Continuing Education Activity

Rodenticides or "rat poisons" are mixed compounds used to eradicate rodents. They are one of the most toxic agents commonly found in households. Historically, heavy metals such as arsenic were the first agents used to control rodent populations, but the most common rodenticide used in the twenty-first century is anticoagulants. When a clinician suspects rodenticide poisoning, every effort should be made to identify the substance, including package information (i.e., brand name, chemical name, signal word, presence of skull or crossbones on the label) and description (odor, appearance, color). This step may involve staff returning to the point of potential exposure where the patient was last seen and searching for evidence of the rodenticide. In cases of serious ingestion, poison control and/or a medical toxicologist should be contacted. This activity outlines the evaluation and management of various types of rodenticide poisoning. It also highlights the interprofessional team's role in managing rodenticide toxicity patients.

Objectives:

• Identify the etiology of different types of rodenticide toxicity causing different medical conditions and emergencies.
• Review the appropriate evaluation of rodenticide toxicity.
• Outline the management options available for rodenticide toxicity.
• Describe interprofessional team strategies for improving care coordination and communication in managing rodenticide toxicity and improving outcomes.

Introduction

Rodenticides or “rat poisons” are mixed compounds used to eradicate rodents. They are one of the most toxic agents commonly found in households. Historically, heavy metals such as arsenic were the first agents used to control rodent populations, but the most common rodenticide used in the twenty-first century is anticoagulants.[1] When a clinician suspects rodenticide poisoning, every effort should be made to identify the substance, including package information (i.e., brand name, chemical name, signal word, presence of skull or crossbones on the label) and description (odor, appearance, color). This step may involve staff returning to the point of potential exposure where the patient was last seen and searching for evidence of the rodenticide. In cases of serious ingestion, poison control and/or a medical toxicologist should be contacted.

Etiology

Given the wide array of toxins used as rodenticides, symptoms will vary depending on the toxin ingested. Rodenticides are often categorized on their label regarding toxicity.[2]

• "Danger" or highly toxic rodenticides include thallium, sodium monofluoroacetate (fluoroacetate), strychnine, zinc phosphide, aluminum phosphide, elemental phosphorus, arsenic, and barium carbonate. Rarely used or banned dangerous toxins are tetramethylene disulfotetramine (TETS, tetramine), aldicarb, alpha-chloralose, and pyrinuron.
• "Warning" or toxic rodenticides include alpha-naphthyl thiourea (ANTU) and cholecalciferol.
• "Caution" or less toxic rodenticides include anticoagulants (superwarfarins, warfarin), norbormide, bromethalin, and red squill.

Epidemiology

According to the 2017 Annual Report of the American Association of Poison Control Centers, there are almost 10,000 ingestions annually in the United States.[1] Of these, over half of the exposures are in children under six years of age, except strychnine and zinc phosphide. Anticoagulants were the most common cause accounting for 5,186 cases, with 182 of those cases due to warfarin-type rodenticides. The second most common rodenticide was bromethalin, with 1,196 cases reported.[1] The outcomes were generally benign. Seven cases noted major outcomes, and only two deaths were reported.

Pathophysiology

The clinical presentation varies depending on the type of rodenticide ingested. Following is a brief outline with specific pathophysiology and symptoms of common rodenticides:

Thallium

• This substance is a tasteless, odorless powder absorbed via inhalation or through the skin. It works by displacing potassium in sodium-potassium-adenosine triphosphatase and the sulfhydryl or thiol group of mitochondrial membranes, disrupting the Krebs cycle and oxidative phosphorylation, depleting energy production. For additional information, please see the Statpearls article on thallium toxicity.[3]

• Acute Exposure:

  • Acute gastroenteritis (within 48 hours)
  • Cranial nerve dysfunction, peripheral neuropathy, seizure
  • Alopecia that spares the inner third of eyebrows and axilla
  • Hyperpigmentation

• Chronic Exposure:

