Carbamate toxicity

Background

• Class of insecticide
• acetylcholinesterase inhibition --> excess accumulation of acetylcholine at the neuromuscular junction and cholinergic toxicity
• Structurally distinct but toxicity mechanistically similar to organophosphate toxicity
  • Cholinesterase inhibition is more transient than with organophosphates, so clinical course tends to be more benign

Clinical Features

Autonomic Nervous System Receptors and Their Effects

• Parasympathetic - ACh is transm
  • Muscarinic
    • receptors in heart, eye, lung, GI, skin and sweat glands
    • Bradycardia
    • Miosis
    • Bronchorrhea / Bronchospasm
    • Hyperperistalsis (SLUDGE)
    • Sweating
    • Vasodilation
  • Nicotinic
    • receptors in both sympathetic and parasympathetic nervous systems
    • fasciculations, flaccid paralysis
    • ?Mild bradycardia, hypotension
• Sympathetic
  • Alpha effects (vessels, eye, skin)
    • Mydriasis, hypertension, sweating
  • Beta effects (heart, lungs)
    • Tachycardia, bronchodilation
• Symptoms caused by acetylcholine buildup in CNS and PNS.
• CNS symptoms = headache, confusion, vertigo, seizures, coma
• Muscarinic Receptors
  • SLUDGE(M) = Salivation, Lacrimation, Urination, Diarrhea, GI pain, Emesis, Miosis
• Nicotinic Receptors (NMJ)
  • MTWThF = Mydriasis/Muscle cramps, Tachycardia, Weakness, Twitching, Hypertension/Hyperglycemia, Fasiculations
• Common causes of death in organophosphate toxicity
  • Killers B's = Bradycardia, Bronchorrhea, Bronchospasm

Differential Diagnosis

SLUDGE Syndrome

• Carbamate toxicity
• Mushroom toxicity, especially:
  • Amanita muscaria
  • Inocybe
  • Clitocybe
• Organophosphate toxicity
• Nerve agent
  • Sarin
  • VX
  • Novichok agent
• Nicotine toxicity (look alike)
• Acetylcholinesterase inhibitor overdose (e.g in myasthenia gravis or post anesthesia reversal)

Weakness

• Neuromuscular weakness
  • Upper motor neuron:
    • CVA
    • Hemorrhagic stroke
    • Multiple sclerosis
    • Amyotrophic Lateral Sclerosis (ALS) (upper and lower motor neuron)
  • Lower motor neuron:
    • Spinal and bulbar muscular atrophy (Kennedy's syndrome)
  • Spinal cord disease:
    • Infection (Epidural abscess)
    • Infarction/ischemia
    • Trauma (Spinal Cord Syndromes)
    • Inflammation (Transverse Myelitis)
      • Acute flaccid myelitis
    • Degenerative (Spinal muscular atrophy)
    • Tumor
  • Peripheral nerve disease:
    • Guillain-Barre syndrome
    • Toxins (Ciguatera)
    • Tick paralysis
    • Diabetic peripheral neuropathy
  • Neuromuscular junction disease:
    • Myasthenia gravis crisis
    • Botulism
    • Organophosphate toxicity
    • Lambert-Eaton myasthenic syndrome
  • Muscle disease:
    • Rhabdomyolysis
    • Dermatomyositis
    • Polymyositis
    • Alcoholic myopathy
• Non-neuromuscular weakness
  • Can't miss diagnoses:
    • ACS
    • Arrhythmia/Syncope
    • Severe infection/Sepsis
    • Hypoglycemia
    • Periodic paralysis (electrolyte disturbance, K, Mg, Ca)
      • Hypokalemic periodic paralysis
      • Thyrotoxic periodic paralysis
    • Respiratory failure
  • Emergent Diagnoses:
    • Symptomatic Anemia
    • Severe dehydration
    • Hypothyroidism
    • Polypharmacy
    • Malignancy
    • Aortic disease - occlusion, stenosis, dissection
  • Other causes of weakness and paralysis
    • Acute intermittent porphyria (ascending weakness)

