CONCEPTS, COMPONENTS & CONFIGURATIONS antivenin; coagulopathy; CROTALI DAE
Snake Venom Coagulopathy: Use and Abuse of Blood Products in the Treatment of Pit Viper Envenomation Coagulopathies are commonly encountered in victims of pit viper envenomation. In the majority of patients these defects improve with administration of antivenin. However, blood products are often transfused based on arbitrary criteria and with significant risk to the patient. This article documents the effectiveness and risks of antivenin administration and the risks of blood product transfusion. We recommend that blood products not be used except for clearly defined clinical indications. [Burgess JL, Dart RC: Snake venom coagulopathy: Use and abuse of blood products in the treatment of pit viper envenomation. Ann Emerg Med July 199I;20: 795-801.] INTRODUCTION Pit viper (Crotalidae sp) venoms contain toxins capable of inducing a c o a g u l o p a t h y c h a r a c t e r i z e d by p r o l o n g e d c l o t t i n g times, t h r o m bocytopenia, thrombocytosis, hypofibrinogenemia, or a combination of these disorders resembling disseminated intravascular coagulation. 1-3 Although a variety of treatments has been reported, very few have been tested in clinical studies. Antivenin (CROTALIDAE) polyvalent is considered effective by most physicians experienced in the treatment of snakebite. Many reports also include recommendations for the use of blood products to reverse the coagulopathy. However, the criteria used to make these therapeutic decisions vary widely. 1-~ Because the administration of either antivenin or blood products carries significant risks, these decisions should be based on the actual need for treatment and a thorough understanding of the potential benefits and complications of each treatment. We present three case studies that illustrate the spectrum of snake venom poisoning and common treatment errors. They were selected from cases reported to the Western Envenomation DatabaSe, a cooperative effort of the Section of Emergency Medicine of the University of Arizona and the Arizona Poison and Drug Information Center.
Jeffery L Burgess, MD* Richard C Dart, MD, PhD*t Tucson, Arizona From the Section of Emergency Medicine* and the Arizona Poison & Drug Information Center,t University of Arizona, Tucson. Received for publication August 30, 1990. Revision received February 27, 1991. Accepted for publication February 22, 199t. Address for reprints: Richard C Dart, MD, PhD, Section of Emergency Medicine, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, Arizona 85724.
CASE STUDIES Case Report 1 A 65-year-old man was bitten on the left leg by a Western Diamondback rattlesnake (Crotalus atrox). He presented to the hospital approximately 30 minutes after envenomation with diaphoresis, tachycardia, nausea, paresthesias, abdominal and severe left leg pain, and a blood pressure of 60/0 m m Hg. Because of a reaction to a tetanus immunization given 52 years earlier, the patient did not receive antivenin. He was given several liters of isotonic IV fluid and started on a dopamine drip. He later vomited guaiacpositive material and developed epistaxis and hematuria (as many as 100 RBCs/high-powered field) concurrent with a decrease in his platelet count to 1,000/~L. Prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen were normal, but fibrin split products were present. The patient was transfused 10 units of platelets, which initially improved his platelet count to 17,000/~L. The next day, his platelet count again dropped to 1,000/~L. He received a second transfusion of l0 units of platelets, after which his count improved to 25,000/~L. During the second platetet transfusion, the patient developed hives, nausea, and flushing. This transfusion reaction was treated successfully with diphenhydramine.
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FIGURE 1. Treatment of snake venom coagulopathy. Except for a rise in his fibrin degredat i o n p r o d u c t s t o m o r e t h a n 40 txg/mL, other coagulation parameters remained normal. The patient eventually recovered fully. A n t i v e n i n s h o u l d have been administered in this case and m a y have altered the patient's clinical course. Because he developed a severe coagulopathy and active hemorrhage, blood p r o d u c t s were indicated and appropriately transfused. However, antivenin effectively reverses coagulopathies and m a y have obviated the need for blood products and, therefore, the subsequent platelet transfusion reaction. Of special interest in this case was the failure to administer antivenin due to an allergy to a tetanus immun i z a t i o n 52 years earlier. T e t a n u s toxoid was produced from the 1930s through the 1950s using a beef broth culture m e d i u m c o n t a m i n a t e d w i t h proteases and peptones. 4 After this time, a protein-free toxoid was available. s Therefore, reactions to tetanus toxoid before 1950 were due primarily to bovine protein c o n t a m i n a n t s and s h o u l d n o t be considered as a contraindication to antivenin administration. T e t a n u s i m m u n e g l o b u l i n (TIG) was p r o d u c e d f r o m an e q u i n e or bovine source until h u m a n TIG was introduced in the early 1960s. 6 Reactions to TIG after that time are unlikely to represent horse serum sensitivity. Therefore, only those patients who specifically received TIG before the early 1960s are at risk for horse s e r u m s e n s i t i v i t y . T h o s e w h o received tetanus toxoid at any time are not at risk. However, patients with a severe envenomation should still receive antivenin despite proven horse serum allergies because these allergies can be e f f e c t i v e l y c o n t r o l l e d with proper pretreatment and close evaluation during antivenin administration. 7
Case Report 2 A 62-year-old m a n was bitten on the right t h u m b by a Massassauga (Sistrurus catenatus). He presented shortly after envenomation with local swelling but no systemic symptoms. Because of an allergic reaction (hives) to a tetanus immunization 13 years earlier and the minimal extent 138/796
Envenomation
I
Active blood loss?* Yes
No
I C°agil°~ Yes Administer antivenin (Figure 2) I Correct platelets if less than 20,000/mL
No
Observe six to eight hours (Figure 2)
I
and
I
Administer blood products based on specific coagulopathy
I
Correct hemoglobin if less than 7 g/dL
No
Yes
I Repeat antivenin I Administer blood products if
Administer antivenin (Figure 2)
Monitor condition and coagulation studies
bleeding develops
*Active blood loss is definedas guaiac-positiveemesisor stool or a decreasinghematocriLMinor hematuriaor bleedingfrom gumscan be treatedwith antiveninalone.
of apparent envenomation, no antivenin was given. During his hospitalization, the swelling and ecchymosis progressed to his elbow. On discharge from the hospital three days later, all of his coagulation parameters were w i t h i n normal limits except for fibrin split products of more than 10 and less than 40 txg/mL. SiN days after the envenomationl tl~e patient remained a s y m p t o m a t i c w i t h o u t any evidence of bleeding, and his swelling had resolved. However, his fibrinogen had decreased to less than 50 mg/dL; for this reason alone, he w a s t r a n s f u s e d w i t h 15 u n i t s of c r y o p r e c i p i t a t e . T h e r e was no increase in his fibrinogen level for several days. Complete resolution without further t r e a t m e n t occurred over the following two months. Annals of Emergency Medicine
In this case, the patient received blood products without a clear indication, placing h i m at risk for complicating infections. He did not demonstrate clinical evidence of bleeding over six days. We conclude, therefore, that he should not have been transfused. As discussed previously, ~.t: ar~tiven~n is indicated, a presumed allergy to horse products is not an absolute contraindication to its use.
Case Report 3 A 10-year-old boy was bitten on the right index finger by a Western D i a m o n d b a c k rattlesnake (C atrox). He arrived in the emergency departm e n t 40 minutes after envenomation with stable vital signs and pain and swelling limited to his finger. He had a hematocrit of 39.8; decreased plate-
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SNAKE VENOM COAGULOPATHY Burgess & Dart
Patient with snakebite I Vital signs, physical examination
Unstable 3atient
Stable patient
I
Grade envenomation Minimal
Local pain, edema, local ecchymosis, normal coagulation, no progression
Moderate
Severe
Spreading pain, Massive edema, edema, ecchymosis, ecchymosis; markedly mildly abnormal coagulation abnormal coagulation, deftstudies, platelets, brination, DIC syndromes, hemolysis, w e a k n e s s ~ . _ _ f h e m o l y s i s , paralysis, c o
Immediately administer skin test and begin mixing ten to 20 vials antivenin.
Intradermal skin test Skin test 1
Administer antivenin;* if no early reaction, give five to ten vials over one to two hours.
+ Skin test I
Pretreat with H~- and H2blockers; dilute antivenin, and administer slowly.*
j~J
- Skin test I
Administerantivenin;* if no early reaction, give ten to 20 vials over first hour.
If allergic reaction develops, stop antivenin; treat with epinephrine, H~- and H2-blockade; re-evaluate clinical status, and restartantivenin if needed.
Observe six to eight hours for worsening of symptoms or coagulopathy; discharge if no progression.
* All patients requiring antivenin therapy should be admitted.
lets by peripheral blood smear; PT, 11.6 seconds; PTT, 35.9 seconds; and fibrinogen level, 100 mg/dL. After admission, he developed swelling to the wrist, right arm pain extending to the axilla, abdominal pain, and vomiting. The next morning, seven hours after e n v e n o m a t i o n , the h e m a t o c r i t was 37.7; platelets, 30,000/ixL; PT, 22.4 seconds; PTT, more than two minutes; and fibrinogen, less than 50 mg/dL. He was given 10 units of antivenin ( C R O T A L I D A E ) p o l y v a l e n t , and his coagulopathy improved over the next 24 hours with repeat laboratory values of a hematocrit of 28.8% ; platelets, 96,000/txL; PT, 11.5 seconds; PTT, 28.8 seconds; and fibrinogen, 240 mg/dL. The patient was discharged two days later and eventually regained full function of his right index finger.
