Toxicology
Overview
Poisonings
Event resulting from the ingestion of, or contact with, a harmful substance.
May be the result of an overdose or incorrect use of a medication.
Children <3 years of age account for approximately 46% of poisonings.
Male predominance <13 years of age.
Female predominance >13 years of age.
More than 90% of poisonings occur inside the child’s residence.
Poison Control Centers
National poison control hotline.
1-800-222-1222.
Consultation is free to health care professionals and the general public.
Most callers are not referred to a health care facility.
Results in significant health care cost savings.
Selected Poisonings
Acetaminophen
Shawna Mudd
Background
Also known as N-acetyl-p-aminophenol and paracetamol.
Commonly used and widely available analgesic and antipyretic.
Dispensed as a single product, but also found in many combination preparations.
Common in pediatric overdoses.
Etiology
Commonly occurs through dosing errors.
Unintentional ingestions are common in young children.
Intentional ingestions occur more often in older children/adolescents.
Pathophysiology
Rapidly absorbed from the gastrointestinal (GI) tract.
Primarily in the small intestine.
Metabolized primarily by the liver.
When ingested in normal therapeutic levels, primarily metabolized by the liver.
Metabolized to sulfate and glucuronide conjugates.
A small amount is metabolized to N-acetyl-p-benzoquinone imine (NAPQI).
NAPQI is then rapidly conjugated with glutathione and is inactivated to nontoxic cysteine and mercapturic acid conjugates.
Toxic ingestions (as little as 4,000 mg in a single day).
Glutathione conjugation becomes insufficient to meet the metabolic demand.
Result in elevated NAPQI levels.
Subsequent hepatocellular necrosis and can lead to irreversible liver failure.
Clinical Presentation
Initial symptoms, mild.
Vomiting.
Malaise.
>24 hours, symptoms progress.
Increased alanine transaminase (ALT) and aspartate transaminase (AST).
>72 hours, peak toxicity.
Coagulopathy.
Encephalopathy.
Liver failure.
Cerebral edema (some cases).
Possibly, death.
Diagnostic Evaluation
Determine quantity and dosage form ingested.
Determine time of ingestion.
Refer to an emergency department (ED) for:
Children <6 years of age.
>200 mg/kg in children <6 years of age in a 24-hour period.
>150 mg/kg per 24-hour period for the preceding 48 hours.
>100 mg/kg per 24-hour period for 72 hours or longer.
Acetaminophen level.
Draw 4 hours after ingestion, or immediately on presentation if more than 4 hours has elapsed since ingestion.
If presenting <4 hours after ingestion, consider waiting to draw level until 4 hours has passed.
A 4-hour postingestion level is the first value plotted on the acetaminophen serum level nomogram.
Serum acetaminophen levels should be drawn, as well as liver function tests.
See Figure 13.1.
FIGURE 13.1 • Rumack-Matthew Nomogram for Acetaminophen Poisoning. Acetaminophen concentration plotted versus time after exposure to predict potential toxicity and antidote use.
If the ingestion occurred over time, obtain the level 4 hours after the first dose was taken or immediately on presentation if >4 hours have elapsed.
Example: Child began ingesting acetaminophen at 4 p.m. and continued taking additional medication until 7 p.m.; the 4-hour mark will be considered from the 4 p.m. time of first ingestion, and the first level should be obtained at 8 p.m. (or immediately if the child is presenting later than 4 hours after the ingestion).
Acetaminophen serum level nomogram.
Used to assist in determining severity of toxicity and therapy.
Stratifies risk level of ingestion.
Based on serum level and time after ingestion.
First level is 4 hours after ingestion.
Limitations:
Levels obtained prior to 4 hours after ingestion are not interpretable on the nomogram.
Patients presenting late may no longer have a detectable level or may have a low level and may have ingested a lethal dose.
Less predictive in chronic ingestion (rather than acute ingestion).
Less predictive in extended-release formulations.
Management
Antidote: N-acetylcysteine (NAC).
Available formulations.
Intravenous (IV) (Acetadote).
Oral (Mucomyst).
Mechanism of action.
Unclear; likely maintains or restores glutathione levels, allowing for metabolism of acetaminophen without development of hepatocellular necrosis, or may act as an alternative substrate for conjugation with acetaminophen toxic metabolites.
