9.3 Snake and Spider Envenomations & Heavy Metal Chelation

9.3 Snake and Spider Envenomations & Heavy Metal Chelation

Envenomations and heavy metal intoxications represent complex clinical toxicology emergencies requiring targeted biologic and chelating countermeasures. Envenomations by North American pit vipers, coral snakes, and spiders provoke multi-organ toxicities ranging from venom-induced consumptive coagulopathy (VICC) and tissue necrosis to flaccid neuroparalysis and agonizing autonomic cramping. Concurrently, heavy metal poisonings—such as lead and iron—disrupt essential cellular enzymes and mitochondrial energy production, demanding rigorous adherence to chelator administration sequencing and endpoints.

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Crotalinae (Pit Viper) Envenomation & Antivenom Pharmacotherapy

Subfamily Crotalinae (pit vipers) accounts for approximately 95% of native venomous snakebites in the United States, comprising rattlesnakes (Crotalus), copperheads (Agkistrodon contortrix), and cottonmouths/water moccasins (Agkistrodon piscivorus). Pit vipers possess heat-sensing facial pits, retractable front fangs, and triangular heads.

Venom Pathophysiology

Crotalid venom is a sophisticated proteomic mixture of enzymes and non-enzymatic proteins:

1. Metalloproteinases & Hyaluronidase: Degrade vascular basement membranes, extracellular matrix, and collagen, producing intense local tissue necrosis, ecchymosis, bleb formation, and extreme capillary leak.
2. Phospholipase $\text{A}_2$: Induces myonecrosis, cellular lysis, and systemic platelet destruction.
3. Thrombin-like Glycoproteins (e.g., Crotalase): Directly cleave fibrinogen into friable, abnormal fibrin monomers that lack cross-linking, precipitating Venom-Induced Consumptive Coagulopathy (VICC) characterized by severe hypofibrinogenemia, markedly elevated PT/INR, and profound thrombocytopenia.
4. Systemic Manifestations: Hypotension, shock, metallic or minty taste, perioral paresthesias, nausea, vomiting, and diffuse fasciculations.

Antivenom Pharmacotherapy: CroFab vs. Anavip

Definitive treatment for moderate-to-severe Crotaline envenomation is immediate antivenom therapy. Two FDA-approved formulations are available in the United States:

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1. Crotalidae Polyvalent Immune Fab (CroFab, Ovine)

• Structure: Monovalent Fab immunoglobulin fragments (~46 kDa) derived from sheep immunized with venom from four North American pit vipers (Crotalus atrox, C. adamanteus, C. scutulatus, and Agkistrodon piscivorus).
• Initial Loading Dose: 4 to 6 vials IV reconstituted in 250 mL of 0.9% NaCl and infused over 60 minutes (initiate slowly at 25 to 50 mL/h for the first 10 minutes to observe for acute hypersensitivity reactions, then increase to complete within 1 hour).
• Establishing Initial Control: Defined as halting the progression of swelling, normalization of vital signs, and stabilization/reversal of coagulopathy (platelets $>100,000/\mu\text{L}$, fibrinogen $>100\text{ mg/dL}$, normal PT/INR). If initial control is not achieved after the first dose, administer an additional 4 to 6 vials and repeat until control is established.
• Mandatory Maintenance Regimen: Once initial control is secured, administer 2 vials IV every 6 hours for 3 doses (at hours 6, 12, and 18).
• Pharmacokinetic Limitation & Recurrent Coagulopathy: CroFab has a short terminal elimination half-life (~12 to 15 hours). Because venom components have a larger molecular weight and depot slowly from tissue over days, the antivenom clears faster than circulating venom. Consequently, up to 30% to 50% of patients experience delayed recurrent coagulopathy or recurrent thrombocytopenia 2 to 7 days post-discharge. Outpatient follow-up with CBC and PT/INR at 48 to 72 hours and 5 to 7 days is mandatory.

2. Crotalidae Immune $\text{F(ab')}_2$ (Anavip, Equine)

• Structure: Bivalent $\text{F(ab')}_2$ immunoglobulin fragments (~100 kDa) derived from horses immunized with venom from Bothrops asper and Crotalus durissus.
• Initial Loading Dose: 10 vials IV infused over 60 minutes. Re-evaluate at 1 hour; if initial control is not achieved, administer another 10 vials.
• Key Pharmacokinetic Advantage: The larger bivalent $\text{F(ab')}_2$ molecule has a significantly prolonged terminal elimination half-life (~5.5 days [133 hours], compared to ~15 hours for CroFab). Because therapeutic antivenom concentrations persist in the circulation throughout the entire window of tissue venom redistribution, NO scheduled maintenance infusions are required. Anavip dramatically reduces the incidence of late recurrent coagulopathy and recurrent thrombocytopenia.

