Overdosage of acetaminophen is common and can produce severe hepatotoxicity. The incidence of hepatotoxicity in adults and adolescents has been reported to be 10 times higher than in children younger than 5 years. In the latter group, less than 0.1% develop hepatotoxicity after acetaminophen overdose. In children, toxicity most commonly results from repeated overdosage arising from confusion about the age-appropriate dose, use of multiple products that contain acetaminophen, or use of adult suppositories.
Acetaminophen is normally metabolized in the liver. A small percentage of the drug goes through a pathway leading to a toxic metabolite. Normally, this electrophilic reactant is removed harmlessly by conjugation with glutathione. In overdosage, the supply of glutathione becomes exhausted, and the metabolite may bind covalently to components of liver cells to produce necrosis. Some authors have proposed that therapeutic doses of acetaminophen may be toxic to children with depleted glutathione stores. However, there is no evidence that administration of therapeutic doses can cause toxicity, and only a few inadequate case reports have been made in this regard.
Treatment is to administer acetylcysteine. It may be administered either orally or intravenously. Consultation on difficult cases may be obtained from your regional poison control center or the Rocky Mountain Poison and Drug Center (1-800-525-6115). Blood levels should be obtained 4 hours after ingestion or as soon as possible thereafter and plotted on Figure 13–1. The nomogram is used only for acute ingestion, not repeated ingestions. Acetylcysteine is administered to patients whose acetaminophen levels plot in the toxic range on the nomogram. Acetylcysteine is effective even when given more than 24 hours after ingestion, although it is most effective when given within 8 hours postingestion.
Semilogarithmic plot of plasma acetaminophen levels versus time. (Modified with permission from Rumack BH, Matthew H: Acetaminophen poisoning and toxicity. Pediatrics 1975 Jun;55(6):871–876.)
For children weighing 40 kg or more, IV acetylcysteine should be administered as a loading dose of 150 mg/kg administered over 15–60 min; followed by a second infusion of 50 mg/kg over 4 hours, and then a third infusion of 100 mg/kg over 16 hours.
For patients weighing less than 40 kg, IV acetylcysteine must have less dilution to avoid hyponatremia (a dosage calculator is also available at http://www.acetadote.com) (Table 13–2). Patient-tailored therapy is critical when utilizing the IV “20-hour” protocol and those patients who still have acetaminophen measurable and/or elevated aspartate transaminase/alanine transaminase (AST/ALT) may need treatment beyond the 20 hours called for in the product insert.
Table 13–2.Intravenous acetylcysteine administration dosing. ||Download (.pdf) Table 13–2.Intravenous acetylcysteine administration dosing.
|Body Weight ||First 150 mg/kg in 5% Dextrose in 60 min ||Second 50 mg/kg in 5% Dextrose in 4 h ||Third 100 mg/kg in 5% Dextrose in 16 h |
|(kg) ||(lb) ||Acetadote (mL) ||Diluent (mL) ||Acetadote (mL) ||Diluent (mL) ||Acetadote (mL) ||Diluent (mL) |
|100 ||220 ||75 ||200 ||25 ||500 ||50 ||1000 |
|90 ||198 ||67.5 ||200 ||22.5 ||500 ||45 ||1000 |
|80 ||176 ||60 ||200 ||20 ||500 ||40 ||1000 |
|70 ||154 ||52.5 ||200 ||17.5 ||500 ||35 ||1000 |
|60 ||132 ||45 ||200 ||15 ||500 ||30 ||1000 |
|50 ||110 ||37.5 ||200 ||12.5 ||500 ||25 ||1000 |
|40 ||88 ||30 ||200 ||10 ||500 ||20 ||1000 |
|30 ||66 ||22.5 ||100 ||7.5 ||250 ||15 ||500 |
|25 ||55 ||18.75 ||100 ||6.25 ||250 ||12.5 ||500 |
|20 ||44 ||15 ||60 ||5 ||140 ||10 ||280 |
|15 ||33 ||11.25 ||45 ||3.75 ||105 ||7.5 ||210 |
|10 ||22 ||7.5 ||30 ||2.5 ||70 ||5 ||140 |
The oral form of acetylcysteine can also be given and is equally efficacious as intravenous. Consult your regional poison center for dosing recommendations.
AST–serum glutamic oxaloacetic transaminase (AST–SGOT), ALT–serum glutamic pyruvic transaminase (ALT–SGPT), serum bilirubin, and plasma prothrombin time should be followed daily. Significant abnormalities of liver function may not peak until 72–96 hours after ingestion.
The Food and Drug Administration (FDA) has recommended the use of a single concentration of liquid acetaminophen (160 mg/5 mL) for both infants and children to avoid confusion with previous infant formulations. Therapeutic weight-based dosing is 10–15 mg/kg every 4–6 hours.
dose and duration: past, present and future. Clin Toxicol (Phila) Feb 2012;50(2):91–98. doi: 10.3109/15563650.2012.659252.22320209.
Alcoholic beverages, tinctures, cosmetics, mouthwashes, food extracts (vanilla, almond, etc.), rubbing alcohol, and hand sanitizers are common sources of poisoning in children. Alcohol is even available in powdered form for mixing and consumption. Concomitant exposure to other depressant drugs increases the seriousness of the intoxication. In most states, alcohol levels of 50–80 mg/dL are considered compatible with impaired faculties, and levels of 80–100 mg/dL are considered evidence of intoxication. (Blood levels cited here are for adults; comparable figures for children are not available.)
Recent erroneous information regarding hand sanitizers has indicated that a “lick” following application on the hand could cause toxicity in children. In fact, this is not the case, but because these hand sanitizers contain 62% ethanol, toxicity following ingestion is very possible. Potential blood ethanol concentration following consumption of a 62% solution in a 10-kg child is calculated as follows:
In a patient weighing 10 kg, the distribution into total body water (Vd) will be 6 L—this is the amount of the body water into which the ethanol will be distributed.
Based on these calculations, a 10-kg child consuming 0.5 oz would have a concentration of 122.5 mg/dL; a 20-kg child consuming 1 oz would have a concentration of 122.5 mg/dL; a 30-kg child consuming 1 oz would have a concentration of 81.7 mg/dL; and a 70-kg adult consuming 1 oz would have a concentration of 35 mg/dL.
One “pump” from a hand sanitizer bottle dispenses approximately 2.5 mL of the product. If ingested, this amount (containing 62% ethanol) would create a blood ethanol concentration as follows:
In a 10-kg child: 23.1 mg/dL.
In a 20-kg child: 11.6 mg/dL.
In a 30-kg child: 7.7 mg/dL.
Children show a change in sensorium with blood levels as low as 10–20 mg/dL and any child displaying such changes should be seen immediately. Although a “lick” or a “drop” is unlikely to produce toxicity, the accuracy of the history should be considered when determining whether or not to see a child.
Complete absorption of alcohol requires 30 minutes to 6 hours, depending on the volume, the presence of food, and the time spent in consuming the alcohol. The rate of metabolic degradation is constant (about 20 mg/h in an adult). Absolute ethanol, 1 mL/kg, results in a peak blood level of about 100 mg/dL in 1 hour after ingestion. Acute intoxication and chronic alcoholism increase the risk of subarachnoid hemorrhage.
Management of hypoglycemia and acidosis is usually the only measure required. Start an IV drip of D5W or D10W if blood glucose is less than 60 mg/dL. Death is usually caused by respiratory failure. In severe cases, cerebral edema may occur and should be appropriately treated. Secondary evaluation for traumatic injury should also be performed.
AMPHETAMINES & RELATED DRUGS (STIMULANTS, METHAMPHETAMINE, MDMA)
Amphetamine, 3,4-methylenedioxy-N-methylamphetamine (MDMA), and methamphetamine poisoning is common because of the widespread availability of “diet pills” and the use of “ecstasy,” “speed,” “crank,” “crystal,” and “ice” by adolescents. (Care must be taken in the interpretation of slang terms because they have multiple meanings.) A new cause of stimulant poisoning is drugs for treating attention-deficit/hyperactivity disorder, such as methylphenidate. There are also newer designer drugs, synthetic cannabinoids (“spice, K2”) and MPDV or mephedrone (“bath salts, plant food”), which cause effects similar to stimulants.
Symptoms include central nervous system (CNS) stimulation, anxiety, hyperactivity, hyperpyrexia, diaphoresis, hypertension, abdominal cramps, nausea and vomiting, and inability to void urine. MDMA has been associated with hyponatremia and seizures. Severe cases often include rhabdomyolysis. A toxic psychosis indistinguishable from paranoid schizophrenia may occur. Methamphetamine laboratories in homes are a potential cause of childhood exposure to a variety of hazardous and toxic substances. Maternal use and the effect on the fetus as well as exposures of young children are a continuing problem.
Chronic amphetamine users develop tolerance; more than 1500 mg of IV methamphetamine can be used daily. Hyperactivity, disorganization, and euphoria are followed by exhaustion, depression, and coma lasting 2–3 days. Heavy users, taking more than 100 mg/day, have restlessness, incoordination of thought, insomnia, nervousness, irritability, and visual hallucinations. Psychosis may be precipitated by the chronic administration of high doses. Chronic MDMA use can lead to serotonin depletion, which can manifest as depression, weakness, tremors, GI complaints, and suicidal thoughts.
The treatment of choice are benzodiazepines, such as lorazepam, titrated in increments to effect. Very large total doses may be needed. In cases of extreme agitation or hallucinations, droperidol (0.1 mg/kg per dose) or haloperidol (up to 0.1 mg/kg) parenterally has been used. Hyperthermia should be aggressively controlled. Chronic users may be withdrawn rapidly from amphetamines. If amphetamine–barbiturate combination tablets have been used, the barbiturates must be withdrawn gradually to prevent withdrawal seizures. Psychiatric treatment should be provided.
et al: Toxicity of amphetamines: an update. Arch Toxicol 2012;86(8):1167–1231
BZ: Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review. Drug Alcohol
Depend May;1;2015;150:1–13. doi: 10.1016/j.drugalcdep.2015.01.040.25724076.
et al: Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines. J Med Toxicol 2012;8(1):15–32
Intoxication from local anesthetics may be associated with CNS stimulation, acidosis, delirium, ataxia, shock, convulsions, and death. Methemoglobinemia has been reported following local mouth or dental analgesia, typically with benzocaine or prilocaine. It has also been reported with use of topical preparations in infants. The maximum recommended dose for subcutaneous (SQ) infiltration of lidocaine is 4.5 mg/kg (Table 13–3). The temptation to exceed this dose in procedures lasting a long time is great and may result in inadvertent overdosage. PO application of viscous lidocaine may produce toxicity and the FDA has published warnings against its use for teething. Hypercapnia may lower the seizure threshold to locally injected anesthetics.
Table 13–3.Pharmacologic properties of local anesthetics. ||Download (.pdf) Table 13–3.Pharmacologic properties of local anesthetics.
| ||pKa ||Protein Binding (%) ||Relative Potency ||Duration of Action ||Approximate Maximum Allowable Subcutaneous Dose (mg/kg) |
|Chloroprocaine ||9.3 ||Unknown ||Intermediate ||Short ||10 |
|Cocaine ||8.7 ||92 ||Low ||Medium ||3 |
|Procaine ||9.1 ||5 ||Low ||Short ||10 |
|Tetracaine ||8.4 ||76 ||High ||Long ||3 |
|Bupivacaine ||8.1 ||95 ||High ||Long ||2 |
|Etidocaine ||7.9 ||95 ||High ||Long ||4 |
|Lidocaine ||7.8 ||70 ||Low ||Medium ||4.5 |
|Mepivacaine ||7.9 ||75 ||Intermediate ||Medium ||4.5 |
|Prilocaine ||8.0 ||40 ||Intermediate ||Medium ||8 |
|Ropivacaine ||8.2 ||95 ||Intermediate ||Long ||3 |
Local anesthetics used in obstetrics cross the placental barrier and are not efficiently metabolized by the fetal liver. Mepivacaine, lidocaine, and bupivacaine can cause fetal bradycardia, neonatal depression, and death. Accidental injection of mepivacaine into the head of the fetus during paracervical anesthesia has caused neonatal asphyxia, cyanosis, acidosis, bradycardia, convulsions, and death.