  • Tremor, ataxia, distal motor weakness
  • Diplopia, nystagmus
  • Cranial nerve 7 palsy
  • Ocular lens opacities

Fluoroacetamide (Compound 1080), Sodium Monofluoroacetate (SMFA) 

• SMFA is an odorless, tasteless white powder. In the United States, collars are infused with SMFA and placed on livestock to protect against other wildlife. Both fluoroacetamide and SMFA mimic acetate and irreversibly inhibit the Krebs cycle by converting coenzyme A (CoA) to fluoroacetyl CoA, subsequently causing an accumulation of citrate. This complexes with calcium.[4] Cellular aerobic metabolism, fatty acid oxidation, gluconeogenesis, and the urea cycle become inhibited.

• Symptom Onset: 30 minutes to 20 hours

  • Seizures
  • Hypocalcemia
  • Worsening metabolic acidosis
  • Dysrhythmias
  • Shock refractory to resuscitation

• Late Complications

  • Kidney injury
  • Hepatic dysfunction
  • Cerebral or cerebellar atrophy

Strychnine

• This agent is an odorless, colorless powder that becomes bitter when dissolved in water—often seen as pink tablets. Strychnine toxicity presents as involuntary muscle contraction resulting from competitive inhibition of glycine receptors at the postsynaptic and motor neuron level. For further information, please see the Statpearls article on strychnine toxicity.[5]

• Symptom Onset: 10 to 20 minutes

  • Uncontrollable muscle spasms
  • Trismus
  • Risus sardonicus
  • Opisthotonos
  • Rhabdomyolysis
  • Lactic acidosis
  • Hyperthermia

Zinc and Aluminum Phosphide

• When this compound is exposed to water, phosphine gas is released that characteristically has a rotten fish odor. Poisoning is more common in northern India and Iran. When the toxin is ingested, gastric acid converts the element to phosphine gas, which is absorbed from the gastrointestinal tract into the bloodstream; however, this toxin can also spread via inhalation or be absorbed through the skin. The toxin inhibits the cytochrome C oxidase system.[6]

• Symptom Onset: 30 minutes

  • Acute gastritis
  • Cardiac arrhythmias
  • Hemorrhagic pulmonary edema
  • Respiratory failure
  • Intravascular hemolysis with methemoglobinemia
  • Hepatotoxicity
  • Metabolic acidosis
  • Respiratory alkalosis
  • Renal failure

Elemental Phosphorus

• This element has a faint garlic odor and may glow when exposed to oxygen. It exists in two forms: red and white (yellow) phosphorus. The former is utilized for matches. The latter is used in rodenticides. White phosphorus is very toxic, causing damage locally and systemically. When ingested, it directly causes tissue damage with local phosphoric acid and phosphorus pentoxide. In circulation, phosphorous also binds to calcium leading to severe hypocalcemia.[7]
• • Acute gastroenteritis
  • Skin or mucosal burns
  • Phosphorescent emesis or feces (smoking stool)
  • Dysrhythmias
  • Hepatotoxicity
  • Renal failure

Arsenic

• Arsenic is a highly toxic inorganic compound whose exact mechanism of action is unknown. Postulations include inhibition of hexokinase in glycolysis, inhibition of pyruvate dehydrogenase in the Krebs cycle leading to impaired cell respiration and depletion of ATP, and formation of sulfhydryl compounds leading to extensive vasodilation. If there has been significant ingestion, a garlic odor is potentially detectable on the patient's breath. For more information, please see the StatPearls article on arsenic toxicity.[8]

• Symptom onset: 1 to 3 hours

  • Vomiting
  • Bloody diarrhea
  • Garlic taste in the mouth
  • Hypotension
  • Prolonged QT segment
  • Delirium, seizures, coma
  • Renal injury

Barium Carbonate

• This compound easily dissolves in water and is highly toxic, unlike the insoluble counterpart, barium sulfate, which serves as radiographic contrast media. The barium ion inhibits potassium diffusion out of cells resulting in hypokalemia.[9]

