Toxicologic Emergencies

The following topics are addressed in this rotation guide:

• Toxic Ingestion

• Toxidromes

• Treatment/Antidotes

• Acute Agitation

• Chemical Restraints

Other related emergent topics in toxicology are discussed in the following rotation guide:

• Substance Use Disorders (Mental Health)

Toxic Ingestion

General Evaluation

All substances have the potential to be poisonous; toxicity depends on the dose and the duration of exposure. Patients may deteriorate after a benign presentation. Some patients with intentional or accidental poisonings may give an unreliable history. Additional information from family, friends, and emergency medical technicians (EMTs) may be of great value. Keep in mind common toxidromes or symptom complexes that may provide clues to the identity of the offending agent and consider co-ingestions. Finally, call Poison Control early for further recommendations (1-800-222-1222).

General evaluation should include the following:

• History: determine substance/drug, dosage, quantity, extended- or immediate-release formulation, intent, and time of ingestion

• Document: smell, vital signs (including temperature and pulse oximetry), level of consciousness, suggestive signs and symptoms (e.g., diaphoresis, nystagmus, excess salivation, clonus, nausea, vomiting, or diarrhea), reflexes and general tone, pupil size, and serum glucose

• Workup: serum acetaminophen, acetylsalicylic acid, blood ethanol, blood chemistry panel, human chorionic gonadotropin (hCG), urine and serum toxicologic screen, and electrocardiography (ECG)

  • Depending on the suspected exposure, additional tests might include serum osmolality, hepatic function panel, coagulation studies, lactate, and venous blood gas, among others.

  • Specific toxicology screening may confirm exposure to a toxicant but does not usually change management.

  • A kidney, ureter, bladder (KUB) x-ray may be helpful for radiopaque ingestions or insertions in the event of packing.

    • Mnemonic for radiopaque foreign bodies:

  • BAT CHIPS: Barium; Antihistamines; Tricyclic antidepressants; Chloral hydrate, Calcium, Cocaine, and Condoms; Heavy metals (e.g., lead, mercury, arsenic); Iodine and Iron; Phenothiazines and Potassium; Slow release (enteric-coated)

Toxidromes

In this section, we describe signs and symptoms of common toxidromes (toxic syndromes), as well as mnemonics used to assist recall and the associated substances.

Anticholinergic Toxidrome

Signs and symptoms: hot as a hare (hyperthermia), dry as a bone (dry), red as a beet (flushed skin), blind as a bat (mydriasis), mad as a hatter (delirium), full as a flask (urinary retention), tacky as a pink flamingo (tachycardia)

Examples: amantadine, antihistamines (including diphenhydramine), antiparkinsonian agents, antipsychotics, antispasmodics (dicyclomine), belladonna alkaloids (atropine, scopolamine), tricyclic antidepressants, glycopyrrolate, phenothiazine, and plants (jimsonweed, nightshade, Amanita muscaria)

Cholinergic Toxidrome

Mnemonics for signs and symptoms:

• SLUDGE (Salivation, Lacrimation, Urination, Diarrhea, Gastrointestinal hyperactivity, Emesis) syndrome

  • Killer Bs (Bronchorrhea, Bronchoconstriction, Bradycardia)

Examples: acetylcholine, carbamates, mushrooms (some species), organophosphates, physostigmine, edrophonium, pilocarpine, and tobacco/nicotine; often observed in the context of pesticide exposure

Extrapyramidal Toxidrome

Signs and symptoms: ataxia, choreoathetosis (irregular writhing movements), dystonic reactions, hyperreflexia, opisthotonos (spasm and hyperextension of the back), rigidity, seizures, torticollis, slowing of movements, tremor, and trismus

Examples: haloperidol, olanzapine, phenothiazines, and risperidone

Opioid Toxidrome

Signs and symptoms: bradycardia, coma, decreased bowel sounds, hypotension, hypothermia, hypoventilation, miosis

Examples: opioids (codeine, diphenoxylate, fentanyl, heroin, hydrocodone, meperidine, methadone, morphine, oxycodone, pentazocine, and propoxyphene) and dextromethorphan

Sedative/Hypnotic Toxidrome

Signs and symptoms: abnormal gait, apnea, coma, confusion, decreased level of consciousness, hypoventilation, pulse slow or normal, sedation, slurred speech, and stupor

