Spencer Greene, MD, MS, FACEP, FACMT

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1 Spencer Greene, MD, MS, FACEP, FACMT Director of Medical Toxicology Assistant Professor of Emergency Medicine Assistant Professor of Pediatrics Baylor College of Medicine Consulting Toxicologist, SE Texas Poison Center

2 Obligatory disclosure slide I have served as a paid consultant for BTG I will not discuss any off-label uses for any products

3 Objectives Provide a brief overview of medically-relevant snakes Review the clinical features of various snakebites Discuss the role of antivenom in crotaline envenomation Address some of the common mistakes made in the management of snakebites

4 The snakes

5 The herp perps

6 My 2017 data J F M A M J J A S O N D total copperhead cottonmouth rattlesnake 1 1 unknown coral snake exotic 1 1 non-venomous 2 2 total

7 2016 National Poison Data System snake # bites major death % major + death Copperhead % Cottonmouth % Rattlesnake % Unknown crotalid % Coral snake %

8 National Poison Data System snake # bites major death % major + death Copperhead % Cottonmouth % Rattlesnake % Coral snake %

9 Pit vipers

10 Pit vipers of SE Texas

11 Pit vipers of SE Texas 1 1. Canebrake rattlesnake 2. Pygmy rattlesnake 3. Western diamondback 2 3

12 Pit viper

13 What is a pit viper? Non-venomous Non-venomous

14 intubate here Pit viper

15 Texas coral snake

16

17 Who are the victims?

18 Testosterone Twenty-something Truck Tequila Tank top Trailer Tattoos Toothlessness Teasing Trump supporter Taxpayer-dependent Risk factors for snakebites?

19 Why I m screwed

20 Demographics 69.3% males, 30.7% females 28.2% children < 12 y/o (mean age 6.6) Sex distribution 45.2% lower extremity and 54.8% upper extremity in males 77.5% lower extremity and 22.5% upper extremity in females Legitimacy 19% of all bites resulted from intentional interaction with snake 42.6% of upper extremity bites resulted from intentional interaction

21 Legitimately sneaky..

22 Clinical effects

23 Bite envenomation Nothing at all. Nothing at all. Nothing at all.

24 Severity varies by Age and size of snake Venom effects

25 Venom effects The larger the snake, the more significant the envenomation

26 Severity varies by Venom effects Age of snake Time of year Snake species Last meal Last envenomation Amount of venom injected Age of patient Location of bite Patient s co-morbid conditions

27 Venom components General Clinical Effect Local tissue damage Coagulation effects a Platelet effects c Responsible Venom Components Metalloproteinases Phospholipases A 2 Hyaluronidase C-type lectin-like proteins Metalloproteinases b Serine proteases b Phospholipases A 2 Disintegrins C-type lectin-like proteins Metalloproteinases Phospholipases A 2 Neurotoxic effects Phospholipases A 2 a Venom contains both pro- and anticoagulants, with anticoagulant effects predominating in North American crotaline envenomation. b Include thrombin-like enzymes as well as fibrino(geno)lytic enzymes. c Venom may contain factors that inhibit, activate, or affect aggregation of platelets.

28 Clinical features

29 Clinical effects: local damage

30 Clinical effects: local damage

31 Clinical effects: local damage

32 Clinical effects: local damage

33 Clinical effects: local damage

34 Clinical recovery

35 Clinical recovery

36 Clinical effects: systemic toxicity Non-specific signs and symptoms Hematotoxicity Neurotoxicity Airway swelling Cardiovascular collapse

37 Coagulopathy Thrombocytopenia Hypofibrinogenemia Hematotoxicity

38 Hematotoxicity Coagulopathy Thrombocytopenia Hypofibrinogenemia Oozing Clinically significant bleeding

39 Clinical effects: hematologic

40 Hematotoxicity Coagulopathy Thrombocytopenia Hypofibrinogenemia Oozing Clinically significant bleeding Thrombotic events, occasionally Disseminated intravascular coagulation, rarely

41 Clinical effects: neurological Ptosis Diplopia Myokymia Paresthesias Weakness Paralysis Respiratory failure

42 But that s for all pit vipers. I heard that copperheads aren t so bad

43

44 Clinical effects: copperheads Retrospective review of bites reported from 1/1997 9/2000 Clinical features swelling 94% vomiting 11% ecchymosis 53% fainting 19% bullae 13% coagulopathy 30% tissue necrosis 8% active bleeding 5% 83% of untreated patients reported limb dysfunction on follow up Duration of limb dysfunction ranged from days

45 Clinical effects: coral snakes

46 Coral snake bites ~ 5% of reported bites Usually result from intentional interaction

47 Coral snake bites

48 30 50% of bites may be dry behavior anatomy Coral snake bites

49 But if you are envenomated. Locally mild swelling absence of tissue destruction inconspicuous fang marks Morgan et al.

50 But if you are envenomated. Pain Non-specific signs and symptoms headache nausea, vomiting, abdominal pain diaphoresis pallor Neurological signs and symptoms

51 But if you are envenomated. Neurological signs and symptoms fasciculations diplopia hoarseness dysphagia slurred speech paresthesias muscle weakness paralysis respiratory paralysis death Signs and symptoms usually appear within 12 hours

52 Hospital-based management of U.S. crotalid envenomations

53 Now just wait a cotton-pickin minute. How do we know it s a pit viper bite?!

54 Don t generate additional patients. Don t bring in the snake

55 ABCDE Treatment in the hospital Assessment Antivenom Avoidance of unnecessary and/or dangerous interventions

56 Start with the basics DILAUDID ELEVATION

57 Analgesia Avoid NSAIDS until there s more research Choose opioids wisely morphine not idea Ice packs are ok, briefly

58

59 Elevate!

60 Elevate!

61 Assessment Monitor local progression Test for systemic toxicity Watch them for a sufficient amount of time Don t rely on research tools to make clinical decisions

62 Assessment: local progression

63 CBC Assessment: blood tests PT/INR Fibrinogen Chemistry

64 Assessment: radiography?

65 Assessing for neurotoxicity

66 Upper extremity Observation period 8 hours minimum Lower extremity 12 hours minimum Systemic toxicity 24 hours minimum

67 Do NOT use the snakebite severity score

68 Antivenom

69 Antivenom: the 4 questions Does it work? Is it safe? Is it worth it? Is it antivenin or antivenom?.

70 Nomenclature Antivenom World Health Organization (1981). Progress in the characterization of venoms and standardization of antivenoms. What is the only commercially-available, FDAapproved AV for U.S. pit vipers?

71 Antivenom: CroFab

72 CroFab

73 Patients Achieving Initial Control (%) 91% 91% 100% 9% 9% 0% SSS (N=11) ICA (N=11) ICA (N=31) Study 1 Study 2 Study 1: 91% (10/11) of patients enrolled in the study demonstrated efficacy by SSS and ICA Study 2: All 31 patients enrolled in the study achieved initial control of their envenomation with CroFab ICA, Investigator s Clinical Assessment; SSS, Snakebite Severity Scale. CroFab [package insert]. West Conshohocken, PA: BTG International Inc; 2012.

74 Randomized, double-blinded placebo-controlled trial of 74 patients (45 FabAV, 29 placebo) Primary outcome was patient-specific functional scale (PSFS) obtained at 14 days Secondary outcomes included PSFS at other times points, limb-specific functional scales, objective functional measurements, quality of life, pain and analgesic use

75 CroFab for Copperheads PSFS score of 8.6 vs. 7.4 at 14 days 75% of treated patients achieved 10 on PSFS by day 31 versus 57 days for placebo group Patients treated with CroFab did not require opioids after day 21 versus 90 days for placebo group

76 Antivenom: safety

77 11 prospective and retrospective cohort studies of patients receiving FabAV 504 patients 8% incidence of acute hypersensitivity reactions 5 patients unable to complete treatment 13% incidence of serum sickness No deaths or rehospitalizations

78 368 patients treated with FabAV 149 (40.2%) were children Adverse events in 9 patients 5 (2.3%) of adults and 4 (2.7%) of children Most common adverse events rash (0.9%) NASBR hypotension (0.9%) bronchospasm (0.9%) Kleinschmidt ACMT ASM 2017

79 Safety in reexposure

80 Repeat offenders Approximately 22 patients treated for 2 bites No immediate or delayed adverse reaction to AV

81 42 y/o male 19+ treatments CroFab: repeat exposure Two hypersensitivity reactions 1994: mild periorbital edema during the infusion, followed by generalized urticaria 5 hours later 2012: urticaria during the infusion Usually did not receive pre-treatment

82 Antivenom: consider the cost:benefit ratio

83 Antivenom: how it s done.

84 Progressive local findings Hematotoxicity Neurotoxicity CroFab: indications Airway, breathing, or circulatory compromise

85 CroFab use 4 12 vials initially* determine if control has been attained no progression of local damage no hemodynamic instability no worsening of hematologic labs

86 CroFab use

87 CroFab preparation Reconstitute each vial with 18 ml of 0.9% saline Mix by constant manual inversion until no solid material is visible Add to total of 250 ml 0.9% saline

88 CroFab preparation Reconstitute with 25 ml Continuously roll and invert manually Reconstitute in 1.1 min ( min)

89 Time for the final A ANTIVENOM

90 Antibiotics start with A too!

91 Antibiotic prophylaxis Prospective, controlled trial 55 patients treated with IV antibiotics 59 untreated No statistically significant difference in outcomes

92

93 Something else that starts with A

94 The role of surgical intervention

95 Acute surgical intervention

96 96

97 Swine model of crotalid envenomation Hind legs injected with venom and R leg immediately underwent fasciotomy 14.5% of limbs that underwent fasciotomy had myonecrosis vs. 2.5% of limbs without fasciotomy

98 Rabbit model of envenomation 3 mg/kg C. atrox venom injected into L hindleg Compared AV, surgery, AV + surgery, and placebo 100% of AV group survived 80% of AV + surgery group survived 30% of surgery group survived 30% of placebo group survived

99 99 studies evaluated No study supports fasciotomy for the treatment of compartment syndrome with level 1-3 evidence and grade of recommendation A or B Fasciotomy-treated subjects did worse than AVtreated subjects with equally severe envenomations

100 Fasciotomy

101 Fasciotomy

102 What else should you avoid?

103 electric shock

104 Not effective in preventing toxicity in a variety of envenomations pit viper bites coral snake bites spider bites other arthropod bites and stings May cause hypopigmentation and burns Stun gun use has been associated with death in certain populations

105 tourniquet

106 Constriction and pressure immobilization

107 Pressure immobilization? No!

108

109 Venom extraction device Radioactively labeled mock venom injected into humans Extractor removed 0.04% - 2.0% of envenomation load

110 Tissue damage increased in extraction group Venom extraction device Artificial rattlesnake envenomation in pig model Swelling not reduced in extractor-treated group

111 Venom extraction device

112 Venom extraction device

113 Key Points

114 Key points Pit viper viper bites are characterized by local tissue damage and systemic toxicity Copperhead bites can produce serious toxicity Coral snake envenomations are characterized by pain and, occasionally, objective neurotoxicity Most pre-hospital interventions are useless and possibly dangerous Supportive care is essential but often insufficient Antivenom is generally safe and effective

115 Key points Indications for antivenom include progressive local damage and/or significant systemic toxicity Patients who have previously received antivenom may receive it again if indicated Surgical intervention is generally not necessary Antibiotics are rarely indicated

116 Thanksssss for listening

117 Antivenom on the horizon Prospective, double-blind randomized clinical trial 18 clinical sites Compared incidence of late coagulopathy 11/37 (29.7%) of Fab + maintenance 4/39 (10.3%) of Fab 2 + maintenance 2/38 (5.3%) of Fab 2 without maintenance

118 Coral snake antivenom

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