If the anesthetic has been ingested, mucous membranes should be cleansed carefully, topical applications should be cleaned and irrigated. Oxygen administration is indicated, with assisted ventilation if necessary. Symptomatic methemoglobinemia is treated with methylene blue, 1%, 0.2 mL/kg (1–2 mg/kg per dose, IV) over 5–10 minutes; this should promptly relieve the cyanosis. Acidosis may be treated with sodium bicarbonate, hypotension with vasopressors, seizures with benzodiazepines, and bradycardia with atropine. In the event of cardiac arrest, 20% lipid (fat) emulsion therapy should be initiated. Initial 1.5 mL/kg bolus over 1 minute, followed by 0.25 mL/kg/min for up to 20–30 minutes until spontaneous circulation returns. Repeat bolus can be considered. Lipid emulsion therapy has been used with varying success for other pharmaceutical toxicity. Therapeutic levels of mepivacaine, lidocaine, and procaine are less than 5 mg/mL.
et al: Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning. Clin Toxicol (Phila) Sep 8, 2016;1–25. doi: 10.1080/15563650.2016.1214275.27608281.
et al: Systematic review of the effect of intravenous lipid emulsion therapy for non-local anesthetics toxicity. Clin Toxicol (Phila) Mar 2016;54(3):194–221. doi: 10.3109/15563650.2015.1126286.26852931.
et al: Multicenter retrospective evaluation of oral benzocaine
exposure in children. Vet Hum Toxicol 2000;42:228
ANTIHISTAMINES & COUGH & COLD PREPARATIONS
The use of cough and cold preparations in young children has recently been called into question due to potential toxicity. In 2007, manufacturers voluntarily removed preparations intended for use in children younger than 4 from the market. Considerable controversy remains as to the toxicity of these medications if they are used according to labeled directions and an evaluation of the cases on file at FDA stated, “In the cases judged to be therapeutic intent or unknown intent, several factors appeared to contribute to the administration of an overdosage: administration of two medicines containing the same ingredients, failure to use a measuring device, use of wrong units (mL vs teaspoon), use of an adult product, use of the wrong product because of product misidentification, and two or more caregivers administering the same medication. In the cases of nontherapeutic intent, circumstances involved attempts at sedation and several included apparent attempts of overt child abuse and were under investigation by law enforcement authorities.”
Medications included in this area are antihistamine (brompheniramine, chlorpheniramine, diphenhydramine, doxylamine), antitussive (dextromethorphan), expectorant (guaifenesin), and decongestant (pseudoephedrine, phenylephrine). Although antihistamines typically cause CNS depression, children often react paradoxically with excitement, hallucinations, delirium, ataxia, tremors, and convulsions followed by CNS depression, respiratory failure, or cardiovascular collapse. Anticholinergic effects such as dry mouth, fixed dilated pupils, flushed face, fever, and hallucinations may be prominent. Dextromethorphan can lead to altered mentation, hallucinations, nystagmus, and serotonin toxicity in large ingestions or when taken with other serotonergic agents.
They are absorbed rapidly and metabolized by the liver, lungs, and kidneys. A potentially toxic dose is 10–50 mg/kg of the most commonly used antihistamines, but toxic reactions have occurred at much lower doses.
Benzodiazepines, such as lorazepam (0.1 mg/kg IV), can be used to control seizures or agitation. Physostigmine (0.5–2.0 mg IV, slowly administered) dramatically reverses the central and peripheral anticholinergic effects of antihistamines; however the duration of effect is short. It can also be used only for diagnostic purposes in patients without cardiotoxicity or seizures. Cardiac dysrhythmias and hypotension should be treated with normal saline at a dose of 10–20 mg/kg and a vasopressor if necessary. Sodium bicarbonate may be useful if there is QRS widening at a dose of 1–2 mEq/kg, making certain that the arterial pH does not exceed 7.55. Forced diuresis is not helpful. Exchange transfusion was reported to be effective in one case.
et al: Pediatric fatalities associated with over the counter (nonprescription) cough and cold medications. Ann Emerg Med 2009;53:411–417
IM: Adverse events associated with pediatric exposures to dextromethorphan
. Clin Toxicol (Phila) Oct 13, 2016;18. doi: 10.1080/15563650.2016.124080327736263.
et al: Out-of-hospital medication errors among young children in the United States, 2002–2012. Pediatrics 2014:124(5):867–879
BARBITURATES & BENZODIAZEPINES
Barbiturates are rarely used today, and have mostly been replaced with benzodiazepines for their use in seizures or for sedation. The toxic effects of barbiturates include confusion, poor coordination, coma, miotic or fixed dilated pupils, and respiratory depression. Respiratory acidosis is commonly associated with pulmonary atelectasis, and hypotension. Ingestion of more than 6 mg/kg of long-acting or 3 mg/kg of short-acting barbiturates is usually toxic. Benzodiazepines typically cause CNS depression and lethargy without hemodynamic compromise in unintentional oral ingestions. Large oral overdoses, co-ingestants with other sedative/hypnotics, or iatrogenic IV overdose can cause cardiovascular or respiratory depression.
Careful, conservative management with emphasis on maintaining a clear airway, adequate ventilation, and control of hypotension is critical. Urinary alkalinization and the use of multiple-dose charcoal may decrease the elimination half-life of phenobarbital but have not been shown to alter the clinical course. Flumazenil can be considered if severe CNS depression or respiratory depression develops after benzodiazepine overdose using a dose of 0.01 mg/kg IV (maximum dose of 0.2 mg).
et al: Benzodiazepine poisoning: clinical and pharmacological considerations and treatment. Drug Saf 1991;6(4):247
BELLADONNA ALKALOIDS (ATROPINE, JIMSONWEED, POTATO LEAVES, SCOPOLAMINE, STRAMONIUM)
The effects of anticholinergic (or antimuscarinic) compounds include dry mouth; thirst; decreased sweating with hot, dry, red skin; high fever; and tachycardia that may be preceded by bradycardia. The pupils are dilated, and vision is blurred. Speech and swallowing may be impaired. Hallucinations, delirium, and coma are common. Leukocytosis may occur, confusing the diagnosis.
Atropinism has been caused by normal doses of atropine or homatropine eye drops. Many common plants and over-the-counter medications (antihistamines and sleep aids) contain belladonna alkaloids or medications with anticholinergic effects.
Gastric emptying is slowed by anticholinergics, so that gastric decontamination may be useful even if delayed. If the patient is awake and showing no signs or symptoms, administration of activated charcoal can be considered. Benzodiazepines should be administered to control agitation. Bolus dosing should be given in escalating doses, and high doses may be required. Physostigmine (0.5–2.0 mg IV, administered slowly) dramatically reverses the central and peripheral signs of atropinism but should be used only as a diagnostic agent, but clinical improvement is not sustained. Physostigmine infusions have been safely administered. It should not be given in patients with cardiotoxicity or seizures. Hyperthermia should be aggressively controlled. Catheterization may be needed if the patient cannot void.
et al: A comparison of physostigmine
and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med 2000;35:374
et al. Belladoona alkaloid intoxication: the 10-year experience of a large tertiary care pediatric hospital. Am J Ther 2013 Nov, 20
et al: Use of a physostigmine
continuous infusion for the treatment of severe and recurrent antimuscarinic toxicity in a mixed drug overdose. J Med Toxicol 2014;10(2):205–209
β-BLOCKERS & CALCIUM CHANNEL BLOCKERS
β-Blockers and calcium channel blockers primarily cause cardiovascular toxicity; bradycardia, hypotension, and various degrees of heart block; cardiac dysrhythmias may develop. Severe toxicity can cause CNS depression (typically due to hemodynamic collapse). The β-blocker propranolol is associated with seizures and also QRS widening. Hyperglycemia can be seen with calcium channel blocker toxicity.
Initial stabilization with IV fluid resuscitation with isotonic fluids should be initiated. Atropine can be given for symptomatic bradycardia. Calcium at doses of 20 mg/kg and repeated as needed should be administered. Infusions of calcium chloride 10%, 0.2–0.5 mL/kg/h, can be started after initial bolus dosing. Glucagon can be administered; 50–100 mcg/kg (5–10 mg) IV bolus followed by 2–5 mg/h infusion if patient improves. Vasopressors such as epinephrine or norepinephrine should be started if patient continues to be hypotensive and bradycardic. In patients who are severely poisoned and refractory to these initial measures, hyperinsulinemia euglycemic therapy should be started. Your regional poison control center or medical toxicologist should be contacted for further details on dosing of this therapy.
JC: Pharmacology, pathophysiology and management of calcium channel blocker and beta-blocker toxicity. Toxicol Rev 2004;23(4):223–238
JS: High-dose insulin
therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol (Phila) 2011;49(4):277–283
M: Treatment for calcium channel blocker poisoning: a systematic review. Clin Toxicol (Phila) Nov 2014;52(9):926–944. doi: 10.3109/15563650.2014.965827.25283255.
Carbon monoxide is a colorless, odorless gas produced from burning various fuels. The degree of toxicity correlates well with the carboxyhemoglobin concentration taken soon after acute exposure but not after oxygen has been given or when there has been some time since exposure. Onset of symptoms may be more rapid and more severe if the patient lives at a high altitude, has a high respiratory rate (ie, infants), is pregnant, or has myocardial insufficiency or lung disease. Normal blood may contain up to 5% carboxyhemoglobin (10% in smokers). Neonates may have elevated carboxyhemoglobin levels due to breakdown of bilirubin.
Presenting symptoms can include nonspecific symptoms such as headache or flu-like illness. Other effects include confusion, unsteadiness, and coma. Proteinuria, glycosuria, elevated serum aminotransferase levels, or ECG changes may be present in the acute phase. Other signs may include improvement of symptoms after leaving the exposed environment. Permanent cardiac, liver, renal, or CNS damage occurs occasionally. The outcome of severe poisoning may be complete recovery, vegetative state, or any degree of mental injury between these extremes. The primary delayed mental deficits are neuropsychiatric.
The biologic half-life of carbon monoxide on room air is approximately 200–300 minutes; on 100% oxygen, it is 60–90 minutes. Thus, 100% oxygen should be administered immediately. Hyperbaric oxygen therapy at 2.0–2.5 atm of oxygen shortens the half-life to 30 minutes. The use of hyperbaric oxygen therapy for delayed neurologic sequelae can be considered, but remains controversial and the primary focus of care should be acute resuscitation and stabilization. After the level has been reduced to near zero, therapy is aimed at the nonspecific sequelae of anoxia. Evaluation of the source should be performed before the patient returns to the home.
et al: Hyperbaric oxygen
for carbon monoxide poisoning. Cochrane Database Syst Rev 2011;13(4):CD002041
KJ: Characteristics and outcome of children with carbon monoxide poisoning with and without smoke exposure referred for hyperbaric oxygen
therapy. Pediatr Emerg Care 2000;3:151
Both acids and alkalis can burn the skin, mucous membranes, and eyes. Painful swallowing, mucous membrane burns, hematemesis, and abdominal pain can occur after ingestion. Respiratory distress may be due to edema of the epiglottis, pulmonary edema resulting from inhalation of fumes, or pneumonia. In severe cases, mediastinitis, intercurrent infections, or shock can occur. Perforation of the esophagus or stomach is rare. Residual lesions include esophageal, gastric, and pyloric strictures as well as scars of the cornea, skin, and oropharynx.