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Coral Snake Envenomation

Eastern (Micrurus fulvius) and Texas (Micrurus tener) coral snakes belong to the family Elapidae (related to cobras and mambas). They are recognized by the classic ring pattern: "Red on yellow, kill a fellow; red on black, friend of Jack."

Clinical Presentation & Management

• Neurotoxic Mechanism: Unlike pit vipers, coral snake venom contains potent, non-cytotoxic post-synaptic alpha-neurotoxins that bind competitively to nicotinic acetylcholine receptors at the neuromuscular junction, blocking neuromuscular transmission.
• Minimal Local Findings: The bite site typically exhibits little to no pain, zero swelling, and no tissue necrosis, often leading patients and clinicians to underestimate severity.
• Delayed Life-Threatening Paralysis: Neurotoxic symptoms are classically delayed by 12 to 18 hours post-bite. Once clinical weakness begins, rapid deterioration ensues: ptosis, diplopia, bulbar palsies (dysphagia, dysarthria), descending symmetric flaccid paralysis, and fatal diaphragmatic respiratory failure.
• Pharmacotherapy: Administer equine North American Coral Snake Antivenin (Micrurus fulvius) empirically (typically 3 to 5 vials IV infused over 1 hour) for any patient with a confirmed native coral snake bite, BEFORE the onset of neurotoxic symptoms. Once respiratory muscle paralysis has developed, antivenom does not rapidly reverse established receptor blockade; patients require prolonged endotracheal intubation and mechanical ventilation until new receptors are synthesized.

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Spider Envenomations: Black Widow vs. Brown Recluse

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Heavy Metal Toxicity & Chelation Pharmacotherapy

Heavy metals bind cellular functional groups (especially sulfhydryl, amino, and carboxyl groups), inactivating critical metabolic enzymes and generating oxidative free radicals.

1. Lead Poisoning & Encephalopathy

Lead accumulates in erythrocytes, soft tissues (brain, kidney), and bone (95% of total body burden in adults). It inhibits heme biosynthesis enzymes—specifically $\delta$-aminolevulinic acid dehydratase (ALAD) and ferrochelatase—producing microcytic sideroblastic anemia and classic basophilic stippling on peripheral blood smear. Chronic toxicity causes lead colic (severe cramping abdominal pain), motor peripheral neuropathy (bilateral wrist drop, foot drop), nephropathy, and cognitive impairment. Acute severe toxicity provokes lead encephalopathy (cerebral edema, seizures, coma, death).

Chelation Protocols Based on Whole Blood Lead Levels (BLL)

Whole blood lead concentrations determine therapy:

1. BLL 45 to 69 mcg/dL (Asymptomatic or Mild Symptoms):
   • Succimer (DMSA, Dimercaptosuccinic Acid): Oral water-soluble analog of dimercaprol.
   • Dosing: 10 mg/kg PO every 8 hours for 5 days, followed by 10 mg/kg PO every 12 hours for 14 days (total 19-day course). Recheck BLL 2 weeks post-therapy.
   • Adverse Effects: Gastrointestinal distress, transient elevation in hepatic transaminases, neutropenia, and prominent sulfuric breath/urine odor.
2. BLL $\ge 70\text{ mcg/dL}$ or Acute Lead Encephalopathy (Medical Emergency):
   • Requires dual parenteral chelation with Dimercaprol (BAL, British Anti-Lewisite) and Calcium Disodium EDTA ($\text{CaNa}_2\text{EDTA}$).
   • Dimercaprol (BAL): Dosed at 75 mg/$\text{m}^2$ (or 4 mg/kg) deep IM every 4 hours. It is lipophilic, crosses the blood-brain barrier, and chelates intracellular lead. Formulated in peanut oil (strictly contraindicated in severe peanut allergy!).
   • Calcium Disodium EDTA ($\text{CaNa}_2\text{EDTA}$): Dosed at 1,000 to 1,500 mg/$\text{m}^2$/day IV continuous infusion (or divided q8–12h). Chelates extracellular and bone lead, which is excreted renally.

