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Antivenin Polyvalent (Wyeth)
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Pit viper bites may cause severe tissue damage or fatal envenomation, or both. The physician responsible for treatment of an envenomated patient should be familiar with the contents of this brochure and the pertinent medical literature concerning current concepts of first-aid and general supportive therapy as presented in the references listed at the end of this pamphlet.
Antivenin (Crotalidae) Polyvalent, Wyeth, is a refined and concentrated preparation of serum globulins obtained by fractionating blood from healthy horses immunized with the following venoms: Crotalus adamanteus (Eastern diamond rattlesnake), C. atrox (Western diamond rattlesnake), C. durissus terrificus (tropical rattlesnake, Cascabel), and Bothrops atrox ("Fer-de-lance"). Phenol, 0.25%, and thimerosal, 0.005%, are added as preservatives. The product is standardized by its ability to neutralize the lethal action of standard venoms by intravenous injection in mice. 1 Dried from the frozen state, the lyophilized serum has a moisture content of less than 1% and is soluble on addition of the diluent contained in each package (Sterile Water for Injection, USP).
Antivenin (Crotalidae) Polyvalent, Wyeth (hereinafter referred to as Antivenin) contains protective substances capable of neutralizing the toxic effects of venoms of crotalids (pit vipers) native to North, Central, and South America, including rattlesnakes (Crotalus, Sistrurus) ; copperhead and cottonmouth moccasins (Agkistrodon) , including A. halys of Korea and Japan; the Fer-de-lance and other species of Bothrops ; the tropical rattler (Crotalus durissus and similar species); the Cantil (A. bilineatus) ; and bushmaster (Lachesis mutus) of South and Central America.
Antivenin is indicated only for the treatment of envenomation caused by bites of those crotalids (pit vipers) specified in the immediately preceding paragraph.
Pit Viper Bites and Envenomation
The symptoms, signs, and severity of snake-venom poisoning resulting from pit viper bites depend on many factors, including, but not limited to, the following variables: species, age, and size of the biting snake; the number and location of bite(s); the depth of venom deposit by the snake's fangs; the condition of the snake's fangs and venom glands; the length of time the snake "hangs on"; the age, general health, and size of the victim; the type and efficacy of any first-aid treatment rendered in an attempt to remove venom and how soon such treatment was applied. In any venomous snake bite, the actual amount of venom introduced into the victim is always an unknown. Even the type of clothing or leg-footwear through which the snake's fangs pass may affect the amount of venom delivered by the bite. Although most North American pit vipers tend to bite and introduce venom superficially, their fangs may get hung-up in the subcutaneous tissues during the biting act and can penetrate deeper tissues during the attempt to release the bitten part. In some bites the fangs may penetrate into muscle. In such cases, the usual local superficial manifestations of envenomation may not appear early in the course of poisoning. In bites by some species, systemic evidence of envenomation may be present in the absence of significant local manifestations. It may be difficult to determine the severity of envenomation during the first several hours after a pit viper bite and estimates of severity may need to be revised as poisoning progresses. It must be remembered, too, that not all pit viper bites result in envenomation. In approximately 20% of rattlesnake bites, the snake may not inject any venom. The local and systemic symptoms and signs of envenomation include the following:
Swelling - edema is usually seen around the site of bite within five minutes. It may progress rapidly and involve the entire extremity within an hour. More than 95% of all snakebites are inflicted on extremities. 2 Generally, however, edema spreads more slowly, usually over a period of 8 or more hours. Swelling is usually most severe following envenomation by the Eastern diamondback; less severe after bites by the Western diamondback, prairie, timber, red, Pacific, Mojave, and blacktailed rattlers, the sidewinder and cottonmouth moccasins; least severe after bites by copperheads, massasaugas, and pygmy rattlers.
Ecchymosis and discoloration of the skin - often appear in the area of the bite within a few hours. Vesicules may form within a few hours and are usually present at 24 hours. Hemorrhagic blebs and petechiae are common. Necrosis may develop, necessitating amputation of an extremity or a portion thereof.
Pain - frequently a complaint of the victim beginning shortly after the bite by most pit vipers. Pain may be absent after bites by Mojave rattlers.