1. Acids (Hydrochloric, Hydrofluoric, Nitric, & Sulfuric Acids; Sodium Bisulfate)
Strong acids are commonly found in metal and toilet bowl cleaners, batteries, and other products, and can lead to coagulative necrosis.
Hydrofluoric acid is a particularly dangerous acid. Dermal exposure creates a penetrating burn that can progress for hours or days. Large dermal exposure or small ingestion may produce life-threatening hypocalcemia.
2. Bases (Clinitest Tablets, Clorox, Drano, Liquid-Plumr, Purex, Sani-Clor—Examine the Label or Call a Poison Center to Determine Contents)
Alkalis can produce more severe injuries than acids, resulting in liquefactive necrosis. Some substances, such as Clinitest tablets or Drano, are quite toxic, whereas the chlorinated bleaches (3%–6% solutions of sodium hypochlorite) are usually not toxic. When sodium hypochlorite comes in contact with acid in the stomach, hypochlorous acid, which is very irritating to the mucous membranes and skin, is formed. Chlorinated bleaches, when mixed with a strong acid (toilet bowl cleaners) or ammonia, may produce irritating chlorine or chloramine gas, which can cause serious lung injury if inhaled in a closed space (eg, bathroom).
Emetics and lavage are contraindicated. Can be diluted with water, but take care not to induce emesis by excessive fluid administration. Neutralization should not be attempted. Burned areas of the skin, mucous membranes, or eyes should be washed with copious amounts of warm water. The eye should be irrigated for at least 20–30 minutes. Ophthalmologic consultation should be obtained for all alkaline eye burns. Opioids for pain may be needed. An endotracheal tube may be required to alleviate laryngeal edema. The absence of oral lesions does not rule out the possibility of laryngeal or esophageal burns following granular alkali ingestion. Esophagoscopy should be performed if the patient has significant burns or difficulty in swallowing, drooling, vomiting or stridor. Evidence is not conclusive, but corticosteroids may be helpful in significant esophageal burns. Antibiotics may be needed if mediastinitis develops, but they should not be used prophylactically.
Hydrofluoric acid burns on skin are treated with 10% calcium gluconate gel or calcium gluconate infusion. Severe exposure may require large doses of IV calcium or cardiovascular monitoring. Therapy should be guided by calcium levels, the ECG, and clinical signs.
AP: Caustic ingestions-symptoms as predictors of esophageal injury. Am J Dis Child 1984;138:863–865
et al: Caustic esophageal strictures in children: 30 years’ experience. J Pediatr Surg 2003;338:828
et al: High doses of methylprednisone in the management of caustic esophageal burns. Pediatrics 2014;133(6):E1518–E1524
CENTRAL α2-ADRENERGIC AGONIST
Central α2-adrenergic agonists are common over-the-counter and prescribed medication. The imidazolines are found in nasal decongestants and eye drops to relieve redness. Clonidine and guanfacine are used most commonly to treat attention deficit hyperactivity disorder or hypertension. Dexmedetomidine is an IV central α2-adrenergic agonist used for sedation. These medications exert their effects by stimulating presynaptic α2-adrenergic receptors in the brain, resulting in decreased norepinephrine release and decreased sympathetic outflow.
Most common effects are related to CNS sedation. They can present similar to an opioid toxidrome with miosis, CNS depression, and respiratory depression. Other common effects include bradycardia and hypotension.
If the patient becomes obtunded, or has inability to protect their airway, intubation may be indicated. Naloxone has been tried to reverse signs of toxicity with varying success. Symptomatic bradycardia can be treated with IV fluid resuscitation or atropine. Hypotension should be treated initially with IV fluid resuscitation, followed by vasopressors if needed.
et al: Unintentional pediatric exposures to central alpha-2 agonists reported to the National Poison Data System. J Pediatr 2014;164(1):149–152
Cocaine is absorbed intranasally or via inhalation or ingestion. Effects are noted almost immediately when the drug is taken intravenously or smoked. Peak effects are delayed for about an hour when the drug is taken orally or nasally. Cocaine prevents the reuptake of endogenous catecholamines, thereby causing an initial sympathetic discharge, followed by catechol depletion after chronic abuse.
A local anesthetic and vasoconstrictor, cocaine is also a potent stimulant to both the CNS and the cardiovascular system. The initial tachycardia, hyperpnea, hypertension, and stimulation of the CNS are often followed by coma, seizures, hypotension, and respiratory depression. In severe cases of overdose, various dysrhythmias may be seen, including sinus tachycardia, atrial arrhythmias, premature ventricular contractions, bigeminy, and ventricular tachycardia and fibrillation. If large doses are taken intravenously, cardiac failure, dysrhythmias, rhabdomyolysis, or hyperthermia may result in death.
In addition to those poisoned through recreational use of cocaine, others are at risk of overdose. A “body stuffer” is one who quickly ingests the drug, usually poorly wrapped, to avoid discovery. A “body packer” wraps the drug carefully for prolonged transport. A stuffer typically manifests toxicity within hours of ingestion; a packer is asymptomatic unless the package ruptures, usually days later. Newborns of cocaine using mothers may continue to have seizures for months after birth. Cocaine can be contaminated with levamisole, which can lead to systemic vasculitis and agranulocytosis.
Activated charcoal should be considered in body stuffers, and whole bowel irrigation may be useful in cases of body packers. Testing for cocaine in blood or plasma is generally not clinically useful, but a qualitative analysis of the urine may aid in confirming the diagnosis. Cocaine metabolites can be positive in urine for 3–5 days after exposure. For severe cases, an ECG is indicated. In suspected cases of body packing, radiographs of the GI tract may show multiple packets, but are usually not helpful for identifying stuffers. Seizures are treated with IV benzodiazepines such as lorazepam, titrated to response. Hypotension is treated with standard agents. Because cocaine abuse may deplete norepinephrine, an indirect agent such as dopamine may be less effective than a direct agent such as norepinephrine. Agitation is best treated with a benzodiazepine.
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exposure as a risk factor for later developmental outcomes. JAMA 2001;286:46
et al: “Drug mules” as a radiological challenge: sensitivity and specificity in identifying internal cocaine
in body packers, body pushers, and body stuffers by computer tomography, plain radiography and Lodox. Eur J Radiol 2012;81(10):2518–2526
et al: Cocaine
use and the likelihood of nonfatal myocardial infarction and stroke: data from the Third National Health and Nutrition Examination Survey. Circulation 2001;103:502
SJ: Passive multistate surveillance for neutropenia after use of cocaine
or heroin possibly contaminated with levamisole. Ann Emerg Med Apr;2013;61(4):468–474. doi: 10.1016/j.annemergmed.2012.10.036.23374417.
COSMETICS & RELATED PRODUCTS
Cosmetics and personal care products are the most frequently involved substance in pediatric patients younger than 5 years (14% of all calls reported to NPDS) and second most common in all ages. Luckily, most of them do not cause significant toxicity. The relative toxicities of commonly ingested products in this group are listed in Table 13–4.
Table 13–4.Relative toxicities of cosmetics and similar products. ||Download (.pdf) Table 13–4.Relative toxicities of cosmetics and similar products.
Permanent wave neutralizers
Fingernail polish remover
Metallic hair dyes
Home permanent wave lotion
Hair tonic (alcoholic)
Cologne, toilet water
Vegetable hair dye
Hair dressing (nonalcoholic)
Hand lotion or cream
Cyclic antidepressants (eg, amitriptyline, imipramine) have a very low ratio of toxic to therapeutic doses, and even a moderate overdose can have serious effects. Diphenhydramine toxicity can have similarly symptoms as cyclic antidepressants and is more readily available.
Cyclic antidepressant overdosage can cause a progression of illness beginning with sudden onset coma within 1–2 hours of ingestion, followed by convulsions, hypotension, and dysrhythmias. Usually significant clinical effects occur within hours after the ingestion, may be life-threatening and require rapid intervention. One agent, amoxapine, differs in that it causes fewer cardiovascular complications, but it is associated with a higher incidence of seizures.
After a significant ingestion, decontamination should include administration of activated charcoal unless the patient is already symptomatic. Benzodiazepines should be given for seizures.
An ECG should be obtained in all patients. A QRS interval greater than 100 milliseconds specifically identifies patients at risk to develop seizures and dysrhythmias. If dysrhythmias or tachycardia are demonstrated, the patient should be admitted and monitored until free of irregularity for 24 hours. The onset of dysrhythmias is rare beyond 24 hours after ingestion.
Alkalinization with sodium bicarbonate (0.5–1.0 mEq/kg IV) may dramatically reverse ventricular dysrhythmias and narrow the QRS interval. If intubated, hyperventilation may be helpful. Lidocaine may be added for treatment of arrhythmias. Bolus administration of sodium bicarbonate (1–2 mEq/kg) is recommended for all patients with QRS widening to above 120 milliseconds and for those with significant dysrhythmias, to achieve a pH of 7.5–7.6. Lipid-emulsion therapy has been used in the setting of cardiotoxicity.
Cyclic antidepressants block the reuptake of catecholamines, thereby producing initial hypertension followed by hypotension. Vasopressors (such as norepinephrine, 0.1–1 mcg/kg/min, titrated to response) are generally effective. Diuresis and hemodialysis are not effective and physostigmine is contraindicated.
et al: “Lipid rescue” for tricyclic antidepressant cardiotoxicity. J Emerg Med 2012;43(3):465–467
et al: Tricyclic antidepressant overdose: a review. Emerg Med J 2001;18:236
et al: Tricyclic antidepressant poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2007;45(3):203–333
DIGITALIS & OTHER CARDIAC GLYCOSIDES
Acute toxicity is typically the result of incorrect dosing, and chronic toxicity is due to unrecognized renal insufficiency. Clinical features include nausea, vomiting, diarrhea, headache, delirium, confusion, and, occasionally, coma. Cardiac dysrhythmias typically involve bradydysrhythmias, but every type of dysrhythmia has been reported in digitalis intoxication, including atrial fibrillation, paroxysmal atrial tachycardia, and atrial flutter. Transplacental intoxication by digitalis has been reported. Cardiac glycosides, such as yellow oleander and foxglove, can cause digitalis toxicity in large ingestions as well.
If patient is awake and alert, consider administering activated charcoal. Potassium is contraindicated in acute overdosage unless there is laboratory evidence of hypokalemia. In acute overdosage, hyperkalemia is more common. Hypokalemia is common in chronic toxicity.
The patient must be monitored carefully for ECG changes. Bradycardias have been treated with atropine. Phenytoin, lidocaine, magnesium salts (not in renal failure), amiodarone, and bretylium have been used to correct arrhythmias.
Definitive treatment is with digoxin immune Fab (ovine) (Digifab). Indications for its use include hypotension or any dysrhythmia, typically ventricular dysrhythmias and progressive bradydysrhythmias, or hyperkalemia (K > 5) in an acute overdose. Elevated T waves indicate high potassium and may be an indication for digoxin immune Fab (DigiFab) use. Techniques of determining dosage and indications related to levels, when available are described in product literature. High doses of digoxin immune Fab may be needed in cardiac glycoside overdose. Extracorporeal treatment is not indicated for digoxin poisoning.
JB: Extracorporeal treatment for digoxin
poisoning: systematic review and recommendations from the EXTRIP Workgroup. Clin Toxicol (Phila) 2016;54(2):103–114. doi:10.3109/15563650.2015.1118488.26795743.