Examples: anticonvulsants, antipsychotics, barbiturates, benzodiazepines, ethanol, zolpidem, and meprobamate

Serotonin Syndrome Toxidrome

Signs and symptoms: autonomic instability, confusion, diaphoresis, fever, flushing, hyperreflexia, irritability, myoclonus, and tremor

Examples: selective serotonin-reuptake inhibitors (SSRIs; fluoxetine, paroxetine, sertraline), serotonin and norepinephrine-reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), St. John’s wort, dextromethorphan, methylene blue, linezolid, and trazodone

Sympathomimetic Toxidrome

Signs and symptoms: agitation, diaphoresis, hypertension, hyperthermia, mydriasis, seizures (central nervous system excitation), and tachycardia

Examples: aminophylline, amphetamines, caffeine, cocaine, ephedrine, epinephrine, lysergic acid diethylamide (LSD), methylphenidate, phencyclidine, phenylpropanolamine, pseudoephedrine, methylenedioxymethamphetamine (MDMA), and theophylline

Delayed Toxidrome

Signs and symptoms: Patients may not have any initial symptoms.

Examples: acetaminophen, extended-release cardiac medications, oral hypoglycemic agents, sustained-release or delayed-release formulations, iron, and warfarin

Elevated Anion-Gap Metabolic Acidosis

Mnemonics for causes:

• A CAT MUD PILES (Alcoholic ketoacidosis and Acetaminophen, Cyanide and Carbon monoxide, Alcohol, Toluene, Methanol and Metformin, Uremia, Diabetic ketoacidosis, Paraldehyde, Iron and Isoniazid, Lactic acidosis, Ethylene glycol, Salicylates and Strychnine)

• GOLD MARK (Glycols, Oxyproline, L-lactate, D-lactate, Methanol, Aspirin, Renal failure, Ketoacidosis)

(Source: Physiological Approach to Assessment of Acid-Base Disturbances. N Engl J Med 2014.)

Treatment/Antidotes

Treatment

Symptomatic and supportive care is the mainstay of treatment for a poisoned patient .

Absorption, delaying uptake, blocking effect, and speeding metabolism are all means of minimizing the effect of a toxicologic ingestion, and each has separate indications.

Extracorporeal removal, typically via intermittent hemodialysis, is most helpful for treatment of toxicity from substances with low molecular weight, low protein binding, water solubility, or small volume of distribution (e.g., salicylates, toxic alcohols, lithium, and theophylline).

Lipid emulsion is thought to compartmentalize the offending agent away from the target receptors into the lipid; however, the exact mechanism of action has not been proven. This therapy has been used primarily for local anesthetic toxicity (especially with bupivacaine). Broadening indications for lipid emulsion treatment include toxicity from beta-blockers, calcium-channel blockers, bupropion, and tricyclic antidepressants in certain clinical situations.

Gastric lavage is rarely recommended currently, given its relative risk and minimal benefits.

Whole-bowel irrigation is similarly rarely indicated except for specific toxic exposures with metals, drug packing, or extended-release formulations.

Activated Charcoal

Activated charcoal is an efficacious decontamination method in patients with suspected ingestions with serious toxicity or without known antidotes. Its use should be limited to patients who are awake and alert and/or have a protected airway, given the expected side effects of nausea and subsequent risk of aspiration and pneumonitis. It is most beneficial when used within one hour of ingestion or if the ingested toxin is still in the gastrointestinal tract due to delayed gastric motility or absorption. Activated charcoal can be administered as either a single dose or multidose in discussion with a toxicologist or Poison Control Center.

• Mnemonic for suspected ingestions of substances for which activated charcoal may be helpful:

  • Killer Cs: Cyanide, Colchicine, Calcium-channel blockers, Cyclic antidepressants, Cardiac glycosides, Cyclopeptide mushrooms, Cocaine, Cicutoxin (i.e., water hemlock), Salicylates

• Mnemonic for substances poorly adsorbed by activated charcoal:

  • PHAILS to bind charcoal: Pesticides; Hydrocarbons and Heavy metals; Alcohols, Alkali, and Acids; Iron and Ions [lithium]; Laxatives; Solvents

Urine Alkalization

Increasing the urine pH by administration of intravenous (IV) sodium bicarbonate can charge substances, thus trapping them in the tubular lumen for excretion. Urine alkalization is first-line treatment in patients with moderately severe salicylate poisoning whose condition does not meet the criteria for hemodialysis. Other agents amenable to alkaline diuresis are long-acting barbiturates, lithium, and isoniazid.

