Etiology
Most toxic ingestions in young children (<6 years old) are unintentional. Children explore their environment through experimentation, and mimic the actions of others, including taking medications. They have a reduced ability to distinguish medications or potentially harmful household chemicals from beverages, food, or candy, and may ingest these substances if they are accessible. Children may also ingest toxic mushrooms, berries, or household plants. Pica is a medical disorder in which children develop an appetite for non-nutritive substances, which increases the risk of a toxic ingestion.
Deliberate ingestion usually occurs in an older child. The ingestion usually represents a cry for help and children rarely intend to commit suicide. The child usually, but not always, informs a friend or relative. In rarer cases, there may be a history of mental illness or depression with suicidal ideation, in which case the ingestion represents a genuine suicide attempt. The substance is most likely a medication that is either present in the house or can be easily purchased without a prescription. A readily available chemical in the garage, attic, or store may also be ingested. Girls are more likely than boys to consider self-harm.[3]
Deliberate ingestion may also occur in an attempt to get "high." This usually occurs in older children and adolescents where peer pressure is significant. Ethanol remains one of the most popular ingested compounds for recreational use. Other agents include dextromethorphan and diphenhydramine (both found in cough and cold preparations), methylphenidate and amphetamine, inhalation of organic solvents or asphyxiants, benzodiazepines (such as alprazolam), and opioids (such as hydrocodone and oxycodone).
Pathophysiology
Once a toxin is ingested, the agent must transit the gastrointestinal (GI) tract and be absorbed either in the stomach (ethanol) or the small intestine (most other agents). Strong acids and alkalis may injure the mouth, pharynx, esophagus, and other more distal portions of the GI tract. Most agents are rapidly absorbed, but some toxins retard their own absorption (e.g., opioids, salicylates, sustained-release calcium-channel blockers, and antimuscarinic agents such as diphenhydramine), and others have delayed absorption due to their formulation (e.g., sustained-release products). Some agents are inhaled.
The extent and nature of the toxicity depends on the substance or substances consumed.
Acetaminophen: overdose produces increased amounts of the toxic intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQI), exceeding the level that the liver can detoxify. NAPQI causes mitochondrial toxicity and hepatocyte death, leading to potentially fatal liver failure.[4]
Ibuprofen: as a nonsteroidal anti-inflammatory drug (NSAID), toxicity is produced through inhibiting cyclooxygenase and inhibiting the synthesis of prostaglandins. The majority of overdoses are asymptomatic or have mild symptoms. However, with large doses, GI symptoms (including abdominal pain, nausea, vomiting, and bleeding) and acute renal impairment are possible. Central nervous system (CNS) symptoms can be seen in overdose and include a depressed level of consciousness. Generalized seizures and apnea have also been reported.[5]
Salicylates: toxicity produces local irritation of the GI tract, uncoupling of oxidative phosphorylation, direct stimulation of the respiratory center in the brainstem, stimulation of metabolic rate, disturbance of carbohydrate and lipid metabolism, and disturbances in hemostasis. The increased respiratory rate produces a respiratory alkalosis, but this is overridden by the metabolic disturbances, which produce a metabolic acidosis caused by the accumulation of organic acids.[6]
Opioids: toxic effects are mediated by stimulation of mu and kappa receptors in the CNS and peripheral nervous system. Stimulation of the mu receptor produces analgesia, euphoria, respiratory depression, and miosis. Stimulation of the kappa receptor produces analgesia, miosis, respiratory depression, and sedation.[7]
Sympathomimetics (alpha agonists, beta agonists, amphetamines/psychostimulants, monoamine oxidase inhibitors [MAOIs]): these drugs produce activation of the sympathetic nervous system by direct stimulation of alpha- or beta-adrenoceptors, indirect release of presynaptic norepinephrine, prevention of presynaptic uptake of norepinephrine, or inhibition of norepinephrine metabolism. Toxicity produces overactivation of the sympathetic nervous system, leading to bronchospasm, hyperthermia, extreme hypertension, cardiac arrhythmias or ischemia, seizures, strokes, or intracranial bleeds. Some sympathomimetics have multiple mechanisms of action. This can vary with dosing. For example, phenylephrine - a component of some over-the-counter decongestant medications - exerts its effects primarily as an alpha agonist, but at extremely high doses it also can exert beta agonist activity.