S: Management of yellow oleander poisoning. Clin Toxicol (Phila) 2009;47(3):206–212
et al: The use of digoxin-specific Fab fragments for severe digitalis intoxication in children. N Engl J Med 1992;326:17–39
DIPHENOXYLATE WITH ATROPINE (LOMOTIL) & LOPERAMIDE (IMODIUM)
Loperamide (Imodium) has largely replaced Lomotil and does not produce significant toxicity. Ingestions of up to 0.4 mg/kg can safely be managed at home. Both acute and chronic abuse of loperamide has been associated with cardiac dysrhythmias.
Lomotil is still widely available and contains diphenoxylate hydrochloride, a synthetic narcotic, and atropine sulfate. Small amounts are potentially lethal in children; it is contraindicated in children younger than 2 years. Early signs of intoxication with this preparation result from its anticholinergic effect and consist of fever, facial flushing, tachypnea, and lethargy. However, the miotic effect of the narcotic predominates. Later, hypothermia, increasing CNS depression, and loss of the facial flush occur. Seizures are probably secondary to hypoxia. Any ingestion of Lomotil must be observed for 8–12 hours as delayed respiratory arrest may be encountered.
Prolonged monitoring (24 hours) with pulse oximetry and careful attention to airway is sufficient in most cases. Naloxone hydrochloride (0.4–2.0 mg IV in children and adults) should be given for signs of respiratory depression. Repeated doses may be required because the duration of action of diphenoxylate is considerably longer than that of naloxone.
W: Notes from the field: cardiac dysrhythmias after loperamide
abuse–New York, 2008-2016. MMWR Morb Mortal Wkly Rep Nov 18, 2016;65(45):1276–1277. doi: 10.15585/mmwr.mm6545a7.27855148.
et al: Diphenoxylate-atropine (Lomotil) overdose in children: an update. Pediatrics 1991;87:694
CP: Epidemiologic trends in loperamide
abuse and misuse. Ann Emerg Med Nov 4, 2016. doi: 10.1016/j.annemergmed.2016.08.444.27823872.
DISINFECTANTS & DEODORIZERS
Naphthalene is now less commonly found in mothballs, disinfectants, and deodorizers. Naphthalene’s toxicity is often not fully appreciated. It is absorbed not only when ingested but also through the skin and lungs. It is potentially hazardous to store baby clothes in naphthalene, because baby oil is an excellent solvent that may increase dermal absorption. Metabolic products of naphthalene may cause severe hemolytic anemia, similar to that due to primaquine toxicity, 2–7 days after ingestion. Other physical findings include vomiting, diarrhea, jaundice, oliguria, anuria, coma, and convulsions.
If the patient is awake and alert, consideration can be given for administering activated charcoal. Methemoglobinemia and hemolysis may occur 24–48 hours after ingestion. Life-threatening hemolysis and anemia may require blood transfusions.
S: Mothball toxicity. Pediatr Clin North Am 1986;33:369
2. p-Dichlorobenzene, Phenolic Acids, & Others
Disinfectants and deodorizers containing p-dichlorobenzene or sodium sulfate are now more commonly found in mothballs and much less toxic than those containing naphthalene. They typically cause mucous membrane irritation and GI upset. Camphor can cause seizures after ingestion.
Disinfectants containing phenolic acids are highly toxic, especially if they contain a borate ion. Phenol precipitates tissue proteins and can also cause systemic toxicity resulting in respiratory alkalosis followed by metabolic acidosis. Some phenols cause methemoglobinemia. Phenol is readily absorbed topically and from the GI tract, causing local injury, diffuse capillary damage and, in some cases, methemoglobinemia. Pentachlorophenol, which has been used in terminal rinsing of diapers, has caused infant fatalities by causing metabolic acidosis.
The toxicity of alkalis, quaternary ammonium compounds, pine oil, and halogenated disinfectants varies with the concentration of active ingredients. Wick deodorizers are usually of moderate toxicity. Iodophor disinfectants are the safest. Spray deodorizers are not usually toxic, because a child is not likely to swallow a very large dose.
Signs and symptoms of acute quaternary ammonium compound ingestion include diaphoresis, strong irritation, thirst, vomiting, diarrhea, cyanosis, hyperactivity, coma, convulsions, hypotension, abdominal pain, and pulmonary edema. Acute liver or renal failure may develop later.
Mainstay to phenol toxicity is symptomatic and supportive care. The metabolic acidosis must be managed carefully. Anticonvulsants or measures to treat shock may be needed.
Because phenols are absorbed through the skin, exposed areas should be irrigated copiously with water. Undiluted polyethylene glycol may be a useful solvent as well.
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FA: Survival after acute benzalkonium chloride poisoning. Hum Toxicol 1988;7:191
toxicity following cutaneous exposure to creolin®
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DISK-SHAPED “BUTTON” BATTERIES
Small, flat, smooth disk-shaped batteries measure between 10 and 25 mm in diameter. About 69% of them pass through the GI tract in 48 hours and 85% in 72 hours. Some may become entrapped and lead to caustic injury.
Batteries impacted in the esophagus may cause symptoms of refusal to take food, increased salivation, vomiting with or without blood, and pain or discomfort. Aspiration into the trachea may also occur. Fatalities have been reported in association with esophageal perforation or fistula formation.
When a history of disk battery ingestion is obtained, radiographs of the entire respiratory tract and GI tract should be taken immediately so that the battery can be located and the proper therapy determined.
Any disk battery ingestion should be referred for evaluation and radiographs. If the disk battery is located in the esophagus, it must be removed immediately. Any prolonged time in the esophagus can cause injury, leading to esophageal perforation, or erosion/fistula formation into a blood vessel. Consultation with GI or surgical subspecialty is recommended.
Location of the disk battery below the esophagus has been rarely associated with tissue damage, but the course is benign in most cases. Perforated Meckel diverticulum has been the major complication. It may take as long as 7 days for spontaneous passage to occur, and lack of movement in the GI tract may not require removal in an asymptomatic patient.
Some researchers have suggested repeated radiographs and surgical intervention if passage of the battery pauses, but this approach may be excessive. Batteries that have opened in the GI tract have been rarely associated with some toxicity due to mercury, but the patients have recovered.
Asymptomatic patients, with known time of ingestion, and with disk batteries past the lower esophageal junction may simply be observed and stools examined for passage of the battery. If the battery has not passed within 7 days or if the patient becomes symptomatic, radiographs should be repeated. If the battery has come apart or appears not to be moving, a purgative, enema, or nonabsorbable intestinal lavage solution should be considered. If these methods are unsuccessful, surgical intervention may be required. Levels of heavy metals (mainly mercury) should be measured in patients in whom the battery has opened or symptoms have developed.
Centers for Disease Control and Prevention (CDC): Injuries from batteries among children aged < 13 years—United States, 1995–2010. MMWR 2012;61(34):661–666
et al: Severe esophageal injuries caused by accidental button battery ingestion in children. J Emerg Trauma Shock 2014;7(4):316–321
et al: Pediatric battery-related emergency department visits in the United States, 1990–2009. Pediatrics 2012;129(6):1111
ETHYLENE GLYCOL & METHANOL
Ethylene glycol and methanol are the toxic alcohols. The primary source of ethylene glycol is antifreeze, whereas methanol is present in windshield wiper fluid and also as an ethanol denaturant. Ethylene glycol causes severe metabolic acidosis and renal failure. Methanol causes metabolic acidosis and blindness. Onset of symptoms with both agents occurs within several hours after ingestion, longer if ethanol was ingested simultaneously. Rarely, glycol ethers can cause acidosis, but only in the setting of large ingestions.
The primary treatment is to block the enzyme alcohol dehydrogenase, which converts both agents to their toxic metabolites. This is accomplished with fomepizole (loading dose of 15 mg/kg). Ethanol could be used if fomepizole is unavailable, but can lead to CNS depression and hypoglycemia in children. Hemodialysis is indicated with high concentrations, persistent metabolic acidosis, or end-organ toxicity.
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ingestion: prompt recognition and management in the emergency department. Emerg Med Pract Sep 2016;18(9):1–20
for the treatment of pediatric ethylene and diethylene glycol, butoxyethanol, and methanol poisonings. Clin Toxicol (Phila) 2010;48(5):401–406
et al: Severe poisoning after accidental pediatric ingestion of glycol ethers. Pediatrics 2012;130(4):e1026–e1029
et al: Fomepizole
versus ethanol in the treatment of acute methanol poisoning: Comparison of clinical effectiveness in a mass poisoning outbreak. Clin Toxicol (Phila) 2015;53(8):797–806. doi: 10.3109/15563650.2015.1059946.26109326.
γ-HYDROXYBUTYRATE, γ-BUTYROLACTONE, BUTANEDIOL, FLUNITRAZEPAM, & KETAMINE
γ-Hydroxybutyrate (GHB), γ-butyrolactone (GBL), and butanediol have become popular drugs of abuse in adolescents and adults. GHB is a CNS depressant that is structurally similar to the inhibitory neurotransmitter γ-aminobutyric acid. GBL and butanediol are converted in the body to GHB. These drugs cause deep but short-lived coma; the coma often lasts only 1–4 hours. Flunitrazepam (Rohypnol) is a benzodiazepine that can lead to somnolence and CNS depression. Ketamine is a disassociative anesthetic that can also cause rapid onset altered mental status and CNS depression. Although all of these drugs are often referred to as “date rape” drugs, ethanol is the most commonly used substance in drug-facilitated assault.
Treatment consists of supportive care with close attention to airway and endotracheal intubation if respiratory depression or decreased gag reflex complicates the poisoning. Atropine has been used successfully for symptomatic bradycardia.
Withdrawal from GHB, GBL, or butanediol can cause several days of extreme agitation, hallucination, or tachycardia. Treatment with high doses of sedatives such as benzodiazepines or with butyrophenones (eg, haloperidol or droperidol) or secobarbital may be needed for several days.
et al: The clinical toxicology of gamma-hydroxybutyrate, gamma-butyrolactone and 1,4-butanediol. Clin Toxicol (Phila) 2012;50(6):458–470
HYDROCARBONS (BENZENE, CHARCOAL LIGHTER FLUID, GASOLINE, KEROSENE, PETROLEUM DISTILLATES, TURPENTINE)
Ingestion of hydrocarbons may cause irritation of mucous membranes, CNS depression, or aspiration pneumonitis. Hydrocarbons with high volatility, low viscosity, and low surface tension have more risk or aspiration pneumonitis. Benzene, kerosene, red seal oil furniture polish, and some of the essential oils are very dangerous. A dose exceeding 1 mL/kg is likely to cause CNS depression. A history of coughing or choking, as well as vomiting, suggests aspiration with resulting hydrocarbon pneumonia. Several weeks may be required for full resolution of hydrocarbon pneumonia. Pulmonary edema and hemorrhage, blebs, cardiac dilation and dysrhythmias, hepatosplenomegaly, proteinuria, and hematuria can occur following large overdoses.
Both emetics and lavage should be avoided. Initial supportive care, observing for CNS depression or respiratory distress. Patients who are asymptomatic with a normal chest x-ray (CXR) after 8 hours are unlikely to develop significant illness; however, patients who develop respiratory symptoms, hypoxia, or CXR changes should be observed.
Epinephrine should be avoided with halogenated hydrocarbons because it may affect an already sensitized myocardium. The usefulness of corticosteroids is debated, and antibiotics should be reserved for patients with infections (pneumonitis can cause fevers and infiltrates). Oxygen and mist are helpful. Surfactant therapy for severe hydrocarbon-induced lung injury has been used successfully. Extracorporeal membrane oxygenation has been successful in at least two cases of failure with standard therapy.