Weakness; faintness; nausea; sweating; numbness or tingling around the mouth, tongue, scalp, fingers, toes, site of bite; muscle fasciculations; hypotension; prolongation of bleeding and clotting times; hemoconcentration, early followed by a decrease in erythrocytes; thrombocytopenia; hematuria; proteinuria; vomiting, including hematemesis; melena; hemoptysis; epistaxis. In fatal poisoning, a frequent cause of death is associated with destruction of erythrocytes and changes in capillary permeability, especially of the pulmonary vascular system, leading to pulmonary edema; hemoconcentration usually occurs early, probably as a result of plasma loss secondary to vascular permeability; the hemoglobin may fall, and bleeding may occur throughout the body as early as 6 hours after the bite. Renal involvement is not uncommon. Mojave rattler venom may cause neuromuscular changes leading to respiratory failure.
An estimate of the severity of envenomation should be made as soon as possible and before any Antivenin is administered. The amount (volume) of the first dose of Antivenin is determined on this estimate of severity. Every symptom, sign, laboratory-test result, and any other pertinent information should be considered in estimating severity-local manifestations; systemic manifestations, including abnormal laboratory findings; species and size of the biting snake, if known; number and location of bite(s); size and health of the patient; type of first-aid treatment rendered; and interval between bite and arrival for treatment. Russell et al, 3 , 4 and Wingert and Wainschel 5 grade severity as follows:
No envenomation - no local or systemic manifestations.
Minimal envenomation - local swelling and other local changes; no systemic manifestations; normal laboratory findings.
Moderate envenomation - swelling progressing beyond the site of bite and one or more systemic manifestations; abnormal laboratory findings, for example, a fall in hematocrit or platelets.
Severe envenomation - marked local response, severe systemic manifestations and significant alteration in laboratory findings.
Parrish and Hayes, 6 McCollough and Gennaro, 7 and Watt and Gennaro 8 have used a Grade 0 (no envenomation) through Grade IV (very severe) classification of severity which was developed for the most part in treatment of envenomation by the Eastern diamondback and timber rattlers.
This classification is more dependent on local manifestations, or the absence thereof, as the venoms of these species seem to be more consistent in inducing local tissue damage.
Any suspected envenomation should be treated as a medical emergency, and until careful observation provides clear evidence that envenomation has not occurred or is minimal, the following procedures are recommended:
If practical, immobilize victim immediately and completely. Carry the victim to the nearest hospital as soon as possible. If complete immobilization is not practical, splint the bitten extremity to limit spread of venom. If the biting snake was killed, bring it to the hospital also.
Monitor vital signs at frequent intervals: Blood pressure, pulse, respiration.
Draw sufficient blood as soon as possible for baseline laboratory studies, including type and cross match, CBC, hematocrit, platelet count, prothrombin time, clot retraction, bleeding and coagulation times, BUN, electrolytes, bilirubin. Some of these studies may need to be repeated at daily intervals, or less, depending on the severity of envenomation and the response to treatment. During the first 4 or 5 days of severe envenomations, hemoglobin, hematocrit, and platelet counts should be carried out several times a day. Additional studies that may be useful include an electrocardiogram, chest radiograph, fibrinogen levels, fibrin split products and arterial blood gas analysis. 9
Obtain urine samples at frequent intervals for analysis, with special attention to microscopic examination for presence of erythrocytes.
Chart fluid intake and urine output.
Measure and record the circumference of the bitten extremity just proximal to the bite and at one or more additional points each several inches closer to the trunk. Repeat measurements every 15 to 30 minutes to obtain information about progression of edema.
Have available and ready for immediate use: oxygen, resuscitation equipment including airway, tourniquet, epinephrine, injectable antihistaminic agents and corticosteroids.
Start an intravenous infusion in one or two extremities: one line to be used for supportive therapy, if needed, such as whole blood, plasma, packed red cells, specific clotting factors, platelet transfusion, plasma expanders; the other line to be used for administration of Antivenin (Crotalidae) Polyvalent (equine origin) and electrolytes.
Carry out and interpret a skin test for horse-serum sensitivity. (See PRECAUTIONS section below.)
For persons with pit viper envenomations threatening life or limb, there are no contraindications to administration of Antivenin. However, administration to persons known to be allergic to horse serum, either by history or as a result of an appropriate sensitivity test, requires careful judgement and considerable experience in the use of antivenoms, as well as experience in the management of severe, immediate allergic reactions (anaphylaxis). 5 , 10 , 11 , 12
Antivenin should never be administered prophylactically to asymptomatic patients. 13
There have been isolated reports of cardiac arrest and death associated with Antivenin use.
Patients sensitive to Antivenin or horse serum may develop anaphylaxis, therefore, it is essential that prior to intravenous (IV) or intramuscular (IM) Antivenin administration a proper skin test be performed, interpreted, and therapy modified if indicated.
Constant attendance and observation of the patient for untoward reactions are mandatory when Antivenin is administered.