Chemical weapons

• Blister chemical agents (Vesicants)
  • Lewisite (L)
  • Sulfur mustard (H)
  • Phosgene oxime (CX)
• Pulmonary chemical agents (Choking agents)
  • Ammonia toxicity
  • Methyl isocyanate
  • Methyl bromide
  • Hydrochloric acid
  • Chlorine gas
  • Phosgene
• Incendiary agents
  • Agent orange
  • White phosphorus
• Cyanide chemical weapon agents (Blood agents)
  • Prussic acid (AKA hydrogen cyanide, hydrocyanic acid, or formonitrile)
• Nerve Agents (organophosphates)
  • Acetylcholinesterase inhibitors
  • Household and commercial pesticides (diazinon and parathion)
  • G-series (sarin, tabun, soman)
  • V-series (VX)
• Lacrimating or riot-control agents
  • Pepper spray
  • Chloroacetophenone
  • CS

Symptomatic bradycardia

• Cardiac
  • Inferior MI (involving RCA)
  • Sick sinus syndrome
• Neurocardiogenic/reflex-mediated
  • Increased ICP
  • Vasovagal reflex
  • Hypersensitive carotid sinus syndrome
  • Intra-abdominal hemorrhage (i.e. ruptured ectopic)
• Metabolic/endocrine/environmental
  • Hyperkalemia
  • Hypothermia (Osborn waves on ECG)
  • Hypothyroidism
    • Myxedema coma
  • Hypoglycemia (neonates)
• Toxicologic
  • B-blocker
  • Ca-channel blocker
  • Clonidine
  • Digoxin toxicity
  • Ethanol
  • Opioids
  • Organophosphates
  • Xylazine toxicity
• Infectious/Postinfectious
  • Chagas disease
  • Lyme disease
  • Syphilis
• Other
  • Brash syndrome

Evaluation

• Clinical diagnosis- RBC cholinesterase levels are available but of limited utility
• CBC, BMP
• CXR- may show pulmonary edema
• ECG- may show AV block, QT prolongation, ventricular dysrhythmias

Management

• Pralidoxime not useful with carbamates but should be given unless organophosphate toxicity completely ruled out

Decontamination

• Providers should wear appropriate PPE during decontamination.
  • Neoprene or nitrile gloves and gown (latex and vinyl are ineffective)
• Dispose of all clothes in biohazard container
• Wash patient with soap and water

Supportive Care

• IVF, O2, Monitor
• Aggressive airway management is of utmost importance.
  • Intubation often needed due to significant respiratory secretions / bronchospasm.
  • Use nondepolarizing agent (Rocuronium or Vecuronium)
  • Succinylcholine is absolutely contraindicated
• Benzodiazepines for seizures

Antidotes

• Dosing with atropine and pralidoxime are time dependent and provides ability to reverse symptoms while awaiting agent metabolism
• For exposure to nerve agents, manufactured IM autoinjectors are available for rapid administration:
  • Mark 1
    • Contains 2 separate cartridges: atropine 2 mg + 2-PAM 600 mg
    • Being phased out with newer kits
  • DuoDote
    • Single autoinjector containing both medications
    • Same doses as Mark 1: atropine 2 mg + 2-PAM 600 mg

Antidotes

Atropine

• Competitively blocks muscarinic sites (does nothing for nicotinic-related muscle paralysis)
• May require massive dosage (hundreds of milligrams)
• Dosing
• Adult: Initial bolus of 2-6mg IV; titrate by doubling dose q5-30m until tracheobronchial secretions controlled
  • Once secretions controlled → start IV gtt 0.02-0.08 mg/kg/hr
  • Child: 0.05-0.1mg/kg (at least 0.1mg) IV; repeat bolus q2-30m until tracheobronchial secretions controlled
  • Once secretions controlled → start IV gtt 0.025 mg/kg/hr
• No max dose, doses >400mg have been reported

Pralidoxime

• AKA 2-PAM
• For Organophosphate poisoning only - reactivates AChE by removing phosphate group → oxime-OP complex then excreted by kidneys.
  • This must be done before "aging" occurs - conformational change that makes OP bond to AChE irreversible
  • Pralidoxime can actually bind and inhibit AChE once all AChE enzymes have aged, and can make the toxicity worse
  • Window to aging depends on the agent, and is a matter of debate, but pralidoxime within 1-2 hours of exposure is the goal
• Dosing
  • Adult: 1-2gm IV over 15-30min; repeat in 1 hour if needed or 50 mg/hr infusion.
  • Child: 20-40mg/kg IV over 20min; repeat in 1 hour if needed or 10-20 mg/kg/hr infusion.

Disposition

• Admit all patients with respiratory or CNS compromise and all who require atropine

See Also

• Organophosphate toxicity