AG: Respiratory complications following hydrocarbon aspiration in children. Pediatr Pulmonol Jun 2016;51(6):560–569. doi: 10.1002/ppul.23392.26910771.
et al: Early administration of intratracheal surfactant (calfactant
) after hydrocarbon aspiration. Pediatrics 2011;127(6):e1600–e1604
LM: Hydrocarbon toxicity: a review. Clin Toxicol (Phila) 2014;52(5):479–489
Most exposures in children do not produce symptoms. In one study, for example, children ingesting up to 2.4 g remained asymptomatic. When symptoms occur, the most common are abdominal pain, vomiting, drowsiness, and lethargy. In rare cases, apnea (especially in young children), seizures, metabolic acidosis, and CNS depression leading to coma have occurred.
If a child has ingested less than 100 mg/kg, supportive care for GI upset is typically all that is needed. When the ingested amount is more than 400 mg/kg, seizures or CNS depression may occur. There is no specific antidote. Neither alkalinization of the urine nor hemodialysis is helpful in elimination of ibuprofen. However, hemodialysis may be needed to correct acid-base abnormalities.
et al: NSAID-induced nephrotoxicity from the fetus to the child. Drug Safety 2001;242:9
et al: Massive ibuprofen
overdose requiring extracorporeal membrane oxygenation for cardiovascular support. Pediatr Crit Care Med 2007;8:180–182
INSECT STINGS (BEE, WASP, & HORNET)
Insect stings are painful but not usually dangerous; however, death from anaphylaxis may occur. Bee venom has hemolytic, neurotoxic, and histamine-like activities that can on rare occasion cause hemoglobinuria and severe anaphylactoid reactions. Massive envenomation from numerous stings may cause hemolysis, rhabdomyolysis, and shock leading to multiple-organ failure.
The physician should remove the stinger, taking care not to squeeze the attached venom sac. For allergic reactions, epinephrine 1:1000 solution, 0.01 mL/kg, should be administered IV or SQ above the site of the sting. Albuterol, corticosteroids, and diphenhydramine are useful ancillary drugs but have no immediate effect. Ephedrine or antihistamines may be used for 2 or 3 days to prevent recurrence of symptoms.
For the more usual stings, cold compresses, aspirin, and diphenhydramine (1 mg/kg PO) are sufficient.
et al: Effectiveness of specific immunotherapy in the treatment of hymenoptera venom hypersensitivity: a meta-analysis. Clin Ther 2000;22:351
et al: Mass envenomations by honey bees and wasps. West J Med 1999;170:223
The petroleum distillates or other organic solvents used in these products are often as toxic as the insecticide itself.
1. Chlorinated Hydrocarbons (eg, Aldrin, Carbinol, Chlordane, DDT, Dieldrin, Endrin, Heptachlor, Lindane, Toxaphene)
Signs of intoxication include salivation, GI irritability, abdominal pain, vomiting, diarrhea, CNS depression, and convulsions. Inhalation exposure causes irritation of the eyes, nose, and throat; blurred vision; cough; and pulmonary edema.
Chlorinated hydrocarbons are absorbed through the skin, respiratory tract, and GI tract. Decontamination of skin with soap and evacuation of the stomach contents should be considered in significant ingestions. All contaminated clothing should be removed. Convulsions should be treated with diazepam (0.1–0.3 mg/kg IV). Epinephrine should cautiously be used as it may precipitate cardiac arrhythmias.
2. Organophosphate (Cholinesterase-Inhibiting) Insecticides (eg, Chlorothion, Co-Ral, DFP, Diazinon, Malathion, Paraoxon, Parathion, Phosdrin, TEPP, Thio-TEPP)
Dizziness, headache, blurred vision, miosis, tearing, salivation, nausea, vomiting, diarrhea, hyperglycemia, cyanosis, sense of constriction of the chest, dyspnea, sweating, weakness, muscular twitching, convulsions, loss of reflexes and sphincter control, and coma can occur.
The clinical findings are the result of cholinesterase inhibition, which causes an accumulation of acetylcholine. The onset of symptoms occurs within 12 hours of the exposure. Red cell cholinesterase levels should be measured as soon as possible. (Some normal individuals have a low serum cholinesterase level.) Normal values vary in different laboratories. In general, a decrease of red cell cholinesterase to below 25% of normal indicates significant exposure.
Repeated low-grade exposure may result in sudden, acute toxic reactions. This syndrome usually occurs after repeated household spraying rather than agricultural exposure.
Although all organophosphates act by inhibiting cholinesterase activity, they vary greatly in their toxicity. Parathion, for example, is 100 times more toxic than malathion. Toxicity is influenced by the specific compound, type of formulation (liquid or solid), vehicle, and route of absorption (lungs, skin, or GI tract).
Decontamination of skin, nails, hair, and clothing with soapy water is extremely important. Atropine plus a cholinesterase reactivator, pralidoxime, is an antidote for organophosphate insecticide poisoning. After assessment and management of the ABCs, atropine should be given and repeated every few minutes until airway secretions diminish. An appropriate starting dose of atropine is 2–4 mg IV in an adult and 0.05 mg/kg in a child. The patient should receive enough atropine to stop secretions (mydriasis in not an appropriate stopping point). Severe poisoning may require gram quantities of atropine administered over 24 hours. Glycopyrrolate can also be used if delirium occurs.
Because atropine antagonizes the muscarinic parasympathetic effects of the organophosphates but does not affect the nicotinic receptor, it does not improve muscular weakness. Pralidoxime should also be given immediately in more severe cases and repeated every 6–12 hours as needed (25–50 mg/kg diluted to 5% and infused over 5–30 minutes at a rate of no > 500 mg/min). Pralidoxime should be used in addition to—not in place of—atropine if red cell cholinesterase is less than 25% of normal. Pralidoxime is most useful within 48 hours after the exposure but has shown some effects 2–6 days later. Morphine, theophylline, aminophylline, succinylcholine, and tranquilizers of the reserpine and phenothiazine types are contraindicated. Hyperglycemia is common in severe poisonings.
3. Carbamates (eg, Carbaryl, Sevin, Zectran)
Carbamate insecticides are reversible inhibitors of cholinesterase. The signs and symptoms of intoxication are similar to those associated with organophosphate poisoning but are generally less severe. Atropine titrated to effect is sufficient treatment. In combined exposures to organophosphates, give atropine but reserve pralidoxime for cases in which the red cell cholinesterase is depressed below 25% of normal or marked effects of nicotinic receptor stimulation are present.
4. Botanical Insecticides (eg, Black Flag Bug Killer, Black Leaf CPR Insect Killer, Flit Aerosol House & Garden Insect Killer, French’s Flea Powder, Raid)
Allergic reactions, asthma-like symptoms, coma, and convulsions have been reported. Pyrethrins, allethrin, and rotenone do not commonly cause significant toxicity. Antihistamines, short-acting benzodiazepines, and atropine are helpful as symptomatic treatment.
Y: Index of suspicion: case 1. Organophosphate intoxication. Pediatr Rev 2000;21:205
CK: Organophosphate and carbamate poisoning. Emerg Med Clin North Am Feb;2015;33(1):133–151. doi: 10.1016/j.emc.2014.09.010.25455666.
et al: Pesticide exposure in children. Pediatrics 2012;130(6):e1765–e1788
Iron has many different formulations with varying amounts of elemental iron. Three common formulations include ferrous fumarate (33%), ferrous sulfate (20%), and ferrous gluconate (12%). Typically, doses of more than 20 mg/kg of elemental iron will cause symptoms. Five stages of intoxication may occur in iron poisoning: (1) Hemorrhagic gastroenteritis, which occurs 30–60 minutes after ingestion and may be associated with shock, acidosis, coagulation defects, and coma; this phase usually lasts 4–6 hours; (2) phase of improvement, lasting 2–12 hours, during which patient looks better; (3) delayed shock, which may occur 12–48 hours after ingestion; Metabolic acidosis, fever, leukocytosis, and coma may also be present; (4) liver damage with hepatic failure; and (5) residual pyloric stenosis, which may develop about 4 weeks after the ingestion.
Once iron is absorbed from the GI tract, it is not normally eliminated in feces but may be partially excreted in the urine, giving it a red color prior to chelation. A reddish discoloration of the urine suggests a serum iron level greater than 350 mg/dL, but is neither sensitive nor specific.
GI decontamination is based on clinical assessment. The patient should be referred to a health care facility if symptomatic or if the history indicates toxic amounts (typically > 20 mg/kg of elemental iron). Gastric lavage and whole bowel irrigation should be considered in potentially life-threatening overdoses.
Shock is treated in the usual manner. Deferoxamine, a specific chelating agent for iron, is a useful adjunct in the treatment of severe iron poisoning. It forms a soluble complex that is excreted in the urine. It is contraindicated in patients with renal failure unless dialysis can be used. IV deferoxamine chelation therapy should be instituted if the patient has a metabolic acidosis, persistent symptoms, and a serum iron determination cannot be obtained readily, or if the peak serum iron exceeds 500 mcg/dL at 4–5 hours after ingestion.
Deferoxamine should not be delayed until serum iron levels are available in serious cases of poisoning. IV administration is indicated if the patient is in shock, in which case it should be given at a dosage of 10–15 mg/kg/h. Infusion rates up to 35 mg/kg/h have been used in life-threatening poisonings. Rapid IV administration can cause hypotension, facial flushing, urticaria, tachycardia, and shock. Deferoxamine, 90 mg/kg IM every 8 hours (maximum, 1 g), may be given if IV access cannot be established, but the procedure is painful. The indications for discontinuation of deferoxamine have not been clearly delineated. Generally, it can be stopped after 12–24 hours if the acidosis has resolved and the patient is improving. Use of deferoxamine for greater than 24 hours has been associated with acute respiratory distress syndrome (ARDS).
Hemodialysis, peritoneal dialysis, or exchange transfusion can be used to increase the excretion of the dialyzable complex. Urine output should be monitored and urine sediment examined for evidence of renal tubular damage. Initial laboratory studies should include blood typing and cross-matching; total protein; serum iron, sodium, potassium, and chloride; Pco2; pH; and liver function tests. Serum iron levels fall rapidly even if deferoxamine is not given.
After the acute episode, liver function studies and an upper GI series are indicated to rule out residual damage.
et al: Child abuse by intentional iron poisoning presenting as shock and persistent acidosis. Pediatrics 2003;111:197
C: Iron poisoning: a literature-based review of epidemiology, diagnosis, and management. Pediatr Emerg Care Oct 2011;27(10):978–985. doi: 10.1097/PEC.0b013e3182302604.21975503.
et al: Iron poisoning in young children: association with the birth of a sibling. CMAJ 2003;165:1539
Lead poisoning (plumbism) causes vague symptoms, including weakness, irritability, weight loss, vomiting, personality changes, ataxia, constipation, headache, and colicky abdominal pain. Late manifestations consist of developmental delays, convulsions, and coma associated with increased intracranial pressure, which is a medical emergency.
Plumbism usually occurs insidiously in children younger than age 5 years. The most likely sources of lead include flaking leaded paint, artist’s paints, fruit tree sprays, solder, brass alloys, home-glazed pottery, fumes from burning batteries and foreign country remedies. Only paint containing less than 1% lead is safe for interior use (eg, furniture, toys). Repetitive ingestions of small amounts of lead are far more serious than a single massive exposure. Toxic effects are likely to occur if more than 0.5 mg of lead per day is absorbed. In the United States, lead levels continue to decline and are more common abroad, so particular attention should be paid to immigrant and refugee populations or use of foreign remedies.