Should any systemic reaction occur, administration should be discontinued immediately and appropriate treatment initiated. Those responsible for administration and/or monitoring administration of Antivenin should be familiar with current recommendations for treatment of severe, immediate, systemic reactions (anaphylaxis) associated with use of heterologous sera.
Therapy with beta-adrenergic blockers, including cardioselective agents, has been associated with an increased severity of acute anaphylaxis (See Drug Interactions ).
Before administration of any product prepared from horse serum, appropriate measures must be taken in an effort to detect the presence of dangerous sensitivity: (1) A careful review of the patient's history, including any report of (a) asthma, hay fever, urticaria, or other allergic manifestations; (b) allergic reactions upon exposure to horses; and (c) prior injections of horse serum. (2) A suitable test for detection of sensitivity. A skin test should be performed in every patient prior to administration, regardless of clinical history.
Skin test - Inject intradermally 0.02 to 0.03 mL of a 1:10 dilution of Normal Horse Serum or Antivenin. A control test on the opposite extremity, using Sodium Chloride Injection, USP, facilitates interpretation. Use of larger amounts for the skin-test dose increases the likelihood of false-positive reactions, and in the exquisitely sensitive patient, increases the risk of a systemic reaction from the skin-test dose. A 10% rate of false negative skin test reactions has been reported. 14 A 1:100 or greater dilution should be used for preliminary skin testing if the history suggests sensitivity. A positive reaction to a skin test occurs within five to thirty minutes and is manifested by a wheal with or without pseudopodia and surrounding erythema. In general, the shorter the interval between injection and the beginning of the skin reaction, the greater the sensitivity.
If the history is negative for allergy and the result of a skin test is negative, proceed with administration of Antivenin as outlined below. If the history is positive and a skin test is strongly positive, administration may be dangerous, especially if the positive sensitivity test is accompanied by systemic allergic manifestations. In such instances, the risk of administering Antivenin must be weighed against the risk of withholding it, keeping in mind that severe envenomation can be fatal. (See last paragraph of this section.)
A negative allergic history and absence of reaction to a properly applied skin test do not rule out the possibility of an immediate reaction. Also, a negative skin test has no bearing on whether or not delayed serum reactions (serum sickness) will occur after administration of the full dose.
If the history is negative, and the skin test is mildly or questionably positive, administer as follows to reduce the risk of a severe immediate systemic reaction: (a) Prepare, in separate sterile vials or syringes, 1:100 and 1:10 dilutions of Antivenin. (b) Allow at least 15 minutes between injections and proceed with the next dose if no reaction follows the previous dose. (c) Inject subcutaneously, using a tuberculin-type syringe, 0.1, 0.2, and 0.5 mL of the 1:100 dilution at 15-minute intervals; repeat with the 1:10 dilution, and finally undiluted Antivenin. (d) If a systemic reaction occurs after any injection, place a tourniquet proximal to the site of injections and administer an appropriate dose of epinephrine, 1:1000, proximal to the tourniquet or into another extremity. Wait at least 30 minutes before injecting another dose. The amount of the next dose should be the same as the last that did not evoke a reaction. (e) If no reaction occurs after 0.5 mL of undiluted Antivenin has been administered, switch to the intramuscular route and continue doubling the dose at 15-minute intervals until the entire dose has been injected intramuscularly or proceed to the intra-venous route as described below under DOSAGE AND ADMINISTRATION .
Obviously, if the just-described schedule is used, 3 to 5 or more hours would be required to administer the initial dose suggested for a moderate or severe envenomation, and time is an important factor in neutralization of venom in a critically ill patient. Wingert and Wainschel 4 have described a procedure based on the experience of their group which they have used in some severely envenomated patients who have positive sensitivity tests: 50 to 100 mg of diphenhydramine hydrochloride is given intravenously, followed by slow intravenous infusion of diluted Antivenin for 15 to 20 minutes while carefully observing the patient for symptoms and signs of anaphylaxis; if anaphylaxis does not occur, Antivenin is continued, maintaining close observation of the patient. Patients who require Antivenin but develop signs of impending anaphylaxis in spite of this or the procedure described earlier present a difficult problem, and consultation should be sought.
Therapy with beta-adrenergic blockers, including cardioselective agents, has been associated with an increased severity of acute anaphylaxis.