Hemodialysis

In an unstable overdosed patient, consultation with a nephrologist for emergency hemodialysis may be indicated before the results of definitive diagnostic studies or drug-level measurements are available.

• Mnemonic for dialyzable toxins:

  • PLASMA TV: Phenobarbital, Lithium, Acidosis, Salicylates, Metformin, Alcohols (isopropanol, methanol, ethylene glycol), Theophylline, Valproic acid

Antidotes

Airway, breathing, and circulation take precedence over most of these antidotes.

Acetaminophen poisoning: N-acetylcysteine (NAC; see Acetylcysteine for Acetaminophen Poisoning for more information on management of acetaminophen overdose)

• The FDA maximum recommended dose of acetaminophen is 4 g/day; acute ingestion of ≥150 mg/kg is considered toxic.

• In patients who have alcohol use disorder, are undernourished, or who have underlying liver disease, glutathione stores are chronically depleted, making them more susceptible to acetaminophen toxicity.

• American College of Emergency Physicians (ACEP) clinical policy Level B recommendation:

  • Administer NAC to patients with acute acetaminophen overdose with either possible or probable risk for hepatotoxicity as determined by a 4-hour acetaminophen level and the Rumack-Matthew nomogram to reduce the incidence of severe hepatotoxicity and mortality, ideally within 8-10 hours post-ingestion.

  • Administer NAC to patients with hepatic failure thought to be due to acetaminophen.

Anticholinergic poisoning: physostigmine

• Symptomatic treatment: Most patients improve with symptomatic treatment, including the use of benzodiazepines as first-line therapy to treat related agitation and delirium.

• Physostigmine: Recommended when there is a high suspicion for anticholinergic toxicity and the patient develops the following:

  • narrow complex tachydysrhythmias with hemodynamic compromise (Note: In patients with cardiac conduction disturbances such as wide-complex dysrhythmias, physostigmine is contraindicated, and instead IV sodium bicarbonate should be administered.)

  • intractable seizures

  • severe agitation or psychosis not responsive to benzodiazepines

Lead, mercury, or arsenic poisoning: Prevention is key.

• Lead: Any patient with encephalopathy or who is otherwise symptomatic with a blood lead level (BLL) >70 µg/dL and all pediatric patients with a BLL ≥45 μg/dL, even if asymptomatic, should receive chelation therapy with either dimercaprol or calcium ethylenediaminetetraacetic acid (EDTA). Succumer (dimercaptosuccinic acid [DMSA]) an approved oral agent. D-penicillamine is used orally as an off-label treatment for lead poisoning in children.

• Mercury: Chelation therapy with DMSA or dimercaprol has been used to treat poisoning due to mercury vapor or inorganic mercury (not methyl mercury or ethyl mercury); however, no level has been established at which chelation should be initiated.

• Arsenic: Chelation therapy with dimercaprol or DMSA succimer may be necessary in symptomatic patients with arsenic poisoning. The use of chelators in patients exposed to arsine gas is controversial.

Benzodiazepine overdose: flumazenil

• Flumazenil risks appear to outweigh benefits for use in management of suspected benzodiazepine intoxication:

  • It does not consistently reverse central respiratory depression.

  • In tolerant or chronically exposed patients, it can precipitate withdrawal and result in exacerbation of the condition.

  • It can lead to intractable seizures unresponsive to benzodiazepines (contraindicated in patients with increased risk of seizure, seizure history, head injury, cardiac dysrhythmia, or chronic benzodiazepine use).

• Flumazenil should be considered in pediatric ingestion, reversal of iatrogenic toxicity, or occasionally in isolated benzodiazepine overdose in naive patients.

Black widow spider bite: Latrodectus antivenom

• Treatment is symptomatic.

• Ensure updated tetanus.

• Antibiotics are not recommended.