Blood lead levels are used to assess the severity of exposure. A complete blood count and serum ferritin concentration should be obtained; iron deficiency increases absorption of lead. Glycosuria, proteinuria, hematuria, and aminoaciduria occur frequently. Abnormal capillary blood lead levels should be repeated with venous sample in asymptomatic patients to rule out laboratory error. Specimens must be meticulously obtained in acid-washed metal-free containers. A normocytic, slightly hypochromic anemia with basophilic stippling of the red cells and reticulocytosis may be present in plumbism. Stippling of red blood cells is absent in cases involving only recent ingestion.
The cerebrospinal fluid (CSF) protein is elevated, and the white cell count usually is less than 100 cells/mL. CSF pressure may be elevated in patients with encephalopathy; lumbar punctures must be performed cautiously to prevent herniation.
Refer to the CDC guidelines for the most up to date recommendations on lead treatment and evaluation. There is no “safe” concentration of lead. Removing the source of exposure is the most important initial treatment to toxicity. Succimer is an orally administered chelator approved for use in children and reported to be as efficacious as calcium edetate. Succimer should be initiated in asymptomatic children at blood lead levels over 45 mcg/dL. The initial dose is 10 mg/kg (350 mg/m2) every 8 hours for 5 days. The same dose is then given every 12 hours for 14 days. At least 2 weeks should elapse between courses. Blood lead levels increase somewhat (ie, rebound) after discontinuation of therapy. Courses of dimercaprol/BAL (300–450 mg/m2/day) and calcium sodium edetate/CaNa2EDTA (1000–1500 mg/m2/day) should be considered in symptomatic children or levels over 70 mcg/dL.
Encephalopathy associated with cerebral edema needs to be treated with standard measures. Anticonvulsants may be needed. A high-calcium, high-phosphorus diet and large doses of vitamin D may remove lead from the blood by depositing it in the bones. A public health team should evaluate the source of the lead. Necessary corrections should be completed before the child is returned home.
et al: Lead screening and prevalence of blood lead levels in children aged 1–2 years—Child Blood Lead Surveillance System, United States, 2002–2010 and National Health and Nutrition Examination Survey, United States, 1999–2010. MMWR Surveill Summ 2014 Sep 12;63(Suppl 2):36–42
et al: Treatment of lead-exposed children trial group: the effect of chelation therapy with succimer
on neuropsychological development in children exposed to lead. N Engl J Med 2001;344:1421
Although not strictly toxic, small magnets have been found to cause bowel obstructions in children. Recent cases have resulted in warnings and a recall by the Consumer Product Safety Commission following intestinal perforation and death in a 20-month-old child. Obstruction may occur following ingestion of as few as two magnets. Radiographs should be obtained and surgical consultation may be indicated.
CR: Magnetic Foreign Body Ingestions. Pediatr Emerg Care Oct 2016;32(10):698–702. doi: 10.1097/PEC.0000000000000927.27749667.
et al: Ingested magnets and gastrointestinal complications. J Paediatr Child Health 2007:43:497
Marijuana is becoming more readily available as over half of US states have allowed medical marijuana, and several more allowing recreational marijuana. It is also available for use in multiple forms including high concentrated products (dabs, butters, waxes), vaporizers and infused edible products that all can have high concentrations of THC (tetrahydrocannabinol), the most psychoactive component.
Young children who ingest edible products can have a range of symptoms. These symptoms can be mild such as sleepiness and ataxia. However, more severe symptoms can develop including CNS depression, coma, and respiratory depression requiring mechanical ventilation. Symptoms in young children can sometimes last over 24 hours. Inhalational use/abuse of high concentrated products can lead to tachycardia, hypertension, agitation, and acute psychosis. Symptomatic and supportive care is mainstay for treatment: supporting cardiorespiratory adverse effects, and treating psychosis and agitation with benzodiazepines or antipsychotics.
et al: The implications of marijuana legalization in Colorado. JAMA Jan 20, 2015;313(3):241–242. doi: 10.1001/jama.2014.17057
et al: Unintentional pediatric exposures to marijuana in Colorado, 2009-2015. JAMA Pediatr Sep 6, 2016;170(9):e160971. doi: 10.1001/jamapediatrics.2016.0971.
Toxic mushrooms are often difficult to distinguish from edible varieties. Contact a poison control center to obtain identification assistance. Symptoms vary with the species ingested, time of year, stage of maturity, quantity eaten, method of preparation, and interval since ingestion. Most mushrooms lead to early GI symptoms and do not lead to significant toxicity; however, some can be fatal and so it is critical to determine from poison center experts what mushroom may have been involved. A mushroom that is toxic to one individual may not be toxic to another. Drinking alcohol and eating certain mushrooms may cause a reaction similar to that seen with disulfiram and alcohol. Cooking destroys some toxins but not the deadly one produced by Amanita phalloides, which is responsible for 90% of deaths due to mushroom poisoning. Mushroom toxins are absorbed relatively slowly. Onset of symptoms within 2 hours of ingestion suggests muscarinic toxin, whereas a delay of symptoms for 6–48 hours after ingestion strongly suggests Amanita (amanitin) poisoning. Patients who have ingested A phalloides may relapse and die of hepatic or renal failure following initial improvement.
Treatment of mushroom poisoning is highly specialized and consultation with a poison center is highly recommended. Supportive care with IV fluid resuscitation may be needed due to emesis and diarrhea. If the patient has muscarinic signs, give atropine, 0.05 mg/kg IM (0.02 mg/kg in toddlers), and repeat as needed (usually every 30 minutes) to keep the patient atropinized. Atropine, however, is used only when cholinergic effects are present and not for all mushrooms. Hypoglycemia is most likely to occur in patients with delayed onset of symptoms. Try to identify the mushroom if the patient is symptomatic. Local botanical gardens, university departments of botany, and societies of mycologists may be able to help. Supportive care is usually all that is needed; however, in the case of A phalloides, silibinin, biliary drainage, and aggressive management of fluids including hemodialysis may be indicated. Currently, there is clinical trial using intravenous silibinin for amatoxin induced hepatic failure, protocol available on http://www.clinicaltrials.gov.
et al: Liver transplantation in three family members after Amanita phalloides
mushroom poisoning. Transplant Proc 2002;34:3313
NITRITES, NITRATES, ANILINE, PENTACHLOROPHENOL, & DINITROPHENOL
Nausea, vertigo, vomiting, cyanosis (methemoglobinemia), cramping, abdominal pain, tachycardia, cardiovascular collapse, tachypnea, coma, shock, convulsions, and death are possible manifestations of nitrite or nitrate poisoning.
Nitrite and nitrate compounds found in the home include amyl nitrite, butyl nitrates, isobutyl nitrates, nitroglycerin, pentaerythritol tetranitrate, sodium nitrite, nitrobenzene, and phenazopyridine. Pentachlorophenol and dinitrophenol, which are found in wood preservatives, produce methemoglobinemia and acidosis because of uncoupling of oxidative phosphorylation. Headache, dizziness, and bradycardia have been reported. High concentrations of nitrites in well water or spinach have been the most common cause of nitrite-induced methemoglobinemia. Other common causes of methemoglobinemia include local anesthetics. Symptoms do not usually occur until 15%–50% of the hemoglobin has been converted to methemoglobin. A rapid test is to compare a drop of normal blood with the patient’s blood on a dry filter paper. Brown discoloration of the patient’s blood indicates a methemoglobin level of more than 15%.
In the setting of a recent ingestion, consider administering activated charcoal if the patient is awake and alert. Decontaminate affected skin with soap and water. Oxygen and artificial respiration may be needed. If the blood methemoglobin level exceeds 30%, or if levels cannot be obtained and the patient is symptomatic, give a 1% solution of methylene blue (0.2 mL/kg IV) over 5–10 minutes. Avoid perivascular infiltration, because it causes necrosis of the skin and subcutaneous tissues. A dramatic change in the degree of cyanosis should occur. Transfusion is occasionally necessary. If reflex bradycardia occurs, atropine should be used.
et al: Methemoglobinemia: a review and recommendations for management. J Cardiothorac Vasc Anesth 2014;28(4):1055–1059
DM: 2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J Med Toxicol Sep 2011;7(3):205–212. doi: 10.1007/s13181-011-0162-6.21739343.
Opioid and opiate-related medical problems may include drug addiction, withdrawal in a newborn infant, and accidental overdoses. They can vary in onset of action and duration of action. Opioids, including heroin, methadone, morphine, and codeine are routinely detected on most urine drug assays. However, many of the more commonly used oral opiates, such as oxycodone, hydrocodone, buprenorphine are not detected on standard urine drug assays. Use of fentanyl analogs (carfentanyl) and fentanyl contamination in heroin and other drugs of abuse have been reported which can lead to severe toxicity and death. Care should be directed on clinical suspicion of ingestion.
Narcotic-addicted adolescents often have other medical problems, including cellulitis, abscesses, thrombophlebitis, tetanus, infective endocarditis, human immunodeficiency virus (HIV) infection, tuberculosis, hepatitis, malaria, foreign body emboli, thrombosis of pulmonary arterioles, diabetes mellitus, obstetric complications, nephropathy, and peptic ulcer.
Opioids and opiates can cause respiratory depression, stridor, coma, increased oropharyngeal secretions, sinus bradycardia, and urinary retention. Pulmonary edema rarely occurs in children but has been reported; deaths usually result from aspiration of gastric contents, respiratory arrest, and cerebral edema. Convulsions may occur with propoxyphene overdosage.
The indication for the administration of naloxone is respiratory depression. Although suggested doses for naloxone hydrochloride range from 0.01 to 0.1 mg/kg, it is generally unnecessary to calculate the dosage on this basis. This extremely safe antidote should be given in sufficient quantity to reverse opioid-binding sites. Doses as low as 0.04 mg have been affective for reversal. For children younger than 1 year, one ampoule (0.4 mg) should be given initially; if there is no response, five more ampoules (2 mg) should be given rapidly. Older children should be given 0.4–0.8 mg, followed by 2–4 mg if there is no response. An improvement in respiratory status may be followed by respiratory depression, because the antagonist’s duration of action is less than 1 hour. Neonates poisoned in utero may require 10–30 mg/kg to reverse the effect. Naloxone infusion can be used for persistent symptoms. Depending on the formulation, some exposures (such as buprenorphine and methadone) may need to be observed for 24 hours due to the duration of effect.
B. Withdrawal in the Addict
Benzodiazepines such as diazepam (10 mg every 6 hours PO) and antiemetics have been recommended for the treatment of mild narcotic withdrawal in ambulatory adolescents. Management of withdrawal in the confirmed addict may be accomplished with the administration of clonidine, by substitution with methadone or buprenorphine, or with reintroduction of the original addicting agent, if available through a supervised drug withdrawal program. A tapered course over 3 weeks will accomplish this goal. Death rarely, if ever, occurs. The abrupt discontinuation of narcotics (cold turkey method) is not recommended and may cause severe physical withdrawal signs.
C. Withdrawal in the Newborn
A newborn infant in opioid withdrawal is usually small for gestational age and demonstrates yawning, sneezing, decreased Moro reflex, hunger but uncoordinated sucking action, jitteriness, tremor, constant movement, a shrill protracted cry, increased tendon reflexes, convulsions, vomiting, fever, watery diarrhea, cyanosis, dehydration, vasomotor instability, seizure, and collapse.
The onset of symptoms commonly begins in the first 48 hours but may be delayed as long as 8 days, depending on the timing of the mother’s last fix and her predelivery medication. The diagnosis can be confirmed easily by identifying the narcotic in the urine of the mother and the newborn.
Several treatment methods have been suggested for narcotic withdrawal in the newborn. Phenobarbital (8 mg/kg/day IM or PO in four doses for 4 days and then reduced by one-third every 2 days as signs decrease) may be continued for as long as 3 weeks. Methadone may be necessary in those infants with congenital methadone addiction who are not controlled in their withdrawal by large doses of phenobarbital. Dosage should be 0.5 mg/kg/day in two divided doses but can be increased gradually as needed. After control of the symptoms is achieved, the dose may be tapered over 4 weeks.