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This case demonstrates the reversal of a c o a g u l o p a t h y with antivenin alone, thus sparing the patient the risks of blood product transfusion. DISCUSSION Use of Antivenin Although there have been no randomized human trials, antivenin has repeatedly been reported to reduce morbidity and mortality.~,s, 9 Case reports and uncontrolled series support the concept that antivenin is effective in the reversal of coagulation defects.2,1o, zl /n vivo animal experiments also support the use of antivenin. In rabbits, antivenin alone was more effective than surgery Or a combination of surgery and antivenin in reducing mortality and preserving limb muscle function. La In another rabbit study, antivenin reduced the degree of t h r o m b o c y t o s i s , hypoAnnals of Emergency Medicine
FIGURE 2. Clinical management of suspected pit viper envenomation. fibrinogenemia, and fibrin degredation products but did not reverse thrombocytopenia. [a In mice, polyvalent antivenin was capable of neutralizing the hemorrhagic activity of both Crotalus viridis viridis and C atrox venom 14 as well as local myonecrosis by C atrox venom. 15 Administration of antivenin has potential complications. In several studies, the incidence of immediate hypersensitivity reactions was 5% to 33%, including nausea, rash, warm flushes, bronchospasm, and hypotension.7,16,17 The incidence of serum sickness was 36% to 75%, occurring from two to 23 days after antivenin administration. Signs and symptoms included nausea and vomiting, malaise, diarrhea, urticaria, pruritis, fe797/139
SNAKE VENOM COAGULOPATHY Burgess & Dart
ver, s y n c o p e , b r o n c h o s p a s m , or edema.7,16,17 There does not appear to be a tight linear relationship b e t w e e n the dose of a n t i v e n i n and the s e v e r i t y of ser u m sickness, t 7 M o s t patients receiving m o r e than five vials of a n t i v e n i n will develop s e r u m sickness. D e a t h s after a n t i v e n i n a d m i n i s t r a t i o n have been claimed, a l t h o u g h these cases are poorly documented, and it is unclear w h e t h e r these deaths were due to a n t i v e n i n or e n v e n o m a t i o n . In t h r e e c l i n i c a l series, a n t i v e n i n adm i n i s t r a t i o n r e s u l t e d in no m o r t a l ity, no l o n g - t e r m side effects, a n d only transient morbidity. 7,16,17 Wingeft and Chan found no severe s e r u m sickness requiring either admission or p r o l o n g e d t r e a t m e n t in 211 patients receiving antivenin. 9 O u r experience from t h e W e s t e r n Envenomation Database currently i n c l u d e s 118 p a t i e n t s w h o have received antivenin. Of these, 26 of 112 (23.2%) suffered a c u t e r e a c t i o n s to antivenin. N o p a t i e n t died, and n o n e a p p e a r e d to s u f f e r s e q u e l a e f r o m their reactions. During the one-tos i x - m o n t h follow-up period, 49 of 79 (62.0%) d e v e l o p e d s e r u m s i c k n e s s , but t h e r e was no l a s t i n g m o r b i d i t y . In conclusion, a n t i v e n i n is considered r e l a t i v e l y safe w h e n a d m i n i s tered p r o p e r l y in an i n t e n s i v e care setting.
Use of Blood Products Blood products have been administered alone and in addition to antivenin in patients w i t h snakebite-induced coagulopathies (cases 1 and 2). These blood products include platel e t s , f r e s h - f r o z e n p l a s m a (FFP), c r y o p r e c i p i t a t e , a n d RBCs. B l o o d p r o d u c t t r a n s f u s i o n c a r r i e s significant risks, w h i c h have been well des c r i b e d in t h e m e d i c a l l i t e r a t u r e . Transfusion risks can be categorized into hemolytic reactions, nonh e m o l y t i c reactions, and i n f e c t i o u s complications. Unless otherwise stated, we will use the RBC unit as a basis for c a l c u l a t i o n of t r a n s f u s i o n risk. As the .amount t r a n s f u s e d increases, infectious risks are additive and t r a n s f u s i o n r e a c t i o n s i n c r e a s e , although the relationship has not been clearly defined. Hemolytic transfusion reactions can be classified as i m m e d i a t e or delayed. The total incidence of hemolytic r e a c t i o n s has b e e n r e p o r t e d as from one in 1,400 to one in 6,200 140/798
cases per u n i t RBCs transfused. 1s-2o I m m e d i a t e h e m o l y t i c r e a c t i o n s are m o s t often due to h u m a n error, eit h e r in t r a n s f u s i n g A B O - i n c o m p a t ible blood or, m o r e rarely, in transfusing type-specific blood that had not been cross matched. Fatal hemolytic reactions were previously estim a t e d to occur in one in 1 m i l l i o n cases 21 but are n o w believed to occur w i t h a f r e q u e n c y of one in 100,000 cases per unit RBCs transfused. 18 Delayed h e m o l y t i c transfusion reactions vary in severity but in general are m u c h m o r e benign. T h e y develop three to 13 days after transfus i o n w i t h an i n c i d e n c e of o n e in 1,500 cases per u n i t RBCs transfused a n d for p r a c t i c a l p u r p o s e s are n o t p r e v e n t a b l e . ~9 Because of t h e a n t i body-containing p l a s m a contained in each pack, platelet transfusions m a y also cause hemolytic reactions, w h i c h are u s u a l l y m i l d and rarely result in hypotension, d i s s e m i n a t e d intravascular coagulation, or renal failure. 2 2 N o n h e m o l y t i c t r a n s f u s i o n reactions are generally benign and occur w i t h an i n c i d e n c e of one in 100 to one in 200.18,23 T h e y include febrile r e a c t i o n s a s s o c i a t e d w i t h the presence of w h i t e cell agglutinins in the p a t i e n t ' s or d o n o r ' s s e r u m . In rare c a s e s , t h e y m a y l e a d to n o n c a r diogenic p u l m o n a r y edema. The use of l e u k o c y t e - d e p l e t e d p r o d u c t s decreases the incidence of febrile reactions. 24 Platelets also are depleted by these procedures. 25 Allergic reactions to p l a s m a proteins include urticaria and, rarely, a n a p h y l a x i s . T r u e anap h y l a x i s is m o s t often seen in the t r a n s f u s i o n of I g A - c o n t a i n i n g blood p r o d u c t s to IgA-deficient recipients, and it occurs in from one in 20,000 to one in 47,000 transfusions. 26 Recently, fatal graft versus host disease has been reported as a delayed complication in blood transfusion from a c l o s e r e l a t i v e , 27 b u t t h i s p r o b a b l y occurs in only very l i m i t e d circumstances. Transfusion-transmitted diseases c o n s t i t u t e the third m a j o r group of t r a n s f u s i o n reactions. N o n - A / n o n - B hepatitis p r e s e n t l y has an incidence of one in 100 to one in 500 cases per u n i t of RBCs transfused,~S, ~8 despite the screening of donors for elevated alanine aminotransferase. H e p a t i t i s B still occurs in from one in 200 to one in 300 cases per u n i t of RBCs transf u s e d d e s p i t e t e s t i n g of d o n 6 r s for Annals of Emergency Medicine
h e p a t i t i s B markers.18, 29 T r a n s m i s s i o n of A I D S h a s b e e n e s t i m a t e d from in one in 40,000 to one in 1 million cases per u n i t of RBCs, despite screening for anti-HIV, because of the "window" between infection with the virus and p r o d u c t i o n of the antibody. 18,3°,3t RBCs, p l a s m a , p l a t e l e t concentrates, cryoprecipitate, and n o n h e a t - t r e a t e d coagulation concentrates have all been found to t r a n s m i t AIDS. 32 HTLV-1 s e r o c o n v e r s i o n occurs in one in 4,500 cases per u n i t RBCs transfused. 3° Other transfusion-related infect i o n s i n c l u d e c y t o m e g a l o v i r u s , Epstein-Barr virus, parasites, and bacteria. C y t o m e g a l o v i r u s i n f e c t i o n occurred in 7% of t r a n s f u s i o n recipie n t s r e c e i v i n g a s i n g l e u n i t of RBCs. 33 M o s t i m m u n o c o m p e t e n t recipients get only a m i l d or inapparent infection, but the immunocomprom i s e d recipient m a y acquire a m u c h more serious infection. WBC-cont a i n i n g p r o d u c t s such as RBCs and platelets transmit cytomegalovirus infection, b u t cell-free p r o d u c t s appear to not t r a n s m i t cytomegalovirus i n f e c t i o n . T r a n s f u s i o n - r e l a t e d Epstein-Barr virus has a similar epidemiology. T r a n s m i s s i o n of malaria is rare in t h e U n i t e d States, b u t it is m u c h m o r e c o m m o n in e n d e m i c a r e a s . B a b e s i o s i s c a n be t r a n s m i t t e d by transfusion, m o s t frequently in N e w E n g l a n d w i t h s o m e r e p o r t e d fatalities. Transfusion is the second m o s t c o m m o n r o u t e of a c q u i r i n g Chagas d i s e a s e in e n d e m i c a r e a s s u c h as South America, but few transfusionr e l a t e d cases have been r e p o r t e d in the U n i t e d States. Syphilis is rarely t r a n s m i t t e d by blood p r o d u c t transfusion.32 R e a c t i o n s to c o n t a m i n a t e d blood products range from m i l d h e m o l y s i s to shock and death, resulting in part f r o m b a c t e r i a l i n f e c t i o n of b l o o d products. Because of their e x t e n d e d r o o m t e m p e r a t u r e shelf life, platelet transfusions are an occasional source of bacterial c o n t a m i n a t i o n . ,~4 Because m o s t t r a n s f u s i o n - r e l a t e d viral i n f e c t i o n s are a s s o c i a t e d w i t h leukocytes, there is great interest in the use of l e u k o c y t e - d e p l e t e d products. R e m o v a l of teukocytes by filtrat i o n has b e e n s h o w n to r e d u c e in vitro HIV infectivity, but residual viruses were still detectable, and it is unknown whether filtration would r e d u c e t h e t r a n s m i s s i o n of HIV in 20:7 July 1991
SNAKE VENOM COAGULOPATHY B u r g e s s & Dart
Standard Administration of Antivenin (CROTALIDAE) Polyvalent 1. Read package insert. 2. Check allergy history, especially to horse serum products. 3. Perform skin test if antivenin is indicated using the skin test material included with the antivenin. Never perform a skin test unless you are sure antivenin will be administered. If skin test is positive (wheal and flare within 20 to 30 minutes) and antivenin is necessary, request consultation through regional poison center. Antivenin may be administered in many cases despite a positive skin test. 4. Dosage and administration of antivenin (CROTALIDAE) polyvalent Dosage Minimal or trivial envenomation: no antivenin Moderate envenomation: five to ten vials Severe or rapidly progressive envenomation: ten to 30 vials, or more Mixing and infusion Add 10 mL of the diluent provided or normal saline to each vial. Mix by rolling between hands. Do not shake. Then, dilute by injecting into normal saline IV bag (eg, five to ten vials in 250 mL). Give intravenously at a slow rate initially and then at a faster rate (about five to ten minutes per vial) if no reaction occurs. Reduce volume of diluent in pediatric patients. Attempt to give total dose during first one to two hours. Use after 24 hours is currently limited to reversal of coagulopathy. 5. Guide to subsequent administration of antivenin should include response to the first dose and evidence of continuing injury. If swelling, coagulopathy, or any other problem is worsening after the initial administration, further antivenin is probably warranted. Consultation with a physician experienced in the treatment of complicated snakebite is recommended.