• Antivenom is associated with shorter duration of symptoms and may be available for severe envenomations; however, its use is limited by declining availability and high risk for serum sickness and anaphylaxis.

Beta-blocker overdose: glucagon

• Initial treatment is symptomatic with IV fluids and atropine, as needed.

• Glucagon is rarely sufficient as the sole agent when treating beta-blocker toxicity, and an infusion may be warranted. Glucagon has a short half-life, and adverse effects include nausea, vomiting, and hyperglycemia.

• Additional treatments include IV calcium, vasopressors, high-dose insulin with dextrose, lipid emulsion, and cardiac pacing in certain clinical situations.

Calcium-channel blocker: calcium gluconate, calcium chloride, high-dose insulin/glucose

• Initial treatment is symptomatic with IV fluids and atropine, as needed.

• Electrolytes (especially potassium) and glucose should be monitored and replaced accordingly.

• High-dose calcium is thought to create a concentration gradient that overcomes the channel blockade. It is usually administered as calcium gluconate or calcium chloride intravenously to patients who present with symptomatic hypotension or heart block.

• High-dose insulin and dextrose can increase inotropy and improve vascular dilatation.

• Glucagon promotes calcium entry into the cells. It can be administered as a bolus, and if beneficial, it can be administered as a drip; however, glucagon’s effect is likely to be temporary unless the patient presents with a betablocker co-ingestion.

• Lipid emulsion therapy and cardiac pacing may be considered.

• Patients require intensive care unit (ICU) monitoring from 6 to 36 hours depending on the ingested preparation and dose.

Cyanide poisoning: hydroxocobalamin

• Indicated for patients with altered mental status or hemodynamic instability

• First-line antidote is hydroxocobalamin (Cyanokit); second-line is sodium thiosulfate/sodium nitrite (Nithiodote kit)

  • _• Patients with more than minimal symptoms that resolve without treatment should still be admitted for observation and supportive care.

Digitalis glycosides toxicity: digoxin-specific antibody (Fab) fragments

• Toxicity can be caused by pharmaceutical (digoxin) and nonpharmaceutical (oleander, foxglove, lily of the valley) sources of cardiac glycosides.

• Digoxin immune Fab is first-line treatment. Indications include strongly suspected or known digoxin toxicity with:

  • acute ingestion of >0.1 mg/kg in children (or 4 mg) and 10 mg in adults

  • chronic ingestion with a steady-state concentration >4 ng/mL in children or >6 ng/mL in adults

  • any digoxin level >10 ng/mL at steady state or >15 ng/ml within 6 hours of ingestion

  • hyperkalemia >5 mEq/L

  • life-threatening arrhythmias, hemodynamic instability, or cardiac arrest

  • evidence of hypoperfusion and end organ disease, including altered mental status, transient ischemic attack (TIA), or ischemic bowel

• Digoxin induces an extracellular shift of potassium, resulting in hyperkalemia, which should be treated with digoxin-specific therapies. Normal hyperkalemia-targeted therapies should be used judiciously because serum potassium decreases with digoxin-immune FAB administration.

• Calcium (contrary to its usual use in hyperkalemia) is not recommended in patients with digitalis toxicity because it can precipitate ventricular dysrhythmias.

• Hypokalemia, which can be precipitated by hypomagnesemia, should be corrected, as it increases digoxin cardiac sensitivity. Magnesium is a good antiarrhythmic temporizing measure before Fab fragments.

• Digoxin levels after Fab administration are falsely elevated because the test also measures digoxin bound to Fab fragments. Only free digoxin levels can be used.

Ethylene glycol: fomepizole, pyridoxine, or ethanol and hemodialysis

• Fomepizole is the first-line treatment and indicated if there is high suspicion for ingestion and additional criteria are met (see table below).

• Pyridoxine is a cofactor in the metabolism of glycolic acid to glycine and is used as an adjunctive therapy with thiamine and sodium bicarbonate for severe acidosis.

• Consider hemodialysis for any ethanol-treated (competitive substrate) patient with a serum concentration of ethylene glycol >8 mmol/L (50 mg/dL), significant acidemia (pH <7.25), or evidence of renal failure.