It is unclear whether prophylactic treatment with these drugs decreases the complication rate. The mortality rate of untreated narcotic withdrawal in the newborn may be as high as 45%.
RC: The underrecognized toll of prescription opioid abuse on young children. Ann Emerg Med 2009;53:419–424
DR: National trends in hospitalizations for opioid poisonings among children and adolescents, 1997 to 2012. JAMA Pediatr Dec 1, 2016;170(12):1195–1201. doi: 10.1001/jamapediatrics.2016.2154.27802492.
law enforcement submissions and increases in synthetic opioid-involved overdose deaths–27 States, 2013-2014. MMWR Aug 26, 2016;65(33):837–843. doi: 10.15585/mmwr.mm6533a2.27560775.
P: Neonatal abstinence syndrome. Pediatrics Aug 2014;134(2):e547–e561. doi: 10.1542/peds.2013-3524.25070299.
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and non-pharmaceutical fentanyls. Drug Alcohol
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ORAL ANTI-DIABETICS (SULFONYLUREAS, METFORMIN)
Noninsulin hypoglycemic and antidiabetic medications include α-glucosidase inhibitors, biguanides (metformin), dipeptidyl peptidase-4 inhibitors (-gliptins), glucagon-like peptides (-glutide), meglitinides (-glinide), sodium glucose transporter inhibitors (-flovzin), sulfonylureas, and thiazolidinediones (-glitazone). They are all used to treat hyperglycemia in diabetics. Sulfonylureas (acetohexamide, glipizide, glyburide) are the only oral hypoglycemic that actively secretes endogenous insulin and can cause hypoglycemia. The meglitinides (nateglinide, repaglinide) have scarce reports of hypoglycemia. Biguanides can rarely cause lactic acidosis in acute large overdose or in renal failure. Hypoglycemic symptoms are variable but can include altered mental status, diaphoresis, seizures, or coma.
Children with possible exposures to sulfonylureas should be admitted for 12–24 hours. Mainstay of treatment is treating hypoglycemia. If patient is awake and alert, with minimal symptoms, PO glucose can be given. With more severe hypoglycemia or symptomatic, immediate treatment with 0.5–1 g/kg IV dextrose bolus should be administered. With repeated episodes of hypoglycemia, once euglycemia is achieved, octreotide should be considered at 1 mcg/kg SC/IV every 6–8 hours as needed for hypoglycemia. Metformin toxicity should be treated supportively, and hemodialysis may be needed for severe acid-base abnormalities or patients with renal failure.
for the treatment of sulfonylurea poisoning. Clin Toxicol (Phila) 2012;50(9):795–804
J: Continuous octreotide
infusion for sulfonylurea-induced hypoglycemia in a toddler. J Emerg Med Dec 2013;45(6):e209–e213. doi: 10.1016/j.jemermed.2013.05.016.23827165.
KR: Hypoglycemia in pediatric sulfonylurea poisoning: an 8-year poison center retrospective study. Pediatrics 2011;127(6):e1558–e1564
ANTIPSYCHOTICS (TYPICAL & ATYPICAL)
Typical antipsychotics include butyrophenones (droperidol, haloperidol), and the phenothiazines (promethazine, chlorpromazine, thioridazine). Atypical antipsychotics include benzapines (clozapine, olanzapine, quetiapine) and indoles (risperidone, ziprasidone).
Episodes characterized by torticollis, stiffening of the body, spasticity, poor speech, catatonia, and inability to communicate although conscious are typical manifestations. Extrapyramidal crises may represent idiosyncratic reactions and are aggravated by dehydration. The signs and symptoms occur most often in children who have received prochlorperazine. They are commonly mistaken for psychotic episodes. These extrapyramidal symptoms are more common with typical antipsychotics (butyrophenones, phenothiazines).
Lethargy and deep prolonged coma are the most common symptoms seen in toxicity. Of the typical antipsychotics, promazine, chlorpromazine, and prochlorperazine are the drugs most likely to cause respiratory depression and precipitous drops in blood pressure. Risperidone and quetiapine are atypical antipsychotics that can cause CNS depression. Clozapine, olanzapine, and quetiapine most commonly cause hypotension and also antimuscarinic symptoms. QTc prolongation can occur, most commonly with thioridazine and ziprasidone. Occasionally, paradoxic hyperactivity and extrapyramidal signs as well as hyperglycemia and acetonemia are present. Seizures are uncommon.
C. Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome is a rare idiosyncratic complication that may be lethal. It is a syndrome involving mental status change (confusion, coma), motor abnormalities (lead pipe rigidity, clonus), and autonomic dysfunction (tachycardia, hyperpyrexia). Typically it occurs 1–2 weeks after starting therapy, can occur at therapeutic doses, and may last for several days.
Extrapyramidal signs are alleviated within minutes by the slow IV administration of diphenhydramine, 1–2 mg/kg (maximum, 50 mg), or benztropine mesylate, 1–2 mg IV (1 mg/min). No other treatment is usually indicated. Further doses may be needed.
Patients with overdoses should receive conservative supportive care. Hypotension may be treated with standard agents, starting with isotonic saline administration. Agitation is best treated with benzodiazepines. Neuroleptic malignant syndrome is treated by discontinuing the drug, and treating hyperthermia and agitation aggressively with benzodiazepines and sedation. In refractory cases, bromocriptine can be considered, although the evidence for its use is not clear.
AM: Overdose of atypical antipsychotics: clinical presentation, mechanisms of toxicity and management. CNS Drugs 2012;26(7):601–611
RG: Toxicology and overdose of atypical antipsychotics. J Emerg Med 2012;43(5):906–913
Many common ornamental, garden, and wild plants are potentially toxic. Only in a few cases will small amounts of a plant cause severe illness or death. Table 13–5 lists the most toxic plants, symptoms and signs of poisoning, and treatment. Contact your poison control center for assistance with identification.
Table 13–5.Poisoning due to plants.a ||Download (.pdf) Table 13–5.Poisoning due to plants.a
| ||Symptoms and Signs ||Treatment |
|Arum family: Caladium, Dieffenbachia, calla lily, dumb cane (oxalic acid) ||Burning of mucous membranes and airway obstruction secondary to edema caused by calcium oxalate crystals. ||Accessible areas should be thoroughly washed. Corticosteroids relieve airway obstruction. Apply cold packs to affected mucous membranes. |
|Castor bean plant (ricin—a toxalbumin) Jequirity bean (abrin—a toxalbumin) ||Mucous membrane irritation, nausea, vomiting, bloody diarrhea, blurred vision, circulatory collapse, acute hemolytic anemia, convulsions, uremia. ||Fluid and electrolyte monitoring. Saline cathartic. Forced alkaline diuresis will prevent complications due to hemagglutination and hemolysis. |
|Foxglove, lily of the valley, and oleanderb ||Nausea, diarrhea, visual disturbances, and cardiac irregularities (eg, heart block). ||See treatment for digitalis drugs in text. |
|Jimsonweed: See Belladonna Alkaloids section in text ||Mydriasis, dry mouth, tachycardia, and hallucinations. ||Benzodiazepines for agitation, physostigmine. |
|Larkspur (ajacine, Delphinium, delphinine) ||Nausea and vomiting, irritability, muscular paralysis, and central nervous system depression. ||Symptomatic. Atropine may be helpful. |
|Monkshood (aconite) ||Numbness of mucous membranes, visual disturbances, tingling, dizziness, tinnitus, hypotension, bradycardia, and convulsions. ||Activated charcoal, oxygen. Atropine is probably helpful. |
|Poison hemlock (coniine) ||Mydriasis, trembling, dizziness, bradycardia. Central nervous system depression, muscular paralysis, and convulsions. Death is due to respiratory paralysis. ||Symptomatic. Oxygen and cardiac monitoring equipment are desirable. Assisted respiration is often necessary. Give anticonvulsants if needed. |
|Rhododendron (grayanotoxin) ||Abdominal cramps, vomiting, severe diarrhea, muscular paralysis. Central nervous system and circulatory depression. Hypertension with very large doses. ||Atropine can prevent bradycardia. Epinephrine is contraindicated. Antihypertensives may be needed. |
|Yellow Jessamine (active ingredient, gelsemine, is related to strychnine) ||Restlessness, convulsions, muscular paralysis, and respiratory depression. ||Symptomatic. Because of the relation to strychnine, activated charcoal and diazepam for seizures are worth trying. |
|Water hemlock (cicutoxin). ||Nausea, vomiting, abdominal pain. Followed by seizures. Severe ingestions can result in rhabdomyolysis, metabolic acidosis, and renal failure. ||Symptomatic. Benzodiazepines for seizures. |
Psychotropic drugs consist of four general classes: stimulants (amphetamines, cocaine, nicotine), depressants (eg, narcotics, barbiturates), antidepressants and tranquilizers, and psychoactive drugs (hallucinogens such as lysergic acid diethylamide [LSD], phencyclidine [PCP]).
The following clinical findings are commonly seen in patients abusing drugs. See also other entries discussed in alphabetic order in this chapter.
Agitation, euphoria, grandiose feelings, tachycardia, fever, abdominal cramps, visual and auditory hallucinations, mydriasis, coma, convulsions, and respiratory depression. Nicotine is associated with vomiting, hypertension and tachycardia, followed by symptoms of cholinergic excess, seizures and weakness.
Emotional lability, ataxia, diplopia, nystagmus, vertigo, poor accommodation, respiratory depression, coma, apnea, and convulsions. Narcotics cause miotic pupils and, occasionally, pulmonary edema.
C. Antidepressants and Tranquilizers
Hypotension, lethargy, respiratory depression, coma, and extrapyramidal reactions.
D. Hallucinogens and Psychoactive Drugs
Belladonna alkaloids cause mydriasis, dry mouth, nausea, vomiting, urinary retention, confusion, disorientation, paranoid delusions, hallucinations, fever, hypotension, aggressive behavior, convulsions, and coma. Psychoactive drugs such as LSD cause mydriasis, unexplained bizarre behavior, hallucinations, and generalized undifferentiated psychotic behavior. Marijuana can cause tachycardia, anxiety, and dysphoria.
Only a small percentage of the persons using drugs come to the attention of physicians; those who do are usually experiencing adverse reactions such as panic states, drug psychoses, homicidal or suicidal thoughts, or respiratory depression.
Even with cooperative patients, an accurate history is difficult to obtain. A drug history is most easily obtained in a quiet spot by a gentle, nonthreatening, honest examiner, and without the parents present. Street drugs are often adulterated with one or more other compounds and the exact dose is unknown. Multiple drugs are often taken together. Friends may be a useful source of information.
Hallucinogens are not life-threatening unless the patient is frankly homicidal or suicidal. A specific diagnosis is usually not necessary for management; instead, the presenting signs and symptoms are treated. Does the patient appear intoxicated? In withdrawal? “Flashing back?” Is some illness or injury (eg, head trauma) being masked by a drug effect? (Remember that a known drug user may still have hallucinations from meningoencephalitis.)
The signs and symptoms in a given patient are a function not only of the drug and the dose but also of the level of acquired tolerance, the “setting,” the patient’s physical condition and personality traits, the potentiating effects of other drugs, and many other factors.
A common drug problem is the “bad trip,” which is usually a panic reaction. This is best managed by “talking the patient down” and minimizing auditory and visual stimuli. Allowing the patient to sit with a friend while the drug effect dissipates may be the best treatment. This may take several hours. The physician’s job is not to terminate the drug effect but to help the patient through the bad experience.
