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<< Diagnosis And Management Of North American Snake And Scorpion Envenomations

Treatment

General Principles

The treatment of patients with snake envenomations entails aggressive supportive care and early administration of adequate doses of antivenom when indicated. 4 Airway, breathing, and circulation are of primary importance. Establish peripheral intravenous access in an unaffected extremity. Hypotensive patients should receive fluid boluses to replace thirdspace losses and may require blood transfusion if a venom-induced coagulopathy has resulted in significant hemorrhage. The transfusion of blood products will only temporize coagulopathy and ongoing blood losses until the venom is neutralized by antivenom. To be clear...fresh frozen plasma does not fix an envenomation induced coagulopathy.

Analgesics

Consider analgesics part of the standard therapy for envenomations. Pain control will usually require parenteral narcotics for the first 24 to 48 hours of therapy in patients that are receiving antivenom.33 Skeletal muscle fasciculations can be treated with parenteral benzodiazepines.

Wound Care

Even in the absence of a clinically significant envenomation, snakebites are puncture wounds and therefore require local wound cleansing and tetanus prophylaxis. Interestingly, there is good data to show that snakebites have very low rates of infection.34-35 In spite of a broad spectrum of oral flora cultured from the mouths of snakes, the venom is postulated to have antibacterial properties.36 Based on these studies, prophylactic antibiotics are not currently recommended for snakebites.33

Compartment Syndrome

In cases with documented pressures above 30mmHg, give an additional four to six vials of antivenom along with 1 to 2gm/kg of mannitol over 30 minutes; limb elevation and re-evaluation of pressures after one hour should occur prior to consideration of fasciotomy. 4,28,32 It is recommended that the appropriate service that handles fasciotomy in your facility (generally, surgery or orthopedics) be consulted early in the course of treatment despite the rarity of envenomations that ultimately require this procedure.

Crotalidae Polyvalent Immune Fab (CroFab™)

CroFab™ was approved by the FDA in October of 2000. CroFab™ is a preparation of ovine Fab (monovalent) immunoglobulin fragments obtained from the blood of healthy sheep flocks. These sheep are immunized with one of the following North American snake venoms: Crotalus atrox (Western Diamondback rattlesnake), Crotalus adamanteus (Eastern Diamondback rattlesnake), Crotalus cutulatus (Mojave rattlesnake), and Agkistrodon piscivorus (Cottonmouth or Water Moccasin).37 Note that copperhead venom is not included in the immunizations.

According to the CroFab™ package insert, patients with allergies to papain, chymopapain, other papaya extracts, or the pineapple enzyme bromelain may be at risk for an allergic reaction to CroFab™. In addition, it has been noted in the literature that some dust mite allergens and some latex allergens share antigenic structures with papain and patients with these allergies may be allergic to papain.38-39

Indications: Initiating treatment of an envenomation with CroFab™ is largely based on physical findings, their severity, and development over time.

Classically, envenomation severity has been determined based on symptoms and quantified using one of a few accepted grading scales. These scales typically break envenomations into four or five categories, ranging from "dry bite" or nonenvenomation to severe/very severe. Table 3 is a synthesis of several scoring systems from different authors and can be used to grade the envenomations of all pit viper or suspected pit viper envenomations3. Envenomations are graded based on the symptom or sign that places the patient in the highest (most severe) category.4 Treat moderate and severe/very severe envenomations (Grades II-IV) with antivenom. We have combined the Grade III and IV categories for simplicity since the treatment remains the same and the signs and symptoms differ only in matter of degree.