Anaphylaxis may be prolonged and resistant to conventional treatment in patients receiving beta-adrenergic blockers. The pharmacotherapeutic actions of epinephrine and other adrenergic agents may be altered, and larger than usual doses may be required. 15
DOSAGE AND ADMINISTRATION
Before administration, read CONTRAINDICATIONS , PRECAUTIONS and ADVERSE REACTIONS sections. Since the possibility of a severe immediate reaction (anaphylaxis) exists whenever a horse-serum-containing product is administered, appropriate therapeutic agents, including a tourniquet, airway, oxygen, epinephrine, an injectable pressor amine, and corticosteroid, must be available and ready for immediate use. Constant attendance and observation of the patient for untoward reactions are mandatory when Antivenin (Crotalidae) Polyvalent (equine origin) is administered. Should any systemic reaction occur, administration should be discontinued immediately and appropriate treatment initiated.
The intravenous route of administration is preferred, and probably should always be used for moderate or severe envenomation. Intravenous administration is mandatory if venom-induced shock is present. To be most effective, Antivenin should be administered within 4 hours of the bite; it is less effective when given after 8 hours and may be of questionable value after 12 hours. However, it is recommended that Antivenin therapy be given in severe poisonings, even if 24 hours have elapsed since the time of the bite. It should be kept in mind that maximum blood levels of Antivenin may not be obtained for 8 or more hours after IM administration.
For intravenous-drip use, prepare a 1:1 to 1:10 dilution of reconstituted Antivenin in Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. To avoid foaming, mix by gently swirling rather than shaking. Allow the initial 5 to 10 mL to infuse over a 3- to 5-minute period, with careful observation of the patient for evidence of untoward reaction. If no symptoms or signs of an immediate systemic reaction appear, continue the infusion with delivery at the maximum safe rate for intravenous fluid administration. The dilution of Antivenin to be used, the type of electrolyte solution used for dilution, and the rate of intravenous delivery of the diluted Antivenin must take into consideration the age, weight, and cardiac status of the patient; the severity of envenomation; the total amount and type of parenteral fluids it is anticipated will be given or are needed; and the interval between bite and initiation of specific therapy.
It is important to begin administration of the entire initial dose of Antivenin as described above as soon as possible, based on the best estimate of the severity of envenomation at the time treatment is begun (see Pit Viper Bites and Envenomation ). The following initial doses are recommended: 3 , 4 , 5 , 16
minimal envenomation-20-40 mL (contents of 2 to 4 vials).
moderate envenomation-50-90 mL (contents of 5 to 9 vials).
severe envenomation-100-150 mL or more (contents of 10 to 15 or more vials).
These recommended initial-dosage volumes are in general accord with those of others. 10 , 17 , 18
The need for additional Antivenin must be based on the clinical response to the initial dose and continuing assessment of the severity of poisoning. If swelling continues to progress or if systemic symptoms or signs of envenomation increase in severity or if new manifestations appear, for example, fall in hematocrit or hypotension, administer an additional 10 to 50 mL (contents of 1 to 5 vials) or more intravenously. For severe envenomation, a total of 200 to 400 mL (contents of 20 to 40 vials) may be necessary. 10 , 19 , 20 , 21 , 22 There is not a recommended maximum dose. The total required dose is the amount needed to neutralize the venom as determined by clinical response. 23
Envenomation by large snakes in children or small adults requires larger doses of Antivenin. The amount administered to a child is not based on weight.
If Antivenin is given intramuscularly, it should be given into a large muscle mass, preferably the gluteal area, with care to avoid nerve trunks. Antivenin should never be injected into a finger or toe.
The effectiveness of corticosteroids in treatment of envenomation per se or venom shock is not resolved. Russell 3 , 4 and others 26 , 27 believe corticosteroids may mask the seriousness of hypovolemia in moderate or severe poisoning and have little, if any, effect on the local-tissue response to rattler venoms. Corticosteroids should not be given simultaneously with Antivenin on a routine basis or during the acute state of envenomation; however, their use may be necessary to treat immediate allergic reactions to Antivenin, and corticosteroids are the agents of choice for treating serious delayed reactions to Antivenin.
Intravascular envenomation characterized by extremely rapid (i.e., within several minutes) onset of severe signs and symptoms has occurred in rare instances. In such cases, neutralization with Antivenin must be instituted immediately. 24
Snakes' mouths do not harbor Clostridium tetani . However, appropriate tetanus prophylaxis is indicated, since tetanus spores may be carried into the fang puncture wounds by dirt present on skin at time of bite or by nonsterile first-aid procedures.
A broad-spectrum antibiotic in adequate dosage is indicated if local tissue damage is evident.
Shock following envenomation is treated like shock resulting from hypovolemia from any cause, including administration of whole blood, plasma, albumin, or other plasma expanders, as indicated.