General Recommendations 1. Do not leave patient unattended. 2. Do not delay immediate or vigorous treatment if patient has a moderate or severe envenomation. 3. Consult poison control center for all bites (for informational purposes). In moderate-to-severe bites, allergic patients, or cases with complicating factors, ask to speak directly to toxicologist on call (Arizona Poison Control Center, 602/626-6016).
Use of Antivenin (CROTALIDAE) Polyvalent in Antivenin-Allergic Patients 1. Possibly allergic patients -- Positive skin test or known allergy to horse serum products Treatment of adult patients at risk for allergic reaction Treatment consists of dilution of the antivenin infusion and beth H1and H2-receptor blockade before antivenin infusion. Diphenhydramine 50 to 100 mg IV
human beings. 35 Further research is needed to determine whether filtration w o u l d affect t r a n s m i s s i o n of other leukocyte-associated disorders. Platelet transfusion carries a greater risk of viral infection than RBCs because of the pooled nature of 20:7: July 1991
Cimetidine 300 mg IV or ranitidine 50 mg IV Dilute antivenin to half or normal concentration -- about one vial/lO0 mL. Start infusion at a rate of 25 to 50 mL/hr, and double the rate every ten to 15 minutes until a rate is reached that will infuse the volume in two hours. In case a severe allergic reaction develops, the patient should be cardiac monitored, and equipment for airway control and epinephrine should be available at the bedside. Pediatric patients Diphenhydramine 1.25 mg/kg IV Cimetidine 5 to 10 mg/kg or ranitidine 1 to 2 mg/kg IV Dilute antivenin to half of normal concentration -- about one vial/lO0 mL (1:10 dilution). However, it is recommended that total volume not exceed 20 mL/kg. Start infusion at a slow rate (about 25 to 50 mL/hr); double the rate every ten to 15 minutes until a rate is reached that will infuse the total volume in two hours. Keep epinephrine 1:1,000 available at the bedside for possible reactions. 2. Patients currently having a reaction Diagnosis -- Any of the following signs or symptoms developing during antivenin infusion: anxiety, chills, weakness, nausea, pruritis, sneezing, feeling of throat constriction, hypotension, strider, urticaria, wheezing, emesis, dyspnea, diaphoresis, fever, or erythematous streaking from injection site Treatment of patients having an allergic reaction Treatment consists of dilution and slowing of antivenin infusion and beth H 1- and H2-receptor blockade Stop antivenin infusion. Epinephrine 1:1,000, 0.3 to 0.5 mg SQ; may be repeated every 15 minutes Diphenhydramine 50 to 100 mg IV Cimetidine 300 mg IV or ranitidine 50 mg IV A second IV line should be established. First line of treatment for hypotension is isotonic fluid infusion. Vasopressors may be needed in particularly severe cases. Reconsider the need for antivenin. The primary considerations include the severity of the envenomation (life- or limb-threatening) and the seriousness of the reaction. This decision may be aided by contacting a physician experienced in the use of antivenin in antivenin-allergic patients. If antivenin is needed, wait ten to 15 minutes for initial reaction to subside and for patient to stabilize. Then, restart infusion at 25 to 50 mL/hr. Increase the rate every 15 minutes until reaching a rate that is 25 mL/hr below the rate at which the allergic response occurred. Continue at this rate until the total volume is infused. Pediatric patients Management is the same, except that doses are reduced as indicated in the pediatric section of "Possibly allergic patients -- Positive skin test or known allergy to horse serum products" (above).
multiple-donor platelets, where each transfusion comes from six to ten donors. Single-donor platelets, produced by platelet apheresis, carry a per-unit risk similar to RBCs. One unit of FFP is believed to have a similar risk to one unit of RBCs in viral infectivity, A n n a l s of Emergency Medicine
FIGURE 3. Guidelines for use of antivenin (CROTALIDAE) polyvalent and m a n a g e m e n t of allergic reactions. including HIV infection. Cryoprecipitate transfusion also carries a greater 799/141
SNAKE VENOM COAGULOPATHY Burgess & Dart
risk of viral infection than RBCs because of its pooled nature, although the per-unit risk is similar to RBCs in i n f e c t i o u s c o m p l i c a t i o n s . O t h e r c o m p l i c a t i o n s of transfusions, such as those s t e m m i n g from ABO compatibility, are m u c h less frequent in platelets and cell-free components such as FFP a n d c r y o p r e c i p i t a t e s than in RBCs. A n t i t h r o m b i n III has r e c e n t l y become c o m m e r c i a l l y available for the t r e a t m e n t of s e v e r a l disorders, including disseminated intravascular coagulation. Because it is a purified, heat-treated product, its administration should t h e o r e t i c a l l y be safe from transfusion-related infection, g6 Its eff i c a c y is s t i l l u n c l e a r , a l t h o u g h in s e v e r a l u n c o n t r o l l e d s t u d i e s it reportedly shortened the duration and improved the course of d i s s e m i n a t e d intravascular coagulation.37, 3s We are not aware of any placebo-controlled trials or studies w i t h clinically relevant end points, g9 A c u m u l a t i v e risk of blood product t r a n s f u s i o n c a n n o t be easily calculated b e c a u s e m a n y studies do n o t indicate the specific n u m b e r of units and types of blood products given to each individual, and the m o r b i d i t y or m o r t a l i t y of e a c h t y p e of r e a c t i o n varies greatly. T r a n s m i s s i o n of nonA / n o n - B h e p a t i t i s is p e r h a p s t h e m o s t s i g n i f i c a n t risk, w i t h an incidence of as high as one in 100 cases per u n i t of RBCs transfused, and hepatitis B sill occurs in some studies as frequently as from one in 200 to one in 300 cases per u n i t of RBCs transfused. The p o t e n t i a l for fatal complic a t i o n s s u c h as HIV i n f e c t i o n or transfusion of m i s m a t c h e d blood is a constant concern. Taken together, these risk are substantial and require that blood products be given only for strict clinical indications.
gums can i n i t i a l l y be treated w i t h antivenin alone. As i l l u s t r a t e d in case 3 and discussed previously, a n t i v e n i n has repeatedly been shown to reverse coagulopathies. If the patient is unstable or actively bleeding or if a n t i v e n i n is not effective, blood c o m p o n e n t transf u s i o n is s u g g e s t e d . B e c a u s e s n a k e v e n o m s vary widely in their effects on t h e c o a g u l a t i o n s y s t e m , b l o o d product transfusion should be based on t h e s p e c i f i c c o a g u l a t i o n abnormality. FFP t r a n s f u s i o n is i n d i c a t e d for m u l t i p l e c o a g u l a t i o n p r o t e i n deficiencies in the u n c o n t r o l l a b l y bleeding p a t i e n t or as a r e p l a c e m e n t for i s o l a t e d factor deficiencies. 4o Platelets are indicated for t h r o m b o c y t o p e nia or a b n o r m a l i t i e s of platelet function w i t h significant bleeding. Platelets are not indicated if t h r o m b o c y t o penia is the sole a b n o r m a l i t y and the platelet count is more than 20,000/ixL or for a bleeding t i m e less than twice the upper l i m i t of n o r m a l unless there are other abnorm a l i t i e s . 4~ P r o p h y l a c t i c p l a t e l e t adm i n i s t r a t i o n m a y be c o n s i d e r e d for counts less than 20,000/txL, although there is no consensus on this topic. 4l H y p o f i b r i n o g e n e m i a s h o u l d be treated w i t h cryoprecipitate only for a level less than 100 mg/dL and clinic a l l y s i g n i f i c a n t h e m o r r h a g e . 4z As d i s c u s s e d in case 2, u n c o m p l i c a t e d h y p o f i b r i n o g e n e m i a s h o u l d n o t be t r e a t e d w i t h b l o o d p r o d u c t s . RBC transfusion is generally indicated for a p a t i e n t w i t h h e m o g l o b i n less than 7 mg/dL and should be considered in p a t i e n t s w i t h a p r e c i p i t o u s drop in hemoglobin. The r o u t i n e transfusion of a stable patient for a h e m o g l o b i n less t h a n lO m g / d L is n o t r e c o m m e n d e d . I8 I n d i v i d u a l j u d g m e n t is suggested for specific cases.