• Symptoms:

  • Gastroenteritis
  • Hypertension
  • Cardiac arrhythmias
  • Shortness of breath
  • Muscle paralysis

Tetramethylene Disulfotetramine (TETS, Tetramine)

• Originating from China, this rodenticide works by irreversibly antagonizing the GABA receptor.[10]

• Symptom onset: 10 minutes to 13 hours

  • Convulsions
  • Coma
  • Respiratory failure
  • Arrhythmias

Aldicarb

• Originating from Latin America, this compound is also known as "tres pasitos," which refers to the three little steps mice take before the poison causes almost immediate death. It works as a potent cholinesterase inhibitor resulting in a cholinergic toxidrome.[11]

• Symptoms:

  • Excess salivation
  • Lacrimation
  • Urination
  • Diarrhea
  • Gastrointestinal upset
  • Emesis (SLUDGE)

Alpha-chloralose:

• Originating from Europe, this compound is used as a veterinarian anesthetic but also is present in rodenticides. The mechanism of action is not clearly defined but similar to barbiturates as a central nervous system depressant.[12]
• Symptoms:
  • Convulsions
  • Hypothermia
  • Respiratory depression

Pyriminil, Pyriminil, N-3-pyridylmethyl-N-p-nitrophenyl Urea, PNU

• Pyriminil works as a nicotinamide antagonist and impairs the synthesis of NAD and NADH, which acutely destroys pancreatic beta cells within two hours.[13]

• Symptoms:

  • Kussmaul breathing
  • Hypotension
  • Encephalopathy
  • Lethargy

Cholecalciferol (Vitamin D3)

• Although it takes a large ingestion to bring about toxicity, cholecalciferol may cause significant symptoms via a hypercalcemic state. Vitamin D3 mobilizes calcium from the bones and increases intestinal calcium absorption, which ultimately causes hypercalcemia.[14]
• Symptoms:
  • Polyuria
  • Polydipsia
  • Vomiting
  • Renal failure
  • Encephalopathy

Anticoagulants (Superwarfarin, Warfarin)

• Superwarfarins (brodifacoum, difenacoum, bromadiolone, and chlorophacinone) are anticoagulant rodenticides similar to warfarin but contain various phenyl groups that replace the terminal methyl group. This group substitution makes superwarfarin 100-fold stronger than warfarin.[15] Warfarin is a competitive inhibitor of the vitamin K epoxide reductase complex 2 (VKORC1) and subsequently inhibits the clotting cascade factors 2, 7, 9, and 10. For more information, please see the StatPearls article on warfarin toxicity.[16]

• Symptoms:

  • Hematuria (earliest symptom) 
  • Hemoptysis
  • Epistaxis
  • Flank pain
  • Easy bruising
  • Intracranial hemorrhage

Norbormide

• This rat poison is essentially non-toxic to humans and works through extreme peripheral vasoconstriction that causes ischemia leading to organ death followed by animal expiration.
• Symptoms may include a drop in blood pressure and/or temperature. This is based on a few human case reports.[17]

Bromethalin

• It is rarely toxic to humans because it takes significant ingestion to exert a toxic effect. Bromethalin uncouples oxidative phosphorylation leading to decreased ATP. It acts as a neurotoxin affecting both central and peripheral nervous systems as a lack of ATP causes increased fluid around neuron sheaths.[18]
• Symptom onset is within 4 hours to 7 days and may include altered mental status and delirium that is secondary to severe cerebral edema. This is based on one human case report.[19]

Red Squill (Urginea maritima)

• It is a glycoside (scillaren A and B) that causes cardiotoxicity and convulsant effects.[20]

• Symptoms:

  • Abdominal pain
  • Vomiting
  • Seizures
  • Hyperkalemia
  • Cardiac arrhythmias (resembles digitalis toxicity)

History and Physical

Patients most often presenting with rodenticide toxicity are children with oral ingestion. The most common rodenticide used in the United States is a long-acting anticoagulant. The presenting symptoms include hematuria, hemoptysis, epistaxis, flank pain, easy bruising, or petechiae under the blood pressure cuff.[21] Other cases include adults with the intention of suicide.[22] Regardless, the most crucial part of history is identifying the substance ingested. The toxicity is categorized by the amount of poison needed to cause death in 50% of those exposed, known as lethal dose 50 or LD50. In some regions, including the United States, this toxicity is denoted by signal words on product labels, such as danger, warning, and caution.