Aspirin or codeine is usually adequate for relieving pain. Sedation with phenobarbital or mild tranquilizers may be used if indicated, but not in the presence of respiratory failure.
The bitten extremity should not be packed in ice, and so-called "cryotherapy" is contraindicated.
Compartment syndromes may complicate pit viper envenomations, especially those caused by bites on the lower extremities. Prompt surgical consultation is indicated whenever a closed-compartment syndrome is suspected. 3 , 4 , 25
Defibrination and disseminated intravascular coagulation (DIC) syndromes have been associated with envenomation caused by some pit vipers native to the United States, and appropriate therapy may be indicated. 3 , 4 , 26 , 27 , 28 , 29
Technique for Reconstituting the Dried Antivenin
Pry off the small metal disc in the cap over the diaphragms of the vials of Antivenin and diluent. Swab the exposed surface of the rubber diaphragms of both vials with an appropriate germicide. With a sterile 10 mL syringe and needle, withdraw the diluent (Sterile Water for Injection, USP) from the vial of diluent and insert the needle through the stopper of the vacuum-containing vial of Antivenin. The vacuum in the Antivenin vial will pull the diluent out of the syringe into the vial. However, delivery of 10 mL of diluent may not always exhaust the vacuum in the Antivenin vial. If all vacuum is not exhausted, reconstitution may be more difficult. Therefore, either disconnect the needle from the syringe and allow room air to be pulled into the Antivenin vial until all vacuum is released from the container or withdraw the syringe with attached needle from the vial, pull 10 mL of room air into the syringe and reinsert needle with attached syringe containing room air through stopper and repeat, if necessary, to release any remaining vacuum. At the first introduction of diluent into the vaccine vial, it is important for the needle to be pointed at the center of the lyophilized pellet of Antivenin so that the diluent stream will wet the pellet. If the diluent stream is not directed at the pellet but allowed to run down the inside wall of the vial, the pellet will float up and adhere to the stopper thereby rendering complete reconstitution much more difficult. Agitate by swirling, NOT by shaking, for 1 minute, at 5-minute intervals. Shaking causes foaming and if the diluent stream is not properly directed as described earlier, pieces of the pellet may get caught in the foam and will be very difficult to wet. Complete reconstitution usually requires at least 30 minutes.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The color of reconstituted Antivenin may vary from clear to slight yellowish or greenish.
Before each administration, gently swirl the vial to dissolve the contents.
Before any Antivenin is administered, an appropriate horse-serum sensitivity test must be done so that, in case administration of Antivenin is subsequently required, a decision on how to proceed will have been made (see PRECAUTIONS ).
Immediate systemic reactions (allergic reactions or anaphylaxis) can occur whenever a horse-serum-containing product is administered. An immediate reaction (e.g. shock, anaphylaxis) usually occurs within 30 minutes. Symptoms and signs may develop before the needle is withdrawn and may include apprehension, flushing, itching, urticaria; edema of the face, tongue, and throat; cough, dyspnea, cyanosis, vomiting, and collapse. There have been isolated reports of cardiac arrest and death associated with Antivenin (Crotalidae) Polyvalent (equine origin) use. However, serious immediate reactions to Antivenin are rare. In skin-test-negative patients, Antivenin caused a true immediate sensitivity reaction in less than 1 percent of patients. 10
Serum sickness usually occurs 5 to 24 days after administration and its frequency may be related to the number of Antivenin vials administered. 30 The incubation period may be less than 5 days, especially in those who have received horse-serum-containing preparations in the past. The usual symptoms and signs are malaise, fever, urticaria, lymphadenopathy, edema, arthralgia, nausea, and vomiting. Occasionally, neurological manifestations develop, such as meningismus or peripheral neuritis. Peripheral neuritis usually involves the shoulders and arms. Pain and muscle weakness are frequently present, and permanent atrophy may develop.
Each combination package contains one vacuum vial to yield 10 mL of Antivenin (with preservatives: phenol 0.25% and thimerosal [mercury derivative] 0.005%) and one 1 mL vial of normal horse serum (diluted 1:10) as sensitivity testing material with preservatives: thimerosal (mercury derivative) 0.005% and phenol 0.35%.
Store original, unused (not reconstituted) vials at temperatures not exceeding 98°F (37°C) - Do not freeze.
Reconstituted Antivenin should be used as soon as possible but may be used up to 4 hours after reconstitution (but not yet diluted) if stored at 36°F to 46°F (2°C to 8°C).
Antivenin which has been reconstituted and then diluted should be used immediately. Any remaining after 12 hours or more after dilution should be discarded.
Gently swirl the vial of reconstituted Antivenin before each administration.