Treatment of Snake Venom Coagulopathy
SUMMARY
The snake envenomation treatm e n t protocol used at the U n i v e r s i t y of Arizona is detailed (Figures 1 and 2). A protocol for the a d m i n i s t r a t i o n of a n t i v e n i n is s h o w n (Figure 3). O n l y moderate or severe envenomat i o n s or m i n i m a l e n v e n o m a t i o n s that are worsening require treatment. A n t i v e n i n s h o u l d be t h e p r i m a r y t r e a t m e n t for s n a k e v e n o m coagulopathy unless the patient is unstable or actively bleeding. Minor bleeding such as h e m a t u r i a or oozing from the 142/800
Coagulopathies are c o m m o n l y encountered in v i c t i m s of snake v e n o m poisoning. Blood p r o d u c t s are often given in an effort to reverse these coagulopathies, but in m a n y cases they are given w i t h o u t a c o m p l e t e knowledge of the i n d i c a t i o n s for transfus i o n or t h e r i s k s of b l o o d p r o d u c t transfusion. The hemolytic, nonh e m o l y t i c , a n d i n f e c t i o u s r i s k s of blood p r o d u c t t r a n s f u s i o n r e a c t i o n s are significant. A n t i v e n i n has proven effective and r e a s o n a b l y safe in t h e t r e a t m e n t of r a t t l e s n a k e biteg; thereAnnals of Emergency Medicine
fore, a n t i v e n i n should be the initial t r e a t m e n t for s n a k e v e n o m coagulopathy. Blood products are indicated o n l y if a n t i v e n i n is n o t efficacious, for active bleeding, or for specific coagulation abnormalities. The authors thank Paul V Holland, MD, for his assistance and Douglas W Huestis, MD, for his review of the manuscript.
REFERENCES 1. Glass TG: M~nagement of Poisonous Snakebite, ed 2. San Antonio, Texas, Glass Publishing Co, 1976, p 3 7. 2. Russell I:E: Snake Venom Poisoning, ed 2. Great Neck, New York, Scholium International, 1983, p 306-343. 3. Corrigan lJ: Hemorrhagic and Thrombotic Diseases in Childhood Adolescence, ed 1. New York, Churchill Livingstone, 1985, p 188-202. 4. Cooke RA, Hampton 8, Sherman WB, et al: Allergy induced by immunization with tetanus toxoid. [AMA 1940; 114:1854-i858. 5. Facktor MA, Bernstein RA, Fireman P: Hypersensitivity to tetanus toxoid. J Al]er Clin Immuno] 1973; 52:1-12. 6. Human antitoxin in prophylaxis and treatment of tetanus. Med Lett 1965;7:13q4. 7. Spaite DW, Dart RC, Hurlbut K, et ah Skin testing: hnplications in the management of pit viper envenomation (abstract). Ann Emerg Med [988;17:389. 8. Christensen PA: Snakebite and the use of antivenin in Southern Africa. S Aft Med / 198l;59:934 938. 9. Wingert WA, Chan L: Rattlesnake bites in Southern California and rationale for recommended treatment. West / Med 1988;148:37-44. 10. Dart RC, Burgess JL: Snakebite coagulopathy. Clin Hclemost Rev 1990;4:6. It. Rifler E, Curry SC, Gerkin R: Successful treatment with antivenin of marked thrombocytopenia without significant coagulopathy following rattlesnake bite. Ann Emer,g Med 1987~16:1297q299. 12. Stewart RM, Page CP, Schwesinger WH, et al: Antivenin and fasciotomy/debridement in the treatment of severe rattlesnake bite. Am J Surg 1989;158:543-547. i3. Simon TL, Grace TG: Envenomation coagulopathy in wounds from pit vipers. N EngI J Med 198[;305: 443-447. 14. Ownby CL, Colberg TR, Odell GV: A new method for quantitating hemorrhage induced by rattlesnake venoms: Ability of polyvalent antivenin to neutralize hemorrhagic activity. Toxicon [984;22:227-233. 15. Ownby CL, Colberg TR: Ability of polyvalent (CrotaIidae} antivenin to neutralize local myonecrosis induced by Crotalus atrox v e n o m Toxfcon i986;24: 201-203. 16. Jurkovich GJ, Lutermal£ A, McCullar K, et al: Complications of Crotalidae antivenin therapy. / Trauma 1988;28:1032 1036. 17. Corrigan P, Russell FE, Wainschel l: Clinical reac tions to antivenin, in Rosenberg P (ed}: Toxins: Animal, Plant, and Microbial. Oxford, Pergamon, 1978, p 457-465. i8. Consensus Conference, Office of Medical Applications of Research, National Institutes of Health: Perioperative red blood cell transfusion. JAMA t988;260: 2700-2703. 19. Taswell HI:, Pineda AA, Moore 8B: Hemolytic transfusion reactions: Frequency and clinical and laboratory aspects, in Bell CA led): A Seminar on ImmuneMediated Ceil Destruction. ed 1. Washington, DC, American Association of Blood Banks, 1981, p 71-92. 20. Pineda AA, Brzica SM, Taswell HI:: Hemolytic transfusion reaction: Recent experience in large blood bank. Mayo Clirl Proc 1978;53:378-390.
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21. Schmidt PJ: The mortality from incompatible transfusion, in Sandier SG, Nusbacher J, Schanfield MS (eds): ImmunobioIogy of the Erthyrocyte, ed 1. New York, Alan R Liss Inc, 1980, p 251-261. 22. Pierce RN, Reich LM, Mayer K: Hemolysis following platelet transfusions from ABO incompatible donors. Transhlsion 1985;25:60-62. 23. Menitove JE, McEIligott MC, Aster RH: Febrile transfusion reaction: What blood component should be given next? Vox Sang I982~42:318-321. 24. Brittingham TE, Chaplin'H: Febrile transfusion reactions caused by sensitivity to donor leukocytes and platelets. JAMA 1957~165:819 825. 25. Hughes ASB, Brozovic B: Leucocyte depleted blood: An appraisal of available techniques. Br J HaematoI 1982;50:381-386. 26. Pineda AA, Taswell HF: Transfusion reactions associated with anti-IgA antibodies: Report of four cases and review of the literature. Transhzsion 1975;15:10 15. 27. Thaler M, Shamiss A, Orgad S, et al: The role of blood from HLA&omozygous donors in fatal transfusion associated with graft versus-host disease after open-heart surgery. N Eng] J Med 1989;321:25 28. 28. Koziol DE, Holland PV, Ailing DW, et ah Antibody to hepatitis B core antigen as a paradoxical marker for non-A non-B hepatitis antigens in donated blood. Ann
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Intern Med 1986;104:488-495. 29. Alter HI, Holland PV, Purcell RH, et al: Posttransfusion hepatitis after exclusion of commercial and hepatitis B antigen-positive donors. Ann Intern Med 1972; 77:691-699. 30. Cohen ND, Munoz A, Reitz BA, et al: Transmission of retroviruses by transfusion of screened blood in pat i e n t s u n d e r g o i n g cardiac surgery. N Engl J M e d 1989;320:i172-1176. 31. Ward JW, Holmberg SD, Allen IR, et ah Transmission of human immunodeficiency virus (HIV) by blood transfusions screened as negative for HIV antibody. N EngI f Med 1988~318:473-478. 32. Rutherford CJ: Transfusion-transmitted diseases, in Churchill WH, Kurtz SR {eds}: Transfusion Medicine, ed 1. Boston, BlackwelI Scientific Publications, 1988, p 107-127. 3.3. Prince AM, Szmuness W, Millian SJ, et ah A se rologic study of cytomegalovirus infections associated with blood transfusions. N EnxI J Med 197l;284: 1125-t13i. 34. Braine HG, Kiekler TS, Charache P, et al: Bacterial sepsis secondary to platelet transfusion: An adverse effect of extended storage at room temperature. Transfu sion 1986;26:391-393. 35. Rawal BD, Busch MP, Endow R, et ah Reduction of human immunodeficiency virus-infected ceils from do
Annals of Emergency Medicine
nor blood by leukocyte filtration. Transfusion i989; 29:460-462. 36. Hoffman DL: Purification and large-scale preparation of antithrombin III. A m J Med 1989;87(snppl 3B}: 23S-268. 37. Blauhut B, Kramar H, Vinazzer H, et al: Substitution of a n t i t h r o m b i n III in shock and DIC: A randomized study. Thromb Res 1985;39:81-89. 38. Maki M, Terao T, Ikenoue T, et ah Clinical evaluation of antithrombin III concentrate (BI 6.013) for disseminated intravascular coagulation in obstetrics. GynecoI Obstet Invest 1987;23:230-240. 39. Bullet HR, ten Cute JW: Acquired antithrombin III deficiency: Laboratory diagnosis, incidence, clinical implications and treatment with antithrombin III concentrate. A m J Med 1989;87{suppl 3B):44S-48S. 40. Consensus Conference, Office of Medical Applications of Research, National Institutes of Health: Fresh frozen plasma: Indications and risks. JAMA 1985; 253:551-553. 41. Consensus Conference, Office of Medical Applications of Research, National Institutes of Health: Platelet transfusion therapy. JAMA i987;257:1777-t780. 42. Huestis DW, Bove JR, Case J: Blood components, fractions, and derivatives, in Practical Blood Transfu sion, ed 4. Boston, Little, Brown and Co, 1988, p 296347.