                    CRITICAL DRUG SEQUENCING IN ACUTE LEAD ENCEPHALOPATHY
  ┌─────────────────────────────────────────────────────────────────────────────┐
  │ STEP 1: Administer DIMERCAPROL (BAL) 75 mg/m2 Deep IM First                 │
  │                            ▼                                                │
  │           WAIT AT LEAST 4 HOURS BEFORE PROCEEDING                           │
  │                            ▼                                                │
  │ STEP 2: Initiate CALCIUM DISODIUM EDTA (CaNa2EDTA) IV Continuous Infusion   │
  │                                                                             │
  │ RATIONALE: Giving EDTA alone mobilizes lead from bone stores and redistributes│
  │ toxic lead into the brain, acutely worsening encephalopathy and death!      │
  │ NEVER USE DISODIUM EDTA (Na2EDTA): Chelates serum calcium -> Fatal Arrest!  │
  └─────────────────────────────────────────────────────────────────────────────┘

2. Acute Iron Toxicity: Corrosive Necrosis & Deferoxamine

Iron is directly corrosive to the gastrointestinal mucosa. Once circulating transferrin is fully saturated, non-transferrin-bound "free iron" catalytically generates highly reactive hydroxyl free radicals via the Fenton reaction, inducing lipid peroxidation, capillary leak, uncoupling of oxidative phosphorylation, and acute hepatocellular necrosis.

The Five Clinical Stages of Iron Toxicity

1. Stage 1 (0.5 to 6 hours post-ingestion): Corrosive gastrointestinal stage: severe vomiting, hematemesis, bloody diarrhea, abdominal pain. Absence of GI symptoms in the first 6 hours reliably excludes serious toxicity.
2. Stage 2 (6 to 24 hours): Apparent "latent" or quiescent phase: gastrointestinal symptoms subside as iron clears from the gut into cells, but severe cellular toxicity quietly smolders.
3. Stage 3 (12 to 48 hours): Shock and metabolic stage: high anion gap metabolic acidosis, distributive and cardiogenic shock, cyanosis, and acute tubular necrosis.
4. Stage 4 (2 to 5 days): Hepatotoxicity stage: acute hepatic failure, hyperbilirubinemia, profound coagulopathy, and hypoglycemia.
5. Stage 5 (2 to 6 weeks): Delayed scarring stage: gastric outlet obstruction and pyloric strictures from cicatricial healing.

Diagnostic Iron Levels & Deferoxamine Protocol

• Peak Serum Iron: Draw serum iron concentration 4 to 6 hours post-ingestion:
  • Peak iron $<350\ \mu\text{g/dL}$: Low risk of systemic toxicity; supportive care.
  • Peak iron $350\text{ to }500\ \mu\text{g/dL}$: Mild to moderate toxicity; observe, consider chelation if symptomatic.
  • Peak iron $>500\ \mu\text{g/dL}$: Severe toxicity; mandatory parenteral chelation.
  • Peak iron $>1,000\ \mu\text{g/dL}$: Life-threatening, catastrophic intoxication.
• Antidote: Deferoxamine Mesylate (Desferal):
  • Mechanism: A microbial hexadentate siderophore that selectively binds free ferric iron ($\text{Fe}^{3+}$) with extreme affinity ($K_a = 10^{31}$), forming ferrioxamine, a water-soluble, non-toxic complex eliminated in the urine.
  • Dosing: Administer as a continuous intravenous infusion at 15 mg/kg/h (the label maximum is 15 mg/kg/h and 6 g per 24 hours; start lower if hypotensive and titrate up, and higher rates are used only under toxicologist guidance). Avoid rapid boluses, which trigger severe histamine release, flushing, and vascular collapse.
  • Vin Rosé Urine: As ferrioxamine is excreted in the urine, it imparts a classic reddish-orange "vin rosé" appearance. The presence of vin rosé urine confirms iron chelation, but its absence does not rule out toxicity.
  • Definitive Treatment Endpoints: Discontinue deferoxamine when:
    1. The patient is clinically asymptomatic and hemodynamically stable.
    2. The high-anion-gap metabolic acidosis has completely resolved.
    3. Serum iron concentration decreases to $<350\ \mu\text{g/dL}$.
    4. The urine clears of vin rosé coloration (returns to normal amber color).
  • Prolonged Infusion Risk: Infusions lasting $>24\text{ to }48\text{ hours}$ elevate the risk of Deferoxamine-induced Acute Respiratory Distress Syndrome (ARDS) and opportunistic infections with Yersinia enterocolitica (which utilizes ferrioxamine as a growth-promoting siderophore).

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Heavy Metal Chelators and Snake Antivenom Reference Matrix