(Source: Fomepizole for Ethylene Glycol and Methanol Poisoning. N Engl J Med 2009.)

Methanol toxicity: fomepizole, folate, or ethanol and hemodialysis

• Fomepizole is first-line treatment and indicated if there is high suspicion for ingestion and additional criteria are met (see table above.

• Catabolizing formic acid requires an enzyme that is dependent on folate; therefore, folate administration is recommended as adjunctive therapy with sodium bicarbonate for severe acidosis.

• Consider hemodialysis for any ethanol-treated (competitive substrate) patient with a serum concentration of methanol >15.6 mmol/L (50 mg/dL), significant acidemia (pH <7.25), visual signs or symptoms, or renal failure.

Hydrofluoric acid toxicity: calcium gluconate or calcium chloride

• In the event of dermal exposure, decontamination with copious irrigation and administration of topical calcium gluconate gel to the site of injury are two elements of successful treatment. Calcium gluconate can also be subcutaneously injected around the site of exposure.

• Potassium and magnesium should also be monitored and repleted.

• Inhalation, ingestion, or massive cutaneous exposure may require oral or parenteral calcium gluconate (see Hydrofluoric Acid Burns for management guidelines and algorithms).

• Hemodialysis may be indicated in severe systemic toxicity but is rare.

Sodium hypochlorite poisoning: no specific antidote

• Sodium hypochlorite is commonly found in bleach and household cleaning supplies.

• Decontamination and irrigation or removal from the source is key.

• Direct visualization of the esophagus is important for determining the extent of injury in all patients suspected of significant ingestion.

• Do not offer activated charcoal; its effectiveness is not proven and it hinders endoscopy.

Iron poisoning: deferoxamine

• Consider whole-bowel irrigation if a large amount of material is seen in the stomach on abdominal x-ray.

• Indications for deferoxamine use include:

  • shock, metabolic acidosis, altered mental status

  • iron levels >500 µg/dL or >350 µg mol/L if the patient is symptomatic

  • chronic iron overload

Isoniazid, hydrazine, and monomethylhydrazine toxicity: pyridoxine (vitamin B₆)

• Isoniazid, hydrazine, and monomethylhydrazine cause seizures through depletion of pyridoxine.

• Pyridoxine deficiency leads to decreased gamma-aminobutyric acid (GABA).

• Large doses of vitamin B₆ are needed to reverse deficiency.

Methemoglobinemia: methylene blue

• Identify and remove possible offending agent.

• Methylene blue is indicated if patient is symptomatic, typically with methemoglobin >30%.

• Methylene blue is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency because it may cause hemolysis.

• The FDA warns against concomitant use of methylene blue with psychiatric drugs due to an increased risk for serotonin syndrome.

Opioids: naloxone

• Unless a patient is in extremis, start with small doses (e.g., 0.4 mg IV) to avoid rapid reversal leading to significant patient discomfort and pulmonary edema. The autoinjectors used in the field contain this dose.

• Escalate to 10 mg total IV if needed.

• If response to treatment is favorable, observe need to repeat dosing or initiate naloxone drip based on dose and time intervals found to be effective.

Organophosphate and carbamate poisoning: atropine and pralidoxime

• Empiric immediate treatment is warranted for any presentation that strongly suggests this type of poisoning.

• Suspect in any multicausality incident where multiple victims have seizures, become comatose, or suffer cardiac arrest.

• Remove the patient from the source of contamination before arrival at the health care facility. Personnel should wear appropriate protective equipment.

• Atropine is indicated until pulmonary secretions are under control. Large quantities of atropine may be required (discuss mobilization of regional stores with pharmacy in case hospital supply is exhausted).

• Pralidoxime is administered as a bolus and then infused.

Viperidae (or rattlesnake) poisoning: CroFab antivenin injection

• Immobilize extremity in functional position, remove jewelry, mark leading edge of skin change.

• Patients who do not exhibit symptoms and are suspected of having “dry bites” may be observed in the emergency department (ED) for 8-12 hours and discharged after two sets of normal labs and no or minimal symptoms.

• Indications to use antivenin are not rigorously defined. If the decision is made to administer antivenin, the patient should be admitted to the ICU because it can cause serum sickness.

• Monitor for compartment syndrome, specifically in rattlesnake bites.