Antimuscarinic agents: toxic effects of drugs such as diphenhydramine are mediated by the blockade of muscarinic receptors. The wide distribution of these receptors results in a characteristic set of symptoms, including hypertension (which is less marked than that produced by sympathomimetics), tachycardia, hyperthermia, mydriasis, flushed red skin, urinary retention, absent bowel sounds, loss of sweating, sedation or agitation, and seizures.
Cholinesterase inhibitors: these include organophosphates, which have a variety of uses. Cholinesterase inhibitors are also found naturally in a range of plants and fungi. Poisoning leads to excessive acetylcholine at sympathetic, parasympathetic, CNS, and neuromuscular junction sites. Parasympathetic effects are predominant early on and cause excessive secretions, bronchospasm, diarrhea, and pinpoint pupils. Sympathetic effects may lead to hypertension and tachycardia. CNS cholinergic effects contribute to seizures and respiratory failure in severe poisonings.[8]
Barbiturates: these drugs potentiate and prolong the effects of gamma-aminobutyric acid (GABA), one of the major inhibitory neurotransmitters in the brain. Direct effects include sedation and hypnotic activity at lower dosages. The CNS depressant effect mimics that of ethanol. Depression of the medullary vasomotor and respiratory centers leads to cardiovascular and respiratory depression.
Benzodiazepines: these drugs potentiate and prolong the effects of GABA. Direct effects include sedation, hypnotic action, and muscle relaxation. Depression of the medullary vasomotor centers causes cardiovascular depression, but mortality from an overdose is rare.
Methanol: used as an industrial and marine solvent, and also used in paint removers, photocopying fluid, shellacs, and windshield-washing fluids. Toxicity following ingestion is produced by the ensuing metabolic acidosis and the formation of formic acid, which damages the eye, producing blindness.[9]
Ethylene glycol: a sweet-tasting, odorless, and colorless liquid used in antifreeze. The substance itself is nontoxic, initially causing inebriation. However, toxicity appears within 12 to 24 hours due to metabolic acidosis and the formation of calcium oxalate from one of the metabolites. Deposition of calcium oxalate in the lungs, myocardium, and kidney leads to respiratory and cardiac damage followed by acute kidney injury. Hypocalcemia can also occur due to the consumption of circulating calcium by crystal formation.[10]
Isopropanol: a solvent used in many mouthwashes, skin lotions, and rubbing alcohol. Toxicity is caused by CNS depression and irritation of the GI tract. In contrast to methanol and ethylene glycol, there is no metabolic acidosis.[11]
Cleaning products: these include a range of corrosives and fluoride-based solutions.[12] Acid or alkaline ingestions cause tissue necrosis; the major site of necrosis is the stomach for acid ingestions and the esophagus for alkaline ingestions. Fluoride has a range of toxic effects, including GI irritation or corrosion, binding of calcium (leading to hypocalcemia, hypomagnesemia, and inhibition of calcium-dependent enzymes, ion channels, and transporters), inhibition of sodium/potassium adenosine triphosphatase (leading to hyperkalemia), and inhibition of acetylcholinesterase.
Foreign bodies: these ingestions may be benign and merit only observation or, in some cases, may potentially lead to more severe clinical consequences. The following are particularly concerning:
Barium salts: these are lubricant additives in cosmetics and pharmaceutical products. They are rapidly absorbed and cause profound, potentially fatal hypokalemia.[16]
Beta-blockers: these drugs block the beta-adrenoceptors. Toxicity results in bradycardia, hypotension, and hypoglycemia. Centrally mediated cardiac depression may also occur.
Calcium-channel blockers: these drugs produce peripheral vasodilation with hypotension and bradycardia due to their direct effects on the cardiovascular system. Inhibition of insulin release leads to hyperglycemia. Inhibition of fatty acid use leads to lactic acidosis.
Sodium-channel blockers: these include class 1 antiarrhythmic drugs and tricyclic antidepressants. The main toxicity is produced by slowing cardiac conduction with resultant arrhythmias and/or hypotension. CNS or GI symptoms may also occur. Disopyramide and quinidine can cause anticholinergic syndromes.
Warfarin: inhibits the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X, and the anticoagulant proteins C and S. Toxicity causes excessive anticoagulation and bleeding.
Digoxin: this drug inhibits the sodium-potassium adenosine triphosphatase pump, producing a positive inotropic effect by increasing intracellular calcium and sodium, and decreasing intracellular potassium. Toxicity can precipitate any arrhythmia, produce altered sensorium or mental status, and GI symptoms.
Sulfonylureas: these drugs lower blood glucose, and toxicity produces hypoglycemia.