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Snake Venom Coagulopathy: Use and Abuse of Blood Products in the Treatment of Pit Viper Envenomation Coagulopathies are commonly encountered in victims of pit viper envenomation. In the majority of patients these defects improve with administration of antivenin. However, blood products are often transfused based on arbitrary criteria and with significant risk to the patient. This article documents the effectiveness and risks of antivenin administration and the risks of blood product transfusion. We recommend that blood products not be used except for clearly defined clinical indications. [Burgess JL, Dart RC: Snake venom coagulopathy: Use and abuse of blood products in the treatment of pit viper envenomation. Ann Emerg Med July 199I;20: 795-801.] INTRODUCTION Pit viper (Crotalidae sp) venoms contain toxins capable of inducing a c o a g u l o p a t h y c h a r a c t e r i z e d by p r o l o n g e d c l o t t i n g times, t h r o m bocytopenia, thrombocytosis, hypofibrinogenemia, or a combination of these disorders resembling disseminated intravascular coagulation. 1-3 Although a variety of treatments has been reported, very few have been tested in clinical studies. Antivenin (CROTALIDAE) polyvalent is considered effective by most physicians experienced in the treatment of snakebite. Many reports also include recommendations for the use of blood products to reverse the coagulopathy. However, the criteria used to make these therapeutic decisions vary widely. 1-~ Because the administration of either antivenin or blood products carries significant risks, these decisions should be based on the actual need for treatment and a thorough understanding of the potential benefits and complications of each treatment. We present three case studies that illustrate the spectrum of snake venom poisoning and common treatment errors. They were selected from cases reported to the Western Envenomation DatabaSe, a cooperative effort of the Section of Emergency Medicine of the University of Arizona and the Arizona Poison and Drug Information Center.
Jeffery L Burgess, MD* Richard C Dart, MD, PhD*t Tucson, Arizona From the Section of Emergency Medicine* and the Arizona Poison & Drug Information Center,t University of Arizona, Tucson. Received for publication August 30, 1990. Revision received February 27, 1991. Accepted for publication February 22, 199t. Address for reprints: Richard C Dart, MD, PhD, Section of Emergency Medicine, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, Arizona 85724.
CASE STUDIES Case Report 1 A 65-year-old man was bitten on the left leg by a Western Diamondback rattlesnake (Crotalus atrox). He presented to the hospital approximately 30 minutes after envenomation with diaphoresis, tachycardia, nausea, paresthesias, abdominal and severe left leg pain, and a blood pressure of 60/0 m m Hg. Because of a reaction to a tetanus immunization given 52 years earlier, the patient did not receive antivenin. He was given several liters of isotonic IV fluid and started on a dopamine drip. He later vomited guaiacpositive material and developed epistaxis and hematuria (as many as 100 RBCs/high-powered field) concurrent with a decrease in his platelet count to 1,000/~L. Prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen were normal, but fibrin split products were present. The patient was transfused 10 units of platelets, which initially improved his platelet count to 17,000/~L. The next day, his platelet count again dropped to 1,000/~L. He received a second transfusion of l0 units of platelets, after which his count improved to 25,000/~L. During the second platetet transfusion, the patient developed hives, nausea, and flushing. This transfusion reaction was treated successfully with diphenhydramine.
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795/13
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FIGURE 1. Treatment of snake venom coagulopathy. Except for a rise in his fibrin degredat i o n p r o d u c t s t o m o r e t h a n 40 txg/mL, other coagulation parameters remained normal. The patient eventually recovered fully. A n t i v e n i n s h o u l d have been administered in this case and m a y have altered the patient's clinical course. Because he developed a severe coagulopathy and active hemorrhage, blood p r o d u c t s were indicated and appropriately transfused. However, antivenin effectively reverses coagulopathies and m a y have obviated the need for blood products and, therefore, the subsequent platelet transfusion reaction. Of special interest in this case was the failure to administer antivenin due to an allergy to a tetanus immun i z a t i o n 52 years earlier. T e t a n u s toxoid was produced from the 1930s through the 1950s using a beef broth culture m e d i u m c o n t a m i n a t e d w i t h proteases and peptones. 4 After this time, a protein-free toxoid was available. s Therefore, reactions to tetanus toxoid before 1950 were due primarily to bovine protein c o n t a m i n a n t s and s h o u l d n o t be considered as a contraindication to antivenin administration. T e t a n u s i m m u n e g l o b u l i n (TIG) was p r o d u c e d f r o m an e q u i n e or bovine source until h u m a n TIG was introduced in the early 1960s. 6 Reactions to TIG after that time are unlikely to represent horse serum sensitivity. Therefore, only those patients who specifically received TIG before the early 1960s are at risk for horse s e r u m s e n s i t i v i t y . T h o s e w h o received tetanus toxoid at any time are not at risk. However, patients with a severe envenomation should still receive antivenin despite proven horse serum allergies because these allergies can be e f f e c t i v e l y c o n t r o l l e d with proper pretreatment and close evaluation during antivenin administration. 7
Case Report 2 A 62-year-old m a n was bitten on the right t h u m b by a Massassauga (Sistrurus catenatus). He presented shortly after envenomation with local swelling but no systemic symptoms. Because of an allergic reaction (hives) to a tetanus immunization 13 years earlier and the minimal extent 138/796
Envenomation
I
Active blood loss?* Yes
No
I C°agil°~ Yes Administer antivenin (Figure 2) I Correct platelets if less than 20,000/mL
No
Observe six to eight hours (Figure 2)
I
and
I
Administer blood products based on specific coagulopathy
I
Correct hemoglobin if less than 7 g/dL
No
Yes
I Repeat antivenin I Administer blood products if
Administer antivenin (Figure 2)
Monitor condition and coagulation studies
bleeding develops
*Active blood loss is definedas guaiac-positiveemesisor stool or a decreasinghematocriLMinor hematuriaor bleedingfrom gumscan be treatedwith antiveninalone.
of apparent envenomation, no antivenin was given. During his hospitalization, the swelling and ecchymosis progressed to his elbow. On discharge from the hospital three days later, all of his coagulation parameters were w i t h i n normal limits except for fibrin split products of more than 10 and less than 40 txg/mL. SiN days after the envenomationl tl~e patient remained a s y m p t o m a t i c w i t h o u t any evidence of bleeding, and his swelling had resolved. However, his fibrinogen had decreased to less than 50 mg/dL; for this reason alone, he w a s t r a n s f u s e d w i t h 15 u n i t s of c r y o p r e c i p i t a t e . T h e r e was no increase in his fibrinogen level for several days. Complete resolution without further t r e a t m e n t occurred over the following two months. Annals of Emergency Medicine
In this case, the patient received blood products without a clear indication, placing h i m at risk for complicating infections. He did not demonstrate clinical evidence of bleeding over six days. We conclude, therefore, that he should not have been transfused. As discussed previously, ~.t: ar~tiven~n is indicated, a presumed allergy to horse products is not an absolute contraindication to its use.
Case Report 3 A 10-year-old boy was bitten on the right index finger by a Western D i a m o n d b a c k rattlesnake (C atrox). He arrived in the emergency departm e n t 40 minutes after envenomation with stable vital signs and pain and swelling limited to his finger. He had a hematocrit of 39.8; decreased plate-
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SNAKE VENOM COAGULOPATHY Burgess & Dart
Patient with snakebite I Vital signs, physical examination
Unstable 3atient
Stable patient
I
Grade envenomation Minimal
Local pain, edema, local ecchymosis, normal coagulation, no progression
Moderate
Severe
Spreading pain, Massive edema, edema, ecchymosis, ecchymosis; markedly mildly abnormal coagulation abnormal coagulation, deftstudies, platelets, brination, DIC syndromes, hemolysis, w e a k n e s s ~ . _ _ f h e m o l y s i s , paralysis, c o
Immediately administer skin test and begin mixing ten to 20 vials antivenin.