Sulfonylurea toxicity: octreotide

• Octreotide inhibits insulin release and increases serum glucose concentration, thereby decreasing the number of hypoglycemic events and supplemental dextrose requirement. Monitor patients after stopping octreotide to ensure no drug or metabolite remains.

Tricyclic antidepressant (TCA) overdose: sodium bicarbonate

• Sodium bicarbonate likely works by increasing serum pH to shift TCAs to inactive form and increase sodium concentrations.

• The greatest risk for seizures and arrhythmia is during the first 6-8 hours.

• QRS duration longer than 100 msec, symptomatic hypotension, and altered mental status are indications to start sodium bicarbonate, targeting a serum pH <7.55 or a sodium level <150 mEq/L.

• Vasopressors and lipid emulsion may be considered in the event of refractory toxicity or shock.

Valproic acid poisoning: carnitine

• Valproic acid is known to deplete serum carnitine levels; the active form of carnitine is an essential cofactor in the beta oxidation of fatty acids in the liver and plays a direct role on metabolism and elimination of valproic acid.

• Although evidence for carnitine as an antidote is limited, its use is still recommended in patients exhibiting a decreased level of consciousness and hyperammonemia.

Acute Agitation

Always consider a medical explanation for agitation (also see Altered Mental Status in the Neurology rotation guide).

Evaluation: Try to elicit a history of organic causes of agitation: trauma, grief reaction, glucose, toxidromes, hypoxia, hypercarbia, encephalitis, meningitis, thyrotoxicosis, psychiatric history, drugs, alcohol, and delirium. Obtain history from EMT, medical record, or family members.

Diagnostics: ECG, labs, imaging, toxicology screen as needed

Management:

• Identify escalating behaviors (e.g., noise, distractions) and attempt de-escalation techniques (e.g., offer food or blankets, try to establish a therapeutic alliance).

• Validate the patient’s concerns.

• Assume a calm, nonconfrontational, firm demeanor.

• Never put yourself in harm’s way (e.g., place yourself where you can get out of the room without difficulty, ask security to escort you); ensure your staff’s safety.

• Place patient in a private room, notify security, remove possessions, and ensure patient safety.

• Physical restraints are the last resort and should be accompanied by chemical sedation; restraints are meant to be temporary and should be repeatedly reassessed.

Chemical Restraints: Patients may perceive administration of drugs by oral (PO) or IV routes as less threatening or traumatic; however, some uncooperative patients may require intramuscular (IM) administration. Choice of chemical restraint(s) should be tailored to the patient’s comorbidities and presentation and can include antipsychotics, benzodiazepines, or, in the event of extreme agitation, ketamine or dexmedetomidine.

• Antipsychotics

  • Haloperidol is nonsedating and has been well studied for treatment of agitation associated with alcohol intoxication. Because it can precipitate extrapyramidal symptoms, some physicians advocate for the addition of diphenhydramine to prevent these adverse effects. If possible, check ECG for prolonged QT interval before administration.

  • Droperidol has quicker onset of action than haloperidol. A black box warning was issued previously due to concern for QTc prolongation, but the warning was based on a small number of adverse events associated with high doses; extrapyramidal symptoms are also possible.

  • Olanzapine is sedating and available in IV, IM, or PO forms. Olanzapine is associated with a lower incidence of extrapyramidal symptoms and QTc prolongation than droperidol.

  • Ziprasidone is available in PO or IM formulations but requires reconstitution for IM administration. It is associated with the highest risk of QTc prolongation among second-generation antipsychotics.

• Benzodiazepines

  • Midazolam is available in multiple formulations, including IV, IM, intranasal, PO, and rectal. Onset of action is more rapid than lorazepam and sedation is relatively shorter. Midazolam is frequently a first choice in patients with undifferentiated agitation.

  • Lorazepam is also available in multiple formulations. It has longer time to onset and longer sedation time than midazolam, although onset is still relatively fast; lorazepam lowers blood pressure.

• Ketamine

  • Ketamine has rapid onset and preserves airway reflexes. At certain doses, it qualifies as procedural sedation and requires subsequent monitoring and documentation.

  • Ketamine may be best suited for patients in whom other agents have failed and rapid control is needed.