Drug therapy is often unnecessary and may complicate the clinical course of a drug-related panic reaction. Although phenothiazines have been commonly used to treat bad trips, they should be avoided if the specific drug is unknown, because they may enhance toxicity or produce unwanted side effects. Benzodiazepines are the drug of choice if a sedative effect is required. Physical restraints are rarely indicated and usually increase the patient’s panic reaction.
After the acute episode, the physician must decide whether psychiatric referral is indicated; in general, patients who have made suicidal gestures or attempts and adolescents who are not communicating with their families should be referred.
et al: Notes from the field: calls to poison centers for exposures to electronic cigarettes—United States. September 2010–February 2014. MMWR 2014;63(13):292–293
The use of childproof containers and publicity regarding accidental poisoning have reduced the incidence of acute salicylate poisoning. Oil of wintergreen ingestion can also lead to salicylate toxicity. Nevertheless, serious intoxication still occurs and must be regarded as an emergency.
Salicylates uncouple oxidative phosphorylation, leading to increased heat production, excessive sweating, and dehydration. They also interfere with glucose metabolism and may cause hypo- or hyperglycemia. Respiratory center stimulation occurs early. The severity of acute intoxication can, in some measure, be judged by serum salicylate levels. High levels are always dangerous irrespective of clinical signs, and low levels may be misleading in chronic cases.
In mild and moderate poisoning, stimulation of the respiratory center produces respiratory alkalosis and may complain of tinnitus or hearing loss. Vomiting is also a common presenting symptom. In severe intoxication (occurring in severe acute ingestion with high salicylate levels and in chronic toxicity with lower levels), respiratory response is unable to overcome the metabolic overdose which may lead to fever, diaphoresis, pulmonary edema, seizures, and death.
Once the urine becomes acidic, less salicylate is excreted. Until this process is reversed, the half-life will remain prolonged, because metabolism contributes little to the removal of salicylate. Chronic severe poisoning may occur as early as 3 days after a regimen of salicylate is begun. Findings usually include vomiting, diarrhea, and dehydration.
Charcoal binds salicylates well and should be given for acute ingestions in patients now vomiting with normal mentation. Mild poisoning may require only the administration of oral fluids and confirmation that the salicylate level is falling (< 30 mg/dL). Moderate poisoning involves moderate dehydration and depletion of potassium. Fluids must be administered at a rate of 2–3 mL/kg/h to correct dehydration and produce urine with a pH of greater than 7.0. Initial IV solutions should be isotonic (D5W with 150 mEq sodium bicarbonate). Once the patient is rehydrated, the solution can contain more free water and approximately 40 mEq/L of K+.
Severe toxicity is marked by major dehydration. Symptoms may be confused with those of Reye syndrome, encephalopathy, and metabolic acidosis. Salicylate levels may even be in the therapeutic range. Major fluid correction of dehydration is required. Once this has been accomplished, hypokalemia must be corrected and sodium bicarbonate given. Usual requirements are sodium bicarbonate, 1–2 mEq/kg/h over the first 6–8 hours, and K+, 20–40 mEq/L. A urine flow of 2–3 mL/kg/h should be established. Despite this treatment, some patients will develop the paradoxical aciduria of salicylism. This is due to hypokalemia and the saving of K+ and excretion of H+ in the renal tubule. Correction of K+ will allow the urine to become alkaline and ionize the salicylate, resulting in excretion rather than reabsorption of nonionized salicylate in acid urine.
Patients with renal failure, pulmonary edema, mental status changes, seizures, or concentrations of greater than 100 mg/dL should be considered for hemodialysis.
JE: Are one or two dangerous? Methyl salicylate exposure in toddlers. J Emerg Med Jan 2007;32(1):63–69. doi: 10.1016/j.jemermed.2006.08.009.17239735.
et al: Extracorporeal treatment for salicylate poisoning: systematic review and recommendations from the EXTRIP workgroup. Ann Emerg Med Aug 2015;66(2):165–181. doi: 10.1016/j.annemergmed.2015.03.031.25986310.
Scorpion stings are common in arid areas of the southwestern United States. Scorpion venom is more toxic than most snake venoms, but only minute amounts are injected. Although neurologic manifestations may last a week, most clinical signs subside within 24–48 hours.
The most common scorpions in the United States are Vejovis, Hadrurus, Androctonus, and Centruroides species. Stings by the first three produce edema and pain. Stings by Centruroides (the Bark scorpion) cause tingling or burning paresthesias that begin at the site of the sting; other findings include hypersalivation, restlessness, muscular fasciculation, abdominal cramps, opisthotonos, convulsions, urinary incontinence, and respiratory failure.
Sedation with benzodiazepines is the primary therapy. Antivenom is reserved for severe poisoning, recommended dosing of 1–3 vials. In severe cases, the airway may become compromised by secretions and weakness of respiratory muscles. Endotracheal intubation may be required. Patients may require treatment for seizures, hypertension, or tachycardia. The prognosis is good as long as the patient’s airway is managed appropriately and sedation is achieved.
et al: Antivenom for critically ill children with neurotoxicity from scorpion stings. N Engl J Med 2009;360:2090–2098
AM: Clinical presentation and outcomes associated with different treatment modalities for pediatric bark scorpion envenomation. J Med Toxicol Aug 3, 2016. doi: 10.1007/s13181-016-0575-3.27487782.
SEROTONIN REUPTAKE INHIBITORS
Fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and many other agents comprise this class of drugs. Adverse effects in therapeutic dosing include suicidal thoughts, aggressive behavior, extrapyramidal effects, and cardiac dysrhythmias, and in overdose may include vomiting, lethargy, seizures, hypertension, tachycardia, hyperthermia, and abdominal pain. The findings in overdose are included in the serotonin syndrome due to the action of these drugs, which results in an increase of serotonin (5-hydroxytryptamine [5-HT]). Despite the degree of toxicity these agents generally are not life-threatening and intervention usually is not necessary.
Laboratory measurements of the drugs are not of benefit other than to establish their presence.
Treatment of agitation, hyperthermia with benzodiazepines is most beneficial. Hypotension may be treated with fluids or norepinephrine. Cyproheptadine is an antagonist of serotonin, but evidence for its use is limited. A dose of 0.25 mg/kg/day divided every 6 hours to a maximum of 12 mg/day may be useful in treating the serotonin syndrome. Adults and older adolescents have been treated with 12 mg initially followed by 2 mg every 2 hours to a maximum of 32 mg/day.
M: The serotonin syndrome. N Engl J Med 2005;352:1112
et al: Recognizing serotonin toxicity in the pediatric emergency department. Pediatr Emerg Care 2012;28(8):817–821
Despite the lethal potential of venomous snakes, human morbidity and mortality rates are surprisingly low. The outcome depends on the size of the child, the site of the bite, the degree of envenomation, the type of snake, and the effectiveness of treatment.
Nearly all poisonous snakebites in the United States are caused by pit vipers (rattlesnakes, water moccasins, and copperheads). A few are caused by elapids (coral snakes), and occasional bites occur from cobras and other nonindigenous exotic snakes kept as pets. Snake venom is a complex mixture of enzymes, peptides, and proteins that may have predominantly cytotoxic, neurotoxic, hemotoxic, or cardiotoxic effects but other effects as well. Up to 25% of bites by pit vipers do not result in venom injection. US pit viper venom causes predominantly local injury with pain, discoloration, edema, and thrombocytopenia.
Swelling and pain occur soon after rattlesnake bite and are a certain indication that envenomation has occurred. During the first few hours, swelling and ecchymosis extend proximally from the bite. The bite is often obvious as a double puncture mark surrounded by ecchymosis. Hematemesis, melena, hemoptysis, and other manifestations of coagulopathy rarely develop in severe cases. Respiratory difficulty and shock are the ultimate causes of death. Even in fatal rattlesnake bites, a period of 6–8 hours usually elapses between the bite and death; as a result, there is usually enough time to start effective treatment.
Coral snake envenomation causes little local pain, swelling, or necrosis, and systemic reactions are often delayed. The signs of coral snake envenomation include bulbar paralysis, dysphagia, and dysphoria; these signs may appear in 5–10 hours and may be followed by total peripheral paralysis and death in 24 hours.
Children in snake-infested areas should wear boots and long trousers, should not walk barefoot, and should be cautioned not to explore under ledges or in holes.
A. Emergency (First-Aid) Treatment
The most important first-aid measure is transportation to a medical facility. Splint the affected extremity and minimize the patient’s motion. Tourniquets and ice packs are contraindicated. Incision and suction are not useful for either crotalid or elapid snake bite.
B. Definitive Medical Management
Blood should be drawn for hematocrit, clotting time and platelet function, and serum electrolyte determinations. Establish two secure IV sites for the administration of antivenom and other medications.
Specific antivenom is indicated when signs of progressive envenomation are present. For coral snake bites, an eastern coral snake antivenom (Wyeth Laboratories) is sparingly available. Patients with pit viper bites should receive polyvalent CrotalidaeFab (CroFab) antivenom if progressive local injury, coagulopathy, or systemic signs (eg, hypotension, confusion) are present. (Antivenom should not be given IM or SQ.) See package labeling or call your certified poison center for details of use. Antivenom will halt progression of symptoms and improve hemorrhage, pain, and shock. For any history of coral snake bites, give three to five vials of antivenom in 250–500 mL of isotonic saline solution if available and observation for at least 24 hours. An additional three to five vials may be required. While generally considered best if administered within the first 6 hours, recent evidence demonstrates that delayed use may be therapeutic.
Administer an opioid or opiate to control pain. Cryotherapy is contraindicated because it commonly causes additional tissue damage. Early physiotherapy minimizes contractures. In rare cases, fasciotomy to relieve pressure within muscular compartments is required. The evaluation of function and of pulses will better predict the need for fasciotomy. Antihistamines and corticosteroids (hydrocortisone, 1 mg/kg, given PO for a week) are useful in the treatment of serum sickness or anaphylactic shock. Antibiotics are not needed unless clinical signs of infection occur. Tetanus status should be evaluated and the patient immunized, if needed. Recurrent coagulopathy and thrombocytopenia may occur after discharge, and patients should have follow up examinations and repeat laboratory values within 1 week after hospital discharge.
J: Efficacy, safety, and use of snake antivenoms in the United States. Ann Emerg Med 2001;37:181
RF: Recurrent coagulopathy and thrombocytopenia in children treated with crotalidae polyvalent immune fab: a case series. Pediatr Emerg Care. Aug 2010;26(8):576–582. doi: 10.1097/PEC.0b013e3181ea722b.20693856.
et al: Crotaline Fab antivenom for the treatment of children with rattle snake envenomation. Pediatrics 2002;110:968
Soap is made from salts of fatty acids. Ingestion of soap bars may cause vomiting and diarrhea, but they have a low toxicity.
Detergents are nonsoap synthetic products used for cleaning purposes because of their surfactant properties. Commercial products include granules, powders, and liquids. Dishwasher detergents are very alkaline and can cause caustic burns. Low concentrations of bleaching and antibacterial agents as well as enzymes are found in many preparations. The pure compounds are moderately toxic, but the concentration used is too small to alter the product’s toxicity significantly, although occasional primary or allergic irritative phenomena have been noted in persons who frequently use such products and in employees manufacturing these products. Unit dose detergents, or packets, have become popular and have packaging attractive to young children. They are usually a mix of glycol ethers, ethyl alcohol and surfactant. They typically cause local irritation but can lead to more severe symptoms including corneal injuries, CNS depression and respiratory distress if ingested. These exposures may need more prolonged observation.
A. Cationic Detergents (Ceepryn, Diaparene Cream, Phemerol, Zephiran)
Cationic detergents in dilute solutions (0.5%) cause mucosal irritation, but higher concentrations (10%–15%) may cause caustic burns to mucosa. Clinical effects include nausