Spencer Greene, MD, MS, FACEP, FACMT

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

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

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

The snakes

The herp perps

My 2017 data J F M A M J J A S O N D total copperhead 2 2 2 5 6 5 5 2 5 1 1 36 cottonmouth 1 1 1 3 rattlesnake 1 1 unknown 1 1 1 4 6 6 2 1 3 25 coral snake 1 1 3 1 2 2 10 exotic 1 1 non-venomous 2 2 total 2 3 4 9 13 13 12 5 8 4 5 78

2016 National Poison Data System snake # bites major death % major + death Copperhead 2048 32 0 1.56% Cottonmouth 242 5 0 2.07% Rattlesnake 804 78 1 9.83% Unknown crotalid 994 77 2 7.95% Coral snake 73 2 0 2.74%

2012 2015 National Poison Data System snake # bites major death % major + death Copperhead 7199 163 2 2.29% Cottonmouth 992 19 0 1.92% Rattlesnake 4108 346 9 8.64% Coral snake 327 10 0 3.06%

Pit vipers

Pit vipers of SE Texas

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

Pit viper

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

intubate here Pit viper

Texas coral snake

Who are the victims?

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

Why I m screwed

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

Legitimately sneaky..

Clinical effects

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

Severity varies by Age and size of snake Venom effects

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

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

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.

Clinical features

Clinical effects: local damage

Clinical recovery

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

Coagulopathy Thrombocytopenia Hypofibrinogenemia Hematotoxicity

Hematotoxicity Coagulopathy Thrombocytopenia Hypofibrinogenemia Oozing Clinically significant bleeding

Clinical effects: hematologic

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

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

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

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 5 365 days

Clinical effects: coral snakes

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

Coral snake bites

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

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

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

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

Hospital-based management of U.S. crotalid envenomations

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

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

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

Start with the basics DILAUDID ELEVATION

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

Elevate!

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

Assessment: local progression

CBC Assessment: blood tests PT/INR Fibrinogen Chemistry

Assessment: radiography?

Assessing for neurotoxicity

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

Do NOT use the snakebite severity score

Antivenom

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

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?

Antivenom: CroFab

CroFab

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.

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

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

Antivenom: safety

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

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 2012-2014 hypotension (0.9%) bronchospasm (0.9%) Kleinschmidt ACMT ASM 2017

Safety in reexposure

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

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

Antivenom: consider the cost:benefit ratio

Antivenom: how it s done.

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

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

CroFab use

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

CroFab preparation Reconstitute with 25 ml Continuously roll and invert manually Reconstitute in 1.1 min (0.9 1.3 min)

Time for the final A ANTIVENOM

Antibiotics start with A too!

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

Something else that starts with A

The role of surgical intervention

Acute surgical intervention

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

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 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

Fasciotomy

What else should you avoid?

electric shock

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

tourniquet

Constriction and pressure immobilization

Pressure immobilization? No!

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

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

Venom extraction device

Key Points

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

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

Thanksssss for listening

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

Coral snake antivenom