CroFab™ was FDA approved in 2000 for the treatment of all "mild to moderate North American Crotalidae envenomations;" however, all of the research upon which this approval was based was done with rattlesnake envenomations.37,40 Copperheads, while a member of the Crotalidae subfamily of vipers, are a separate species from the rattlesnakes and copperhead venom is not used in the preparation of CroFab™. As recently as 2004, authors have recommended against the administration of CroFab™ for copperhead bites because the venom effects were not "serious enough" and the risks of antivenom outweighed the benefits.40 One retrospective review of copperhead bites by a group at Carolinas Medical Center showed that CroFab™ administration resulted in an improvement in local symptoms.41 Unfortunately, this was a small study involving only 32 patients. The selection criteria for treating with antivenom were not standardized and the "treatment group" represented only 8% of the copperhead envenomations that presented to Carolinas Medical Center during the review period. A larger, multicenter, randomized controlled study of CroFab™ in the treatment of copperhead bites is certainly warranted and needs to include comparisons not only of local symptoms, but also of short- and long-term disability and adverse events associated with treatment versus non-treatment.

After the severity of the envenomation has been determined, patients with an indication to receive CroFab™ should have the drug administered as soon as possible. Early (< 6 hrs) administration of CroFab™ has been clinically shown to reduce clinical decline and systemic coagulopathy. Reassess and admit these patients to the ICU for monitoring and the completion of the CroFab™ treatment.

When the possibility of an envenomation by a coral snake or Mojave rattlesnake exists, the scale presented in Table 3 should not be used. The signs and symptoms of such venom may be significantly delayed and have their primary effects on the nervous system. In these cases, extend the observation period to at least 12 hours from the time of the injury to account for this delay.4-5,18 Confusing matters somewhat, some authors recommend admission of all suspected coral snake envenomations for close monitoring.4 Presumably the authors are differentiating "observation" in the ED from "admission" meaning 23 hours or more. Unfortunately, there is no good clinical data upon which these recommendations are based.

Preparation and Administration: If possible, obtain written, informed consent prior to the administration of CroFab™, advising the patient primarily of the risks of anaphylaxis, delayed serum sickness, and/or death. In the initial clinical studies of CroFab™, the rates of allergic reaction were low and skin testing was not done. Skin testing done in the setting of the older polyvalent antivenom administration (which had a much higher anaphylaxis rate) has been shown to have both high false-positive rates and false negative rates, 33% and 10 to 36% respectively. As clinical experience and comfort with CroFabTM have increased, the need for skin testing prior to administration has never been shown to be useful.

Additionally, skin testing delays the onset of definitive treatment and the risk of true anaphylaxis with CroFab™ is substantially lower than with the older Antivenom Crotalid Polyvalent (ACP).42 Despite this data, the treating physician should always be prepared for an anaphylactic reaction to antivenom with basic supplies such as epinephrine, diphenhydramine, airway equipment, oxygen, and pressors.
 
CroFab™ is packaged as a shelf-stable lyophilized powder in a vial. Reconstitute each vial of CroFabTM with 10mL of Sterile Water for Injection USP (diluent is not included). After being thoroughly mixed, further dilute each of the reconstituted vials to be used in a given dose in a single 250mL bag of 0.9% Sodium Chloride USP. Use this reconstituted and diluted product within four hours of mixing. The reconstitution and dilution process is time consuming; even in the most practiced hands, preparation of an initial dose of CroFab™ takes more than 30 minutes. Given this, our recommendation is that the mixing of CroFab™ should begin as soon as the patient demonstrates evidence of a significant envenomation. Occasionally, in select scenerios, when patients are being transported for treament, the
reconstitution of CroFab™ can begin prior to patient arrival. Nonetheless, the eagerness to begin the process of mixing needs to be tempered by the possibility of not needing to use a treatment which has an average cost of nearly $1000 per vial.