Administer within 8 hours of acetaminophen ingestion for greatest efficacy.
Administer in cases with any signs of hepatotoxicity, even if the acetaminophen level is low or undetectable.
Any child with an unknown amount of acetaminophen ingestion or questionable history should have an acetaminophen level drawn and consideration for NAC administration.
Activated charcoal (AC).
Consider administration if child presents to medical attention immediately after ingestion (<2 hours postingestion; ideally <1 hour postingestion).
May also be beneficial in cases of multidrug ingestion.
Alcohols (Ethanol, Methanol, Ethylene Glycol)
Shawna Mudd
Background
Toxic symptoms result from either intentional or accidental ingestion of alcohol-containing products.
Many alcohol products exist that are intended for human consumption; however, some are not intended for human consumption.
All can pose serious health risks for children.
Etiology/Types
Ethyl alcohol (ethanol).
The alcohol most commonly recognized; produced by the fermentation of grains, “grain alcohol.”
Alcoholic beverages and distilled spirits.
Found in accessible household products—hand sanitizer, mouthwash, colognes, and others.
Methyl alcohol (methanol).
Produced from the distillation of wood, “wood alcohol.”
Found in industrial solvents, gasoline blends, plastic products, windshield wiper fluid, paint strippers, glass cleaners, hobby and craft adhesives, food warming cans used under chafing dishes (e.g., Sterno), and others.
Ethylene glycol.
Used in various solvents.
Primary component of automobile antifreeze.
Found in herbicides/pesticides, liquid detergents, paints and paint products, among others.
May have a sweet taste and attractive color which can pose a particular danger to children.
Pathophysiology
Ethanol, methanol, and ethylene glycol are rapidly absorbed from the GI tract and have inherent sedating central nervous system (CNS) properties.
Methanol can result in mild toxicity through cutaneous absorption and inhalation, but this is not common.
End products of methanol and ethylene glycol metabolism in the liver, primarily by alcohol dehydrogenase and aldehyde dehydrogenase, produce the significant toxicity associated with their consumption.
Clinical Presentation
All present with generalized nonspecific CNS depression.
Ethanol.
Symptoms similar to other sedatives.
Vomiting due to GI distress.
Slurred speech, ataxia, lethargy, and coma.
Respiratory depression.
Hypotension.
Bradycardia.
Facial flushing.
Profound hypoglycemia secondary to impaired gluconeogenesis can be problematic, and often is a delayed presentation.
An odor to the breath can sometimes be detected.
Methanol.
Similar to ethanol intoxication in its initial presentation, but the initial inebriation period may diminish for periods ranging from 6 to 30 hours, during which the patient is fairly asymptomatic despite the fact that toxic metabolism is occurring.
Severe metabolic acidosis.
Visual complaints (e.g., blurred vision or seeing spots), headache, seizures.
Tachypnea or hyperpnea.
Pulmonary edema and renal failure.
Coma.
Ethylene glycol.
Similar to ethanol intoxication in its initial presentation, except that no odor is generally present on the breath.
CNS depression may worsen over time.
Tachypnea and hyperpnea.
Shock.
Pulmonary edema.
Acute renal failure.
Acute respiratory failure.
Cerebral edema.
Ocular complaints are generally not present.
Diagnostic Evaluation
Any symptomatic patient or any patient suspected of ingesting methanol or ethylene glycol should be managed in the ED/hospital setting.
Patients require cardiorespiratory monitoring and supportive treatment as appropriate (e.g., airway, breathing, and circulation).
Laboratory.
Serum ethanol (blood alcohol), ethylene glycol, and methanol levels.
In cases of suspected methanol or ethylene glycol ingestions, laboratory evaluation for metabolic acidosis is necessary.
Electrolytes with calcium and anion gap calculation.
Serum osmolality (a large serum osmolality gap should raise suspicion for ingestion of methanol or ethylene glycol).
Arterial or venous blood gas values.
Blood glucose level.
BUN and creatinine level.
Hepatic panel/Liver function tests.
Additional testing may include urinalysis and amylase, lipase, and creatine kinase levels.
Management
Ethanol.
Conservative observation with cardiorespiratory monitoring.
Supportive treatment as appropriate.