• Danger (very toxic): LD50 is 0-50 mg/kg
• Warning (toxic): LD50 is 50-500 mg/kg
• Caution (less toxic): LD50 is 500-5000 mg/kg

Physical findings in patients with rodenticide toxicity are categorized as follows:

• Neurologic toxicity
  • Seizures: SMFA, fluoroacetamide, arsenic, tetramine
  • Cranial neuropathy, coma: arsenic, thallium, bromethalin, pyriminil, alpha-chloralose
• Musculoskeletal toxicity, including muscle rigidity, facial grimacing, trismus
  • Strychnine
• Cardiovascular toxicity, including arrhythmias, refractory shock, cardiac arrest
  • Zinc or aluminum phosphide, white phosphorus, barium carbonate, arsenic, thallium, sodium monofluoroacetate, fluoroacetamide

Please refer to the pathophysiology section for a more detailed description of specific rodenticide symptoms.

Evaluation

Assuming unknown ingestion, the clinician may order the following tests. Rodenticides are noted for associated abnormalities but are non-specific.

• Blood Glucose
  • Hypoglycemia: zinc or aluminum phosphide
  • Hyperglycemia: pyriminil

• Complete Blood Count
  • Anemia: zinc phosphide

• Basic Metabolic Panel
  • Hypocalcemia: white phosphorous, SMFA, fluoroacetamide
  • Hypokalemia: barium carbonate, zinc, or aluminum phosphide
  • Elevated blood urea nitrogen (BUN) or creatinine: thallium, arsenic, white phosphorous, zinc, or aluminum phosphide

• Serum Phosphorous
  • Hyperphosphatemia: white phosphorous

• Hepatic Function Panel
  • Elevated hepatic enzymes: thallium, arsenic, white phosphorous, zinc, or aluminum phosphide

• Coagulation profile including prothrombin time, international normalized ratio, partial thromboplastin time (PT, INR, PTT) 
  • Elevated levels: anticoagulants

• Creatinine Phosphokinase (CPK)[23]
  • Elevated level: strychnine

• Arterial Blood Gas
  • Lactic acidosis: SMFA or fluoroacetamide

• Troponin
  • Cardiotoxicity: zinc and aluminum phosphide

• Lipase
  • Elevated level: pyriminil

• 12 Lead Electrocardiography (ECG)
  • QTc prolongation: SMFA, fluoroacetamide, white phosphorous, or arsenic[24]

• Chest and Abdominal X-ray
  • Radiopaque substances include barium carbonate, arsenic, or thallium

Treatment / Management

Initial Care

Immediate management consists of supporting the airway, breathing, and circulation. Once the patient is stable and if they are visibly contaminated, then the next step involves removing clothes and irrigating the skin with water. Gastric lavage and activated charcoal are not indicated in acute poisoning, according to the American Academy of Toxicology.[25] There is limited data that shows a decrease in morbidity and mortality. If the patient presents within 30 to 60 minutes since ingestion, please call poison control immediately for the most updated guidelines.

Acute gastrointestinal effects may benefit from anti-emetics and rehydration to help correct electrolyte derangements. Initiate cooling mechanisms such as evaporative cooling if severely hyperthermic such as in strychnine poisoning. Cholinergic toxicity may benefit from administering anticholinergic agents such as atropine, glycopyrrolate, and pralidoxime. Further treatment is often mainly supportive.