The recommended initial dose of CroFab™ is four to six vials. Dosage requirements are dependent upon the individual patient response. The use of the recommended adult dosages in the pediatric population appears to be safe.43-44 The initial dose should not be reduced in a pediatric patient because, despite their smaller size, the volume of venom to be neutralized is not reduced. Anecdotal experience with the older ACP venom indicates that antivenom requirements may, in fact, be higher in pediatrics; but no clear clinical correlation between age, size, weight, or snake species and antivenom requirement has ever been demonstrated with either antivenom preparation. However, the fluid status of the pediatric patient should be taken into account when deciding on the initial dilution of the dosage to be given. Most children can handle the 250cc volumes without difficulty as this correlates to a 20cc/kg bolus for a 12.5kg child, but fluid status may become an issue in children less that 10kg.44 Unfortunately, there are no controlled studies to provide guidance on the delivery of higher concentrations.

Deliver the initial dose at a rate of 25 to 50mL/hr for the first ten minutes. If no acute allergic reaction is noted after this initial time; deliver the remainder of the first four to six vial dose at the full rate of 250mL/hr. If a reaction occurs, administer both H1- and H2-receptor blockers. If the symptoms resolve and the reaction was mild, the infusion can be continued with close monitoring. In a retrospective review of CroFab™ safety by Dart and McNally, the two patients with severe reactions (cough and widespread urticaria +/- wheezing) had infusions discontinued, diphenhydramine and an H2-receptor blocker given, and then infusions restarted. In one patient the reaction recurred and no further antivenom was given. In the other patient, the infusion was restarted and completed without incident with the precaution of an epinephrine infusion which is only described as being administered "in standard doses"45-46 or as a "low dose infusion" which was stopped 30 minutes after the completion of the infusion of CroFab™.47

After the initial dose of four to six vials, "initial control" is achieved when an adequate clinical response has occurred, i.e. no further progression of any local symptoms, systemic symptoms, or coagulopathy. Observe the patient while administering two additional vials every six hours for three additional doses. If, after completion of the initial dose, the patient's symptoms continue to progress (worsening of the local injury or systemic effects such as muscle fasciculation, parasthesias, abnormal mental status, tachypnea, tachycardia, or hypotension), an additional four to six vials is recommended. This additional dose is also warranted if laboratory studies show prolonged coagulation times, decreasing fibrinogen levels, or worsening platelet count. If a second four to six vial dose is given, the patient needs to be reassessed for "initial control" and a third round of four to six vials may be needed in the most severe cases. Multiple studies of CroFab™ indicate that the dose required for initial control can range from 4 to 18 vials. If three rounds of four to  six vials fail to achieve control of an envenomation, consider an alternative diagnosis, such as another type of envenomation, a toxic overdose, or an exotic species.

The elimination half-life for CroFab™ is estimated to range from 12 to 23 hours.37 Further study has shown that Fab molecules have a shorter half-life than the IgG used in traditional polyvalent antivenom. 45 Early studies of CroFab™ reported cases of recurrence of signs and symptoms of the original envenomation after intital control. This may be due to a Fab half-life that is shorter than the elimination  half-life of snake venom, thus the administration of CroFab™ includes three additional doses to prevent symptom recurrence. Once initial control is obtained, admit the patient to the ICU and give two vials of CroFab™ at 6, 12, and 18 hours after the completion of the control doses.

Monitoring: After stabilization and initial control of the patient's symptoms have been achieved, and the administration of the scheduled doses has begun, continue close surveillance of the patient's condition. Observation includes monitoring of limb circumference, both above and below the bite, and using a pen
to outline the edematous area every 30 to 60 minutes. Obtain laboratory determinations of the patient's
coagulation status every four hours.28 If symptoms or laboratory data warrants, the treating physician
can give an additional two vials. Any unscheduled re-dosing after initial control does not reset the 6, 12,
18 hour schedule to the beginning.

When compared to polyvalent antivenom, the incidence and severity of reactions to CroFab™ appears to be significantly reduced. In the initial clinical studies discussed above, seven of the first 42 patients treated had an early, though relatively minor, reaction (five urticaria, one cough, one urticaria/dyspnea and wheezing). However, it is important to note that there have been case reports of serious reactions and serum sickness related to CroFab™.46-47

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Last Modified: 05/26/2017
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