Intradermal skin test Skin test 1
Administer antivenin;* if no early reaction, give five to ten vials over one to two hours.
+ Skin test I
Pretreat with H~- and H2blockers; dilute antivenin, and administer slowly.*
j~J
- Skin test I
Administerantivenin;* if no early reaction, give ten to 20 vials over first hour.
If allergic reaction develops, stop antivenin; treat with epinephrine, H~- and H2-blockade; re-evaluate clinical status, and restartantivenin if needed.
Observe six to eight hours for worsening of symptoms or coagulopathy; discharge if no progression.
* All patients requiring antivenin therapy should be admitted.
lets by peripheral blood smear; PT, 11.6 seconds; PTT, 35.9 seconds; and fibrinogen level, 100 mg/dL. After admission, he developed swelling to the wrist, right arm pain extending to the axilla, abdominal pain, and vomiting. The next morning, seven hours after e n v e n o m a t i o n , the h e m a t o c r i t was 37.7; platelets, 30,000/ixL; PT, 22.4 seconds; PTT, more than two minutes; and fibrinogen, less than 50 mg/dL. He was given 10 units of antivenin ( C R O T A L I D A E ) p o l y v a l e n t , and his coagulopathy improved over the next 24 hours with repeat laboratory values of a hematocrit of 28.8% ; platelets, 96,000/txL; PT, 11.5 seconds; PTT, 28.8 seconds; and fibrinogen, 240 mg/dL. The patient was discharged two days later and eventually regained full function of his right index finger.
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This case demonstrates the reversal of a c o a g u l o p a t h y with antivenin alone, thus sparing the patient the risks of blood product transfusion. DISCUSSION Use of Antivenin Although there have been no randomized human trials, antivenin has repeatedly been reported to reduce morbidity and mortality.~,s, 9 Case reports and uncontrolled series support the concept that antivenin is effective in the reversal of coagulation defects.2,1o, zl /n vivo animal experiments also support the use of antivenin. In rabbits, antivenin alone was more effective than surgery Or a combination of surgery and antivenin in reducing mortality and preserving limb muscle function. La In another rabbit study, antivenin reduced the degree of t h r o m b o c y t o s i s , hypoAnnals of Emergency Medicine
FIGURE 2. Clinical management of suspected pit viper envenomation. fibrinogenemia, and fibrin degredation products but did not reverse thrombocytopenia. [a In mice, polyvalent antivenin was capable of neutralizing the hemorrhagic activity of both Crotalus viridis viridis and C atrox venom 14 as well as local myonecrosis by C atrox venom. 15 Administration of antivenin has potential complications. In several studies, the incidence of immediate hypersensitivity reactions was 5% to 33%, including nausea, rash, warm flushes, bronchospasm, and hypotension.7,16,17 The incidence of serum sickness was 36% to 75%, occurring from two to 23 days after antivenin administration. Signs and symptoms included nausea and vomiting, malaise, diarrhea, urticaria, pruritis, fe797/139
SNAKE VENOM COAGULOPATHY Burgess & Dart
ver, s y n c o p e , b r o n c h o s p a s m , or edema.7,16,17 There does not appear to be a tight linear relationship b e t w e e n the dose of a n t i v e n i n and the s e v e r i t y of ser u m sickness, t 7 M o s t patients receiving m o r e than five vials of a n t i v e n i n will develop s e r u m sickness. D e a t h s after a n t i v e n i n a d m i n i s t r a t i o n have been claimed, a l t h o u g h these cases are poorly documented, and it is unclear w h e t h e r these deaths were due to a n t i v e n i n or e n v e n o m a t i o n . In t h r e e c l i n i c a l series, a n t i v e n i n adm i n i s t r a t i o n r e s u l t e d in no m o r t a l ity, no l o n g - t e r m side effects, a n d only transient morbidity. 7,16,17 Wingeft and Chan found no severe s e r u m sickness requiring either admission or p r o l o n g e d t r e a t m e n t in 211 patients receiving antivenin. 9 O u r experience from t h e W e s t e r n Envenomation Database currently i n c l u d e s 118 p a t i e n t s w h o have received antivenin. Of these, 26 of 112 (23.2%) suffered a c u t e r e a c t i o n s to antivenin. N o p a t i e n t died, and n o n e a p p e a r e d to s u f f e r s e q u e l a e f r o m their reactions. During the one-tos i x - m o n t h follow-up period, 49 of 79 (62.0%) d e v e l o p e d s e r u m s i c k n e s s , but t h e r e was no l a s t i n g m o r b i d i t y . In conclusion, a n t i v e n i n is considered r e l a t i v e l y safe w h e n a d m i n i s tered p r o p e r l y in an i n t e n s i v e care setting.
Use of Blood Products Blood products have been administered alone and in addition to antivenin in patients w i t h snakebite-induced coagulopathies (cases 1 and 2). These blood products include platel e t s , f r e s h - f r o z e n p l a s m a (FFP), c r y o p r e c i p i t a t e , a n d RBCs. B l o o d p r o d u c t t r a n s f u s i o n c a r r i e s significant risks, w h i c h have been well des c r i b e d in t h e m e d i c a l l i t e r a t u r e . Transfusion risks can be categorized into hemolytic reactions, nonh e m o l y t i c reactions, and i n f e c t i o u s complications. Unless otherwise stated, we will use the RBC unit as a basis for c a l c u l a t i o n of t r a n s f u s i o n risk. As the .amount t r a n s f u s e d increases, infectious risks are additive and t r a n s f u s i o n r e a c t i o n s i n c r e a s e , although the relationship has not been clearly defined. Hemolytic transfusion reactions can be classified as i m m e d i a t e or delayed. The total incidence of hemolytic r e a c t i o n s has b e e n r e p o r t e d as from one in 1,400 to one in 6,200 140/798
cases per u n i t RBCs transfused. 1s-2o I m m e d i a t e h e m o l y t i c r e a c t i o n s are m o s t often due to h u m a n error, eit h e r in t r a n s f u s i n g A B O - i n c o m p a t ible blood or, m o r e rarely, in transfusing type-specific blood that had not been cross matched. Fatal hemolytic reactions were previously estim a t e d to occur in one in 1 m i l l i o n cases 21 but are n o w believed to occur w i t h a f r e q u e n c y of one in 100,000 cases per unit RBCs transfused. 18 Delayed h e m o l y t i c transfusion reactions vary in severity but in general are m u c h m o r e benign. T h e y develop three to 13 days after transfus i o n w i t h an i n c i d e n c e of o n e in 1,500 cases per u n i t RBCs transfused a n d for p r a c t i c a l p u r p o s e s are n o t p r e v e n t a b l e . ~9 Because of t h e a n t i body-containing p l a s m a contained in each pack, platelet transfusions m a y also cause hemolytic reactions, w h i c h are u s u a l l y m i l d and rarely result in hypotension, d i s s e m i n a t e d intravascular coagulation, or renal failure. 2 2 N o n h e m o l y t i c t r a n s f u s i o n reactions are generally benign and occur w i t h an i n c i d e n c e of one in 100 to one in 200.18,23 T h e y include febrile r e a c t i o n s a s s o c i a t e d w i t h the presence of w h i t e cell agglutinins in the p a t i e n t ' s or d o n o r ' s s e r u m . In rare c a s e s , t h e y m a y l e a d to n o n c a r diogenic p u l m o n a r y edema. The use of l e u k o c y t e - d e p l e t e d p r o d u c t s decreases the incidence of febrile reactions. 24 Platelets also are depleted by these procedures. 25 Allergic reactions to p l a s m a proteins include urticaria and, rarely, a n a p h y l a x i s . T r u e anap h y l a x i s is m o s t often seen in the t r a n s f u s i o n of I g A - c o n t a i n i n g blood p r o d u c t s to IgA-deficient recipients, and it occurs in from one in 20,000 to one in 47,000 transfusions. 26 Recently, fatal graft versus host disease has been reported as a delayed complication in blood transfusion from a c l o s e r e l a t i v e , 27 b u t t h i s p r o b a b l y occurs in only very l i m i t e d circumstances. Transfusion-transmitted diseases c o n s t i t u t e the third m a j o r group of t r a n s f u s i o n reactions. N o n - A / n o n - B hepatitis p r e s e n t l y has an incidence of one in 100 to one in 500 cases per u n i t of RBCs transfused,~S, ~8 despite the screening of donors for elevated alanine aminotransferase. H e p a t i t i s B still occurs in from one in 200 to one in 300 cases per u n i t of RBCs transf u s e d d e s p i t e t e s t i n g of d o n 6 r s for Annals of Emergency Medicine