Supplemental oxygen.
IV fluids.
Glucose (if hypoglycemia is present).
Electrolyte monitoring (particularly if frequent vomiting/diarrhea).
Gastric decontamination or emptying is not recommended.
Methanol and ethylene glycol.
Supportive cardiovascular and respiratory care.
Prompt treatment of hypoglycemia.
Key to treatment of methanol and ethylene glycol toxicity is to interfere in the production of toxic metabolites through the IV administration of fomepizole or by the oral or IV administration of ethanol.
Dialysis effectively clears alcohols; however, it is infrequently needed unless the patient is deteriorating with the administration of fomepizole or ethanol.
May be needed in the cases of concomitant renal failure.
Metformin
Mark D. Weber
Background
Overdose of oral hypoglycemic agents, such as metformin and sulfonylureas, is rare in children.
Metformin overdose leads to lactic acidosis but rarely hypoglycemia.
Sulfonylureas (e.g., glipizide, glyburide, glimepiride) can cause rapid decrease in glucose levels.
Etiology
Inadvertent or accidental ingestion.
Suicide attempt.
Pathophysiology
Metformin is an oral antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes.
Increases glucose tolerance through reducing the basal and postprandial blood glucose level in patients with type 2 diabetes.
Decreases hepatic glucose production and intestinal absorption of glucose.
Increases peripheral glucose uptake and utilization, resulting in improved insulin sensitivity.
The pharmacologic properties of metformin are unique and are unlike other classes of oral antihyperglycemic agents (e.g., sulfonylureas) which can result in acute hypoglycemia.
The exact mechanism of sulfonylureas’ hypoglycemic effect is unknown.
Sulfonylureas bind to receptors that are associated with potassium channels sensitive to adenosine triphosphate in β-cell membrane.
The binding inhibits efflux of potassium ions from the cells, cascading and resulting in release of preformed insulin.
Clinical Presentation
Nausea, abdominal pain, diarrhea.
Dizziness.
Hypoglycemia; rare in metformin overdose (common in other classes of oral antihyperglycemic agents).
Lactic acidosis is primarily noted in adults with preexisting liver and renal insufficiencies.
Diagnostic Evaluation
Baseline blood glucose level.
Comprehensive metabolic panel.
Hepatic function panel.
Lactic acid level.
Management
Gastric lavage with AC; depending on time of presentation related to ingestion.
Glucose-level monitoring.
Hemofiltration, in cases of severe lactic acidosis.
β-Blockers
Melanie Muller
Background
Most ingestions are acute, accidental, occur in a residence and in children <6 years of age.
Definition
Intentional or unintentional ingestion of toxic doses of β-blockers.
Pathophysiology
β1-Receptors are found primarily in myocardial tissue and affect heart rate, contractility, and AV conduction.
Blocking these receptors results in decreased myocardial contractility and decreased conduction through the AV node.
Results in bradycardia and hypotension.
β2-Receptors are primarily found within the smooth muscles of peripheral vasculature and bronchioles.
β-Blockers typically antagonize selective β-adrenergic receptors; however, some medications have both antagonistic and agonistic properties.
β-Blocker medications may also have the following characteristics that affect clinical presentation after ingestion.
Membrane stabilizing activity (MSA)—inhibits myocardium fast sodium channels which could widen QRS and cause dysrhythmia (e.g., propranolol and acebutolol).
Lipophilicity—high lipid solubility, therefore crossing the blood-brain barrier, increasing the patient risk for CNS sequelae following a toxic ingestion (e.g., propranolol and metoprolol).
Intrinsic sympathomimetic activity—partial agonistic or activating effects on receptors, therefore potentially decreasing the risk of severe bradycardia and hypotension with toxic ingestion (e.g., labetalol and propranolol).
Clinical Presentation
Widely variable depending on the amount ingested and the specific drug that was ingested.
Ranges from asymptomatic to cardiac arrest.
Most patients become symptomatic within 2 hours after the ingestion, except in the case of extended-release medications in which symptomatology can be delayed for up to 24 hours.
Most common presentations include:
Bradycardia.
Hypotension.
Ventricular dysrhythmias can be associated with the ingestion of β-blockers with MSA properties.
Seizures and neurologic sequelae can occur if patient experiences severe hypotension or if medication ingested possesses lipophilicity.
