing the venom-induced coagulopathy, hypofibrinogenemia, or thrombocytopenia because they are rapidly consumed by circulating venom. In the absence of active bleeding, administration of blood products is not recommended.

The initial dose of CroFab is 4 - 6 vials reconstituted into 250 mL of normal saline. The infusion should be started slowly, and gradually titrated up to 250 mL/hr. Additional CroFab in increments of 4 - 6 vials may be required to establish control, defined by the cessation of progression of signs and symptoms (range of 4 - 48 or more vials with an average of 12). Recently, cases of recurrent coagulopathy, thrombocytopenia, and swelling in rattlesnake bite victims 36-72 hours after the initial control of signs and symptoms have been reported with the use of CroFab. These effects appear to be related to the relatively short half-life of the Fab fragments in the body as they are cleared by the kidneys. Patients should be observed for at least 24 - 48 hours after control of the envenomation, to monitor for recurrence of symptoms that may necessitate further antivenom therapy. Patients can then be followed up with outpatient lab testing for coagulopathy and platelet count in 48 -72 hours to assess for recurrence. If recurrence is documented, repeat doses of CroFab may be required and administered in 2 - 4 vial increments. In case where it is unclear whether follow up is necessary, a poison information specialist or medical toxicologist can be consulted through the California Poison Control System.

The initial dose of Wyeth Antivenin is 10 - 20 vials reconstituted in 500 mL of normal saline. The infusion should be started slowly and titrated up to 500 mL/hr. Additional vials may be required to establish control and have ranged up to 60 vials with an average of 15 - 20. Patients should again be observed for at least 24 – 48 hours after control of the envenomation.

Anaphylactoid reactions from the antivenom may manifest as pruritus, rash, hypotension, and/or wheezing. If the patient develops any of these reactions, the infusion should be stopped, followed by the administration of antihistamines, epinephrine (4 ug/min or 0.05 ug/kg/min), or both, as necessary. Steroids such as prednisone can also be administered for these reactions. Once the symptoms have abated, the antivenom may be restarted at a slower rate and run to completion.

Animal studies have shown that administering antivenom can increase perfusion into a bitten muscular compartment. Therefore, aggressive antivenom administration should precede any consideration of surgical intervention, such as fasciotomy, unless there is a delay in the presentation of the victim after the snakebite. Patients with minimal clinical signs or symptoms not initially requiring antivenom should be observed for 6 - 8 hours, because the clinical effects may be delayed by several hours especially with bites to the lower extremity.

Discussion of case questions

  1. What are the indications for antivenom therapy in rattlesnake envenomation?
    Progressive swelling or laboratory evidence of coagulopathy or thrombocytopenia.
  2. How much antivenom is needed to gain control of the envenomation?
    For CroFab the initial dose is 4 - 6 vials with additional vials as needed to gain control. Average CroFab administration is approximately 12 vials. For Wyeth Antivenin the initial dose is 10 - 20 vials with an average administration of 15 - 30 vials.
  3. What are the potential adverse effects of crotaline antivenom?
    Acute hypersensitivity reactions. CroFab is a purified Fab fragment and has a relatively low rate of reactions (5%) compared with the Wyeth whole antibody product (36%).