Iron: produces direct corrosive effects on the GI tract and cellular toxicity due to excessive iron uptake. Patients develop metabolic acidosis due to systemic hypoperfusion and uncoupling of oxidative phosphorylation, which can be lethal. Severe toxicity from iron may be missed because of a relatively quiescent period that happens after an initial phase of nausea and vomiting.[17]
Decongestants: over-the-counter medications that are marketed to treat cough and cold symptoms are composed of a variety of active ingredients which will differ depending on a given preparation. Some common ingredients include: antihistamines (e.g., brompheniramine, chlorpheniramine, diphenhydramine, and doxylamine) that can exert antimuscarinic toxic effects, sympathomimetics (including phenylephrine and pseudoephedrine), dextromethorphan, and guaifenesin. The understanding of dextromethorphan’s complex pharmacologic activity continues to evolve, but is thought to include: antagonism of N-methyl-D-aspartate receptors; agonism of neuronal sigma-1 receptors, inhibition of the reuptake of peripheral norepinephrine and serotonin neurotransmitters.[18] It is sold as a cough suppressant, but it can also be used as a drug of abuse - producing psychologic effects at larger than recommended doses. These include euphoria, confusion, and agitation but can progress to dissociative out-of-body experiences and even hallucinations and psychosis at higher doses. Other neurologic manifestations can include nystagmus, mydriasis, loss of motor coordination, ataxia, coma, and seizures. Other physical manifestations of dextromethorphan toxicity include: tachycardia, elevated blood pressure, diaphoresis, muscle rigidity, and rhabdomyolysis. Guaifenesin is marketed as an expectorant that helps to thin and clear mucus and chest congestion. It is not generally thought to be dangerous by itself - with vomiting considered the primary symptom at high doses. It is important to remember that anti-inflammatory medications, including acetaminophen and ibuprofen, may be included in some over-the-counter cough and cold medications.
Heavy metals: ingestion of arsenic-containing ant killer, or lead from the environment, can lead to heavy metal toxicity. Heavy metal exposure causes a wide range of psychiatric and physical (cardiovascular, renal, reproductive, GI, neurologic) sequelae.
Toxic plants or mushrooms: plant or mushroom poisoning occurs after intentional or accidental consumption of toxic plant parts (including fruits, berries, leaves, stems, and roots) or mushrooms. Most cause no or mild clinical consequences; however, several plant and mushroom chemicals can result in severe symptoms, organ dysfunction, and even death. Toxins found in plants and mushrooms include gastrotoxins, hepatotoxins, cardiotoxins (usually cardiac glycosides), neurotoxins (which can produce hallucinations, peripheral neuropathy, neuromuscular weakness, or seizures), dermatotoxins (which cause rashes), hemotoxins (which can produce coagulopathy or bone marrow suppression), and systemic toxins (e.g., anticholinergics or cholinergics).
Cyanide: this toxin inactivates cytochrome oxidase, thereby inhibiting cellular respiration. It affects virtually all body tissues, producing a range of progressive neurologic, GI, and cardiopulmonary symptoms.[19]
Serotonin syndrome: this can occur from exposure to any medication that increases the intrasynaptic serotonin concentration in the CNS. It manifests clinically with the triad of neuromuscular excitation, autonomic effects, and altered mental status. Causative agents include antidepressants (selective serotonin-reuptake inhibitors, venlafaxine, clomipramine, imipramine), opioids (meperidine, tramadol, fentanyl, dextromethorphan), MAOIs, amphetamines, lithium, and tryptophan.[20]
Dopamine-receptor blockers: blockade of the dopamine-2 receptor can cause effects from simple akathisia to tardive dyskinesia. Neurophysiologic changes may be mild or severe and can result in neuroleptic malignant syndrome. Causative medications include phenothiazines, atypical antipsychotics, and antiemetics.
Theophylline: toxicity is related to release of endogenous catecholamines, leading to stimulation of beta-adrenoceptors, and adenosine antagonism. The most common effects are a sinus tachycardia and tremors, although a range of atrial and ventricular arrhythmias may also occur, including ventricular tachycardia, or cardiac arrest with ventricular fibrillation or pulseless electrical activity. Hypotension, hyperpnea, GI symptoms, and CNS excitation may also occur.[21]
Organic solvents: toxicity may come from hypoxia, seizures, hepatotoxicity, or renal damage. Certain hydrocarbons can lead to sensitization of the myocardium to catecholamines, and may lead to unstable ventricular dysrhythmias. Methylene chloride is metabolized to carbon monoxide and may present a special problem by producing occult carbon monoxide poisoning.
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