Diagnostic Evaluation
Accurate history.
Name of agent ingested.
Approximation of number of pills ingested and concentration.
Approximate time of ingestion.
Possibility of co-ingestion.
Any interventions performed prior to seeking assistance.
Evaluation
EKG.
Serum electrolytes.
Urine and serum toxicology screen.
Acetaminophen and salicylate levels to evaluate for co-ingestion.
Management
Depends on the amount ingested and patient symptomatology.
First, evaluate airway, breathing, and circulation.
Consider AC (1 g/kg/dose) if within 1 hour of ingestion.
Fluid bolus (normal saline 20 mL/kg) for hypotension.
Atropine administered IV for bradycardia.
Glucagon infusion for moderate to severe ingestions.
Sodium bicarbonate if the β-blocker ingested possesses MSA properties.
Helps to prevent dysrhythmias.
PEARL
In general, individuals with a history of bronchoreactivity should not take β-blocking medications.
Bath Salts/Spice
Mark D. Weber
Background
Bath salts are compounds that originate from the khat plant (Catha edulis).
Marketed as “bath salts” or “plant food.”
Labeled as “not to be used for human consumption” in order to avoid legislative regulation.
Effects are similar to that of cocaine or amphetamines.
Definition
A synthetically prepared or naturally derived drug from the khat plant that provides effects similar to cocaine or amphetamines.
Common street names.
Plant food.
Bath salts.
Meow meow.
New cocaine.
Clinical Presentation
Diagnostic Evaluation
Not detected by standard drug/toxicology screen analysis.
Advanced detection can be performed by mass spectrometry.
Management
Low-dose benzodiazepines to manage agitation.
Benzodiazepines to treat seizures.
Surface cooling and/or dantrolene to treat hyperthermia.
Prevention of rhabdomyolysis.
Nitroglycerine, morphine, and antiplatelet drugs for coronary vasospasm.
Benzodiazepines
Dana L. Lerma
Background
Class of medications that provide a sedative-hypnotic effect.
Used in the treatment of anxiety, seizures, procedural sedation, withdrawal states, and as muscle relaxants.
While benzodiazepine overdose is relatively common, they generally involve a co-ingested agent.
Overall, patient outcomes are generally good when benzodiazepine ingestion occurs alone.
Pharmacology
Benzodiazepines act on γ-aminobutyric acid A receptors, an inhibitory neurotransmitter in the CNS.
Clinical Presentation
Mild to moderate toxicity:
CNS depression.
Drowsiness, fatigue, confusion, memory loss, ataxia, and slurred speech.
Paradoxical excitement is not uncommon in children.
Respiratory depression is uncommon, but may occur.
Tachycardia or bradycardia may be present; although with mild toxicity, vital signs are normally stable.
Nausea and vomiting.
Severe toxicity.
More profound CNS depression.
Respiratory depression and/or arrest.
Hypothermia and hypotension are common.
Possible coma or death.
Diagnostic Evaluation
Urine toxicity screen should be sent. However, not all benzodiazepines are detected on routine urine drug/toxicology tests, including midazolam, lorazepam, and clonazepam.
Routine laboratory testing should be completed, including glucose to evaluate for hypoglycemia as cause of decreased mental status.
Acetaminophen, salicylate, and ethanol are common co-ingestions.
Evaluation of these serum levels is indicated.
Management
Primarily supportive.
Flumazenil is a rapid benzodiazepine receptor antagonist; only indicated in iatrogenic oversedation or respiratory depression.
Intubation may be required in patients with respiratory depression and loss of airway reflexes.
Fluid resuscitation for hypotension.
Rarely, vasopressors are required to maintain adequate blood pressure.
AC is generally only beneficial when benzodiazepines are co-ingested with another toxic substance.
PEARL
A negative urine toxicology test does not exclude the possibility of benzodiazepine ingestion.
Carbon Monoxide
Mark D. Weber
Background
Inhalation of carbon monoxide (CO) from surrounding environment, leading to tissue hypoxia.
Definition
Acute CO poisoning results from brief exposure to high levels.
Chronic CO poisoning results from long-term exposure to low levels (e.g., tobacco smokers).
Mild CO poisoning (CO <30%) may not be associated with any symptoms.
Moderate CO poisoning (CO level 30%-40%).
Severe CO poisoning (CO level >40%) may result in loss of consciousness.
Death has been associated with CO levels >60%.
Etiology
Exposure to:
Smoke inhalation.
Space heaters; fuel burning.
Furnaces, charcoal grills, fireplaces, portable generators.
Water heaters.
Cooktop ranges.
Wood-burning stoves.
Typically, exposure to these is not of concern unless they are not kept in proper working order or if used in a close or partially closed space.
Car/truck exhaust.
Typically not a concern unless running a car/truck in a closed garage/space with inadequate ventilation.
Pathophysiology
CO has a 200 times greater affinity for hemoglobin than does oxygen.
Large amounts of carboxyhemoglobin (COHb) hinder oxygen delivery to the body.
The relative oxygen saturation of the hemoglobin molecule is then decreased leading to tissue hypoxia (Figure 13.2).
 FIGURE 13.2 • Mechanism of Carbon Monoxide Poisoning. A: The binding site of hemoglobin is a ferrous heme that can reversibly bind oxygen. CO prevents oxygen binding by forming a bond to ferrous heme that is significantly stronger than the heme-oxygen bond (shorter bold line). B: CO interferes strongly with oxygen transport because it both prevents oxygen binding and increases the affinity of heme for oxygen. Under normal conditions (blue line), hemoglobin is 85% saturated with oxygen in the alveoli (where the partial pressure of oxygen is approximately 90 torr). At tissue partial pressures (40 torr), normal hemoglobin is 60% saturated with O2. Thus, under normal conditions, 25% of the hemoglobin sites deliver their oxygen to the tissues. When 50% of oxygen binding sites are occupied by CO (red line), hemoglobin oxygen saturation can be no more than 50% at a partial pressure of 90 torr. At tissue partial pressures (40 torr), the hemoglobin oxygen saturation is still over 35%, indicating that less than 15% of the heme sites can deliver their oxygen to the tissues. |
Clinical Presentation
Symptoms include headache, nausea, dizziness, vomiting, seizures, shortness of breath, hypotension, confusion, loss of consciousness (moderate to severe poisonings).
May initially seem like a flu-like illness.
Can lead to cardiopulmonary arrest, coma, and death.
Cherry-red skin is a rare finding.
Diagnostic Evaluation
Arterial or venous blood gas analysis to assess COHb percentage—normal <2%.
Traditional pulse oximetry may be unable to detect CO binding to hemoglobin, resulting in falsely elevated oxygen saturation reading.
Hemoglobin is saturated, however, with a mixture of oxygen and CO.
Pulse oximeters are unable to discern what substance is bound to the hemoglobin and report a total percentage of saturation; in cases of CO toxicity, the combination of oxygen and CO bound to hemoglobin.
Management
Supplemental oxygen.
Preferably, non-rebreather to maximize oxygen concentration.
Intubation if level of consciousness and respiratory rate indicate.
Hyperbaric oxygen therapy.
Controversial, but may speed recovery and removal of CO.
PEARL
Tobacco smokers typically have an elevated baseline COHb level of approximately 5% to 8%.
Caustic Agents
Andrea M. Kline-Tilford
Background/Definition
Remains an important public health problem despite education and regulatory efforts to decrease its occurrence.
Approximately 5,000 to 15,000 caustic ingestions in the United States annually.
Bimodal pattern.
First peak is at 1 to 5 years of age.
Most are accidental.
Second peak is at 21 years and older.
Most are intentional/suicide attempts.
Results in widespread injury.
Lips, oral cavity, pharynx, and upper airway.
Most serious injuries are a result of involvement of the esophagus.
Etiology
Determined by the identity of the agent, amount consumed, concentration, and duration of exposure to the tissue.
Tissue injury is caused by a chemical reaction.
Greatest concern is acids with a pH <3 and alkalis with a pH >11 (Table 13.1).
Clinical Presentation
Injuries often present hours to days after the ingestion.
Appearances may change after initial presentation; initial presentation may appear deceptively harmless.
Injuries divided into three categories:
Airway/facial burns.
Esophageal/GI burns.
Splash burns.
Burning sensation in the mouth, perioral edema.
Esophageal/pharyngeal edema.
Esophageal injury is rapid.
Acute tissue penetration and deep tissue injury continues for hours.
Injury progresses for the first week after the ingestion.
Inflammation.
Vascular thrombosis.
Ulceration, fibrous crust formation, and granulation tissue develop in the first few days after the event.
TABLE 13.1 Commonly Ingested Caustic Agents
Type of Agent
Examples of Agents
Acid
Hydrochloric acid, nitric acid, sulfuric acid (e.g., swimming pool cleaners, rust removers, toilet bowl cleaners), acetic acid (e.g., descaling agents).
Alkali
Potassium hydroxide, sodium hydroxide (e.g., liquid drain cleaners, oven cleaners, disk batteries), ammonia (household cleaning agents), sodium metasilicate (e.g., dishwashing agents), lithium and calcium hydroxide (hair relaxers).
Other
Bleach/Hypochlorous acid. Peroxide (Mildew cleaners).
Adapted from Lupa, M., Magne, J., Guarisco, L., & Amedee, R. (2009). Update on the diagnosis and treatment of caustic ingestion. The Ochsner Journal, 9, 54-59.
Dyspnea, dysphagia, drooling.
Stridor.
Recurrent emesis.
Hematemesis.
Diagnostic Evaluation
History and physical examination.
Nothing by mouth.
Aggressive IV hydration.
Chest and abdominal radiographs.
Evaluate for free air in mediastinum (esophageal perforation), air under diaphragm (gastric perforation) (see Figure 13.3).
Baseline chest radiograph in anticipation that aspiration pneumonia may develop.
Laryngoscopy: often fiber-optic, to reduce the likelihood of bleeding or increased damage to area associated with procedure.
Surgical airway may be required (e.g., tracheostomy) in some cases.
Endoscopy (airway, esophageal).
Barium esophagram.
More useful in long-term evaluation of esophagus, especially stricture formation.
High false-negative rate in early stages of injury (e.g., prior to stricture formation).
Technetium-labeled sucralfate (nuclear medicine study) (Figures 13.4A & B).
 FIGURE 13.3 • Pneumomediastinum Due to Esophageal Perforation. Posteroanterior chest radiograph shows extensive air within the mediastinum, as well as lucencies around the aortic arch and along the tracheal air column and associated subcutaneous air. |
 FIGURE 13.4 • Corrosive Esophagitis Esophagram. A: Dilated, boggy esophagus with ulceration 8 days after the ingestion of a caustic agent. B: Stricture formation is evident on an esophagram obtained 3 months after the caustic injury. |
Management
Pain control.
Nasogastric tube may be required as a stent for injured area and provide nutrition.
Placed under endoscopic guidance.
Generally left in place for 14 to 21 days.
Strictures often require repeated balloon dilation via endoscopy.
Antibiotics often used, though no evidence to support that they affect stricture formation or rates of infection.
Steroids, controversial.
Avoid induction of emesis; may lead to worse injury from additional exposure to corrosive agent.
PEARLS
Alkaline disk battery ingestion results in damage and leakage within 1 hour, and if lodged in the esophagus, perforation 8 to 12 hours after the ingestion.
Evaluate for potential splash burns to skin and eyes.
Most long-term sequelae occur in the esophagus.
The presence or absence of burns on the lips, mouth, and oropharynx immediately after the event does not always correlate with the extent of injury in the esophagus or GI tract.
Calcium Channel Blockers
Lara G. Smith
Mark D. Weber
Background/Definition
Antihypertensive.
Lethal prescription drug ingestion.
Appealing to children because of candy-like appearance.
Several formulations: short-acting, long-acting, ultra-long-acting.
Relaxation of smooth muscle in the coronary vasculature and dilation of the coronary vessels.
Metabolized in the liver into inactive metabolites.
Half-life.
Dependent on agent ingested.
Example: Nifedipine has a half-life of 2 to 5 hours; amlo-dipine has a half-life of 30 to 50 hours.
It is vital to determine the agent ingested to anticipate patient course.
Pathophysiology
Binds to L-type, slow calcium channels in cell membranes.
Binding reduces the flow of calcium into the cell.
Inhibition of depolarization in cardiac pacemaker cells.
Metabolized primarily in the liver.
Clinical Presentation
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