h e p a t i t i s B markers.18, 29 T r a n s m i s s i o n of A I D S h a s b e e n e s t i m a t e d from in one in 40,000 to one in 1 million cases per u n i t of RBCs, despite screening for anti-HIV, because of the "window" between infection with the virus and p r o d u c t i o n of the antibody. 18,3°,3t RBCs, p l a s m a , p l a t e l e t concentrates, cryoprecipitate, and n o n h e a t - t r e a t e d coagulation concentrates have all been found to t r a n s m i t AIDS. 32 HTLV-1 s e r o c o n v e r s i o n occurs in one in 4,500 cases per u n i t RBCs transfused. 3° Other transfusion-related infect i o n s i n c l u d e c y t o m e g a l o v i r u s , Epstein-Barr virus, parasites, and bacteria. C y t o m e g a l o v i r u s i n f e c t i o n occurred in 7% of t r a n s f u s i o n recipie n t s r e c e i v i n g a s i n g l e u n i t of RBCs. 33 M o s t i m m u n o c o m p e t e n t recipients get only a m i l d or inapparent infection, but the immunocomprom i s e d recipient m a y acquire a m u c h more serious infection. WBC-cont a i n i n g p r o d u c t s such as RBCs and platelets transmit cytomegalovirus infection, b u t cell-free p r o d u c t s appear to not t r a n s m i t cytomegalovirus i n f e c t i o n . T r a n s f u s i o n - r e l a t e d Epstein-Barr virus has a similar epidemiology. T r a n s m i s s i o n of malaria is rare in t h e U n i t e d States, b u t it is m u c h m o r e c o m m o n in e n d e m i c a r e a s . B a b e s i o s i s c a n be t r a n s m i t t e d by transfusion, m o s t frequently in N e w E n g l a n d w i t h s o m e r e p o r t e d fatalities. Transfusion is the second m o s t c o m m o n r o u t e of a c q u i r i n g Chagas d i s e a s e in e n d e m i c a r e a s s u c h as South America, but few transfusionr e l a t e d cases have been r e p o r t e d in the U n i t e d States. Syphilis is rarely t r a n s m i t t e d by blood p r o d u c t transfusion.32 R e a c t i o n s to c o n t a m i n a t e d blood products range from m i l d h e m o l y s i s to shock and death, resulting in part f r o m b a c t e r i a l i n f e c t i o n of b l o o d products. Because of their e x t e n d e d r o o m t e m p e r a t u r e shelf life, platelet transfusions are an occasional source of bacterial c o n t a m i n a t i o n . ,~4 Because m o s t t r a n s f u s i o n - r e l a t e d viral i n f e c t i o n s are a s s o c i a t e d w i t h leukocytes, there is great interest in the use of l e u k o c y t e - d e p l e t e d products. R e m o v a l of teukocytes by filtrat i o n has b e e n s h o w n to r e d u c e in vitro HIV infectivity, but residual viruses were still detectable, and it is unknown whether filtration would r e d u c e t h e t r a n s m i s s i o n of HIV in 20:7 July 1991
SNAKE VENOM COAGULOPATHY B u r g e s s & Dart
Standard Administration of Antivenin (CROTALIDAE) Polyvalent 1. Read package insert. 2. Check allergy history, especially to horse serum products. 3. Perform skin test if antivenin is indicated using the skin test material included with the antivenin. Never perform a skin test unless you are sure antivenin will be administered. If skin test is positive (wheal and flare within 20 to 30 minutes) and antivenin is necessary, request consultation through regional poison center. Antivenin may be administered in many cases despite a positive skin test. 4. Dosage and administration of antivenin (CROTALIDAE) polyvalent Dosage Minimal or trivial envenomation: no antivenin Moderate envenomation: five to ten vials Severe or rapidly progressive envenomation: ten to 30 vials, or more Mixing and infusion Add 10 mL of the diluent provided or normal saline to each vial. Mix by rolling between hands. Do not shake. Then, dilute by injecting into normal saline IV bag (eg, five to ten vials in 250 mL). Give intravenously at a slow rate initially and then at a faster rate (about five to ten minutes per vial) if no reaction occurs. Reduce volume of diluent in pediatric patients. Attempt to give total dose during first one to two hours. Use after 24 hours is currently limited to reversal of coagulopathy. 5. Guide to subsequent administration of antivenin should include response to the first dose and evidence of continuing injury. If swelling, coagulopathy, or any other problem is worsening after the initial administration, further antivenin is probably warranted. Consultation with a physician experienced in the treatment of complicated snakebite is recommended.
General Recommendations 1. Do not leave patient unattended. 2. Do not delay immediate or vigorous treatment if patient has a moderate or severe envenomation. 3. Consult poison control center for all bites (for informational purposes). In moderate-to-severe bites, allergic patients, or cases with complicating factors, ask to speak directly to toxicologist on call (Arizona Poison Control Center, 602/626-6016).
Use of Antivenin (CROTALIDAE) Polyvalent in Antivenin-Allergic Patients 1. Possibly allergic patients -- Positive skin test or known allergy to horse serum products Treatment of adult patients at risk for allergic reaction Treatment consists of dilution of the antivenin infusion and beth H1and H2-receptor blockade before antivenin infusion. Diphenhydramine 50 to 100 mg IV
human beings. 35 Further research is needed to determine whether filtration w o u l d affect t r a n s m i s s i o n of other leukocyte-associated disorders. Platelet transfusion carries a greater risk of viral infection than RBCs because of the pooled nature of 20:7: July 1991
Cimetidine 300 mg IV or ranitidine 50 mg IV Dilute antivenin to half or normal concentration -- about one vial/lO0 mL. Start infusion at a rate of 25 to 50 mL/hr, and double the rate every ten to 15 minutes until a rate is reached that will infuse the volume in two hours. In case a severe allergic reaction develops, the patient should be cardiac monitored, and equipment for airway control and epinephrine should be available at the bedside. Pediatric patients Diphenhydramine 1.25 mg/kg IV Cimetidine 5 to 10 mg/kg or ranitidine 1 to 2 mg/kg IV Dilute antivenin to half of normal concentration -- about one vial/lO0 mL (1:10 dilution). However, it is recommended that total volume not exceed 20 mL/kg. Start infusion at a slow rate (about 25 to 50 mL/hr); double the rate every ten to 15 minutes until a rate is reached that will infuse the total volume in two hours. Keep epinephrine 1:1,000 available at the bedside for possible reactions. 2. Patients currently having a reaction Diagnosis -- Any of the following signs or symptoms developing during antivenin infusion: anxiety, chills, weakness, nausea, pruritis, sneezing, feeling of throat constriction, hypotension, strider, urticaria, wheezing, emesis, dyspnea, diaphoresis, fever, or erythematous streaking from injection site Treatment of patients having an allergic reaction Treatment consists of dilution and slowing of antivenin infusion and beth H 1- and H2-receptor blockade Stop antivenin infusion. Epinephrine 1:1,000, 0.3 to 0.5 mg SQ; may be repeated every 15 minutes Diphenhydramine 50 to 100 mg IV Cimetidine 300 mg IV or ranitidine 50 mg IV A second IV line should be established. First line of treatment for hypotension is isotonic fluid infusion. Vasopressors may be needed in particularly severe cases. Reconsider the need for antivenin. The primary considerations include the severity of the envenomation (life- or limb-threatening) and the seriousness of the reaction. This decision may be aided by contacting a physician experienced in the use of antivenin in antivenin-allergic patients. If antivenin is needed, wait ten to 15 minutes for initial reaction to subside and for patient to stabilize. Then, restart infusion at 25 to 50 mL/hr. Increase the rate every 15 minutes until reaching a rate that is 25 mL/hr below the rate at which the allergic response occurred. Continue at this rate until the total volume is infused. Pediatric patients Management is the same, except that doses are reduced as indicated in the pediatric section of "Possibly allergic patients -- Positive skin test or known allergy to horse serum products" (above).
multiple-donor platelets, where each transfusion comes from six to ten donors. Single-donor platelets, produced by platelet apheresis, carry a per-unit risk similar to RBCs. One unit of FFP is believed to have a similar risk to one unit of RBCs in viral infectivity, A n n a l s of Emergency Medicine
FIGURE 3. Guidelines for use of antivenin (CROTALIDAE) polyvalent and m a n a g e m e n t of allergic reactions. including HIV infection. Cryoprecipitate transfusion also carries a greater 799/141
SNAKE VENOM COAGULOPATHY Burgess & Dart
risk of viral infection than RBCs because of its pooled nature, although the per-unit risk is similar to RBCs in i n f e c t i o u s c o m p l i c a t i o n s . O t h e r c o m p l i c a t i o n s of transfusions, such as those s t e m m i n g from ABO compatibility, are m u c h less frequent in platelets and cell-free components such as FFP a n d c r y o p r e c i p i t a t e s than in RBCs. A n t i t h r o m b i n III has r e c e n t l y become c o m m e r c i a l l y available for the t r e a t m e n t of s e v e r a l disorders, including disseminated intravascular coagulation. Because it is a purified, heat-treated product, its administration should t h e o r e t i c a l l y be safe from transfusion-related infection, g6 Its eff i c a c y is s t i l l u n c l e a r , a l t h o u g h in s e v e r a l u n c o n t r o l l e d s t u d i e s it reportedly shortened the duration and improved the course of d i s s e m i n a t e d intravascular coagulation.37, 3s We are not aware of any placebo-controlled trials or studies w i t h clinically relevant end points, g9 A c u m u l a t i v e risk of blood product t r a n s f u s i o n c a n n o t be easily calculated b e c a u s e m a n y studies do n o t indicate the specific n u m b e r of units and types of blood products given to each individual, and the m o r b i d i t y or m o r t a l i t y of e a c h t y p e of r e a c t i o n varies greatly. T r a n s m i s s i o n of nonA / n o n - B h e p a t i t i s is p e r h a p s t h e m o s t s i g n i f i c a n t risk, w i t h an incidence of as high as one in 100 cases per u n i t of RBCs transfused, and hepatitis B sill occurs in some studies as frequently as from one in 200 to one in 300 cases per u n i t of RBCs transfused. The p o t e n t i a l for fatal complic a t i o n s s u c h as HIV i n f e c t i o n or transfusion of m i s m a t c h e d blood is a constant concern. Taken together, these risk are substantial and require that blood products be given only for strict clinical indications.