Specific Medical Treatment

Renal replacement therapy

• Includes hemodialysis, continuous renal replacement, or charcoal hemoperfusion for heavy metal poisonings such as thallium, arsenic, or barium

Benzodiazepines

• Indicated for muscle spasms and seizures, especially in strychnine poisoning[5] 

British anti-Lewisite

• Used for chelation in acute arsenic poisoning[8] 

Meso-2,3-dimercaptosuccinic acid (DMSA) or 2,3-dimercapto-1-propane sulfonate (DMPS)

• Used for chelation in chronic arsenic poisoning[8] 

Sodium sulfate or magnesium sulfate

• Specifically used for acute barium carbonate ingestion rendering it a non-absorbable barium sulfate compound[9]

Nicotinamide (intravenous)

• Used in cases of pyriminil poisoning to replenish NAD and NADH products for cellular energy metabolism[13] 

Mineralocorticoids

• Used for orthostatic hypotension in pyriminil poisoning

Digoxin immune fab

• Used for symptomatic treatment of red squill poisoning[20]

Most importantly, clinicians should evaluate and manage patients in consultation with regional poison control or a toxicology resource.

Differential Diagnosis

Rodenticides come in various chemical compositions and can have a wide range of clinical presentations. The following is a concise list of differential diagnoses:

• Gastroenteritis
• Foodborne toxin
• Acute viral hepatitis
• Alcoholic hepatitis
• Diabetic ketoacidosis
• Disseminated intravascular coagulation
• Organophosphate toxicity
• Hypocalcemia
• Hypokalemia
• Rattlesnake envenomation
• Carbamate toxicity

Prognosis

The prognosis depends on the specific rodenticide ingested as well as the amount. In general, a better prognosis is associated with early initiation of treatment; however, chronic exposure will have a longer recovery. When standard conservative treatment options fail, liver transplantation is the sole option.[26]

Complications

Complications of rodenticide poisoning include the following:

• Renal failure
• Liver failure
• Permanent neurologic damage
• Diabetes type 1

Consultations

As poisoning is a domain of toxicology, the following consultations are generally required:

• Regional poison control
• Medical toxicologist

Deterrence and Patient Education

Although meant to harm rodents, rodenticides are also toxic to humans, as described previously. A variety of sequelae can lead to organ failure and even death. One should always follow label instructions and take steps to avoid exposure. All rodenticides should be kept out of reach of children and pets, whether they are in use or storage. Children may find rodenticides to be visibly appealing in addition to their taste.

For this reason, tamper-resistant bait stations should be employed to prevent accidental ingestion. When disposing of dead rodents in secure bins, always use gloves to avoid contact with their carcass. It is reasonable to seek medical evaluation even if asymptomatic or with mild symptoms like nausea, as it can be an early manifestation of severe illness.

Enhancing Healthcare Team Outcomes

Managing rodenticide toxicity requires an interprofessional team, including the emergency department, poison control, toxicologist, neurologist, intensivist, and possibly a nephrologist or hepatologist. The specialists involved will depend on the organ systems affected. Pharmacists and nurses may also make significant contributions depending on the poisonous agent and necessary interventions or antidotes. For example, warfarin or warfarin-like anticoagulants may require vitamin K, which the pharmacist can prepare and assist in dosing recommendations and will be administered by the nurses. The initial management includes a primary survey with the ABCDE protocol. Gastric lavage and activated charcoal may be used within one hour of ingestion after proper dermal exposure and decontamination. A collective team effort will provide the most expedient care yielding the best prognosis.

Those with minimal symptoms may recover fully with treatment, but others with severe toxicity may have permanent organ damage, or their case may even result in death. All specialists and other personnel on the case must document their findings and interventions in the patient's record so that all interprofessional team members will have access to the same updated, accurate information. Open communication lines are essential, as miscommunications can have fatal consequences. Interprofessional care coordination and open lines of communication are critical to better patient outcomes in rodenticide toxicity cases. [Level 5]