gums can i n i t i a l l y be treated w i t h antivenin alone. As i l l u s t r a t e d in case 3 and discussed previously, a n t i v e n i n has repeatedly been shown to reverse coagulopathies. If the patient is unstable or actively bleeding or if a n t i v e n i n is not effective, blood c o m p o n e n t transf u s i o n is s u g g e s t e d . B e c a u s e s n a k e v e n o m s vary widely in their effects on t h e c o a g u l a t i o n s y s t e m , b l o o d product transfusion should be based on t h e s p e c i f i c c o a g u l a t i o n abnormality. FFP t r a n s f u s i o n is i n d i c a t e d for m u l t i p l e c o a g u l a t i o n p r o t e i n deficiencies in the u n c o n t r o l l a b l y bleeding p a t i e n t or as a r e p l a c e m e n t for i s o l a t e d factor deficiencies. 4o Platelets are indicated for t h r o m b o c y t o p e nia or a b n o r m a l i t i e s of platelet function w i t h significant bleeding. Platelets are not indicated if t h r o m b o c y t o penia is the sole a b n o r m a l i t y and the platelet count is more than 20,000/ixL or for a bleeding t i m e less than twice the upper l i m i t of n o r m a l unless there are other abnorm a l i t i e s . 4~ P r o p h y l a c t i c p l a t e l e t adm i n i s t r a t i o n m a y be c o n s i d e r e d for counts less than 20,000/txL, although there is no consensus on this topic. 4l H y p o f i b r i n o g e n e m i a s h o u l d be treated w i t h cryoprecipitate only for a level less than 100 mg/dL and clinic a l l y s i g n i f i c a n t h e m o r r h a g e . 4z As d i s c u s s e d in case 2, u n c o m p l i c a t e d h y p o f i b r i n o g e n e m i a s h o u l d n o t be t r e a t e d w i t h b l o o d p r o d u c t s . RBC transfusion is generally indicated for a p a t i e n t w i t h h e m o g l o b i n less than 7 mg/dL and should be considered in p a t i e n t s w i t h a p r e c i p i t o u s drop in hemoglobin. The r o u t i n e transfusion of a stable patient for a h e m o g l o b i n less t h a n lO m g / d L is n o t r e c o m m e n d e d . I8 I n d i v i d u a l j u d g m e n t is suggested for specific cases.
Treatment of Snake Venom Coagulopathy
SUMMARY
The snake envenomation treatm e n t protocol used at the U n i v e r s i t y of Arizona is detailed (Figures 1 and 2). A protocol for the a d m i n i s t r a t i o n of a n t i v e n i n is s h o w n (Figure 3). O n l y moderate or severe envenomat i o n s or m i n i m a l e n v e n o m a t i o n s that are worsening require treatment. A n t i v e n i n s h o u l d be t h e p r i m a r y t r e a t m e n t for s n a k e v e n o m coagulopathy unless the patient is unstable or actively bleeding. Minor bleeding such as h e m a t u r i a or oozing from the 142/800
Coagulopathies are c o m m o n l y encountered in v i c t i m s of snake v e n o m poisoning. Blood p r o d u c t s are often given in an effort to reverse these coagulopathies, but in m a n y cases they are given w i t h o u t a c o m p l e t e knowledge of the i n d i c a t i o n s for transfus i o n or t h e r i s k s of b l o o d p r o d u c t transfusion. The hemolytic, nonh e m o l y t i c , a n d i n f e c t i o u s r i s k s of blood p r o d u c t t r a n s f u s i o n r e a c t i o n s are significant. A n t i v e n i n has proven effective and r e a s o n a b l y safe in t h e t r e a t m e n t of r a t t l e s n a k e biteg; thereAnnals of Emergency Medicine
fore, a n t i v e n i n should be the initial t r e a t m e n t for s n a k e v e n o m coagulopathy. Blood products are indicated o n l y if a n t i v e n i n is n o t efficacious, for active bleeding, or for specific coagulation abnormalities. The authors thank Paul V Holland, MD, for his assistance and Douglas W Huestis, MD, for his review of the manuscript.
REFERENCES 1. Glass TG: M~nagement of Poisonous Snakebite, ed 2. San Antonio, Texas, Glass Publishing Co, 1976, p 3 7. 2. Russell I:E: Snake Venom Poisoning, ed 2. Great Neck, New York, Scholium International, 1983, p 306-343. 3. Corrigan lJ: Hemorrhagic and Thrombotic Diseases in Childhood Adolescence, ed 1. New York, Churchill Livingstone, 1985, p 188-202. 4. Cooke RA, Hampton 8, Sherman WB, et al: Allergy induced by immunization with tetanus toxoid. [AMA 1940; 114:1854-i858. 5. Facktor MA, Bernstein RA, Fireman P: Hypersensitivity to tetanus toxoid. J Al]er Clin Immuno] 1973; 52:1-12. 6. Human antitoxin in prophylaxis and treatment of tetanus. Med Lett 1965;7:13q4. 7. Spaite DW, Dart RC, Hurlbut K, et ah Skin testing: hnplications in the management of pit viper envenomation (abstract). Ann Emerg Med [988;17:389. 8. Christensen PA: Snakebite and the use of antivenin in Southern Africa. S Aft Med / 198l;59:934 938. 9. Wingert WA, Chan L: Rattlesnake bites in Southern California and rationale for recommended treatment. West / Med 1988;148:37-44. 10. Dart RC, Burgess JL: Snakebite coagulopathy. Clin Hclemost Rev 1990;4:6. It. Rifler E, Curry SC, Gerkin R: Successful treatment with antivenin of marked thrombocytopenia without significant coagulopathy following rattlesnake bite. Ann Emer,g Med 1987~16:1297q299. 12. Stewart RM, Page CP, Schwesinger WH, et al: Antivenin and fasciotomy/debridement in the treatment of severe rattlesnake bite. Am J Surg 1989;158:543-547. i3. Simon TL, Grace TG: Envenomation coagulopathy in wounds from pit vipers. N EngI J Med 198[;305: 443-447. 14. Ownby CL, Colberg TR, Odell GV: A new method for quantitating hemorrhage induced by rattlesnake venoms: Ability of polyvalent antivenin to neutralize hemorrhagic activity. Toxicon [984;22:227-233. 15. Ownby CL, Colberg TR: Ability of polyvalent (CrotaIidae} antivenin to neutralize local myonecrosis induced by Crotalus atrox v e n o m Toxfcon i986;24: 201-203. 16. Jurkovich GJ, Lutermal£ A, McCullar K, et al: Complications of Crotalidae antivenin therapy. / Trauma 1988;28:1032 1036. 17. Corrigan P, Russell FE, Wainschel l: Clinical reac tions to antivenin, in Rosenberg P (ed}: Toxins: Animal, Plant, and Microbial. Oxford, Pergamon, 1978, p 457-465. i8. Consensus Conference, Office of Medical Applications of Research, National Institutes of Health: Perioperative red blood cell transfusion. JAMA t988;260: 2700-2703. 19. Taswell HI:, Pineda AA, Moore 8B: Hemolytic transfusion reactions: Frequency and clinical and laboratory aspects, in Bell CA led): A Seminar on ImmuneMediated Ceil Destruction. ed 1. Washington, DC, American Association of Blood Banks, 1981, p 71-92. 20. Pineda AA, Brzica SM, Taswell HI:: Hemolytic transfusion reaction: Recent experience in large blood bank. Mayo Clirl Proc 1978;53:378-390.
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21. Schmidt PJ: The mortality from incompatible transfusion, in Sandier SG, Nusbacher J, Schanfield MS (eds): ImmunobioIogy of the Erthyrocyte, ed 1. New York, Alan R Liss Inc, 1980, p 251-261. 22. Pierce RN, Reich LM, Mayer K: Hemolysis following platelet transfusions from ABO incompatible donors. Transhlsion 1985;25:60-62. 23. Menitove JE, McEIligott MC, Aster RH: Febrile transfusion reaction: What blood component should be given next? Vox Sang I982~42:318-321. 24. Brittingham TE, Chaplin'H: Febrile transfusion reactions caused by sensitivity to donor leukocytes and platelets. JAMA 1957~165:819 825. 25. Hughes ASB, Brozovic B: Leucocyte depleted blood: An appraisal of available techniques. Br J HaematoI 1982;50:381-386. 26. Pineda AA, Taswell HF: Transfusion reactions associated with anti-IgA antibodies: Report of four cases and review of the literature. Transhzsion 1975;15:10 15. 27. Thaler M, Shamiss A, Orgad S, et al: The role of blood from HLA&omozygous donors in fatal transfusion associated with graft versus-host disease after open-heart surgery. N Eng] J Med 1989;321:25 28. 28. Koziol DE, Holland PV, Ailing DW, et ah Antibody to hepatitis B core antigen as a paradoxical marker for non-A non-B hepatitis antigens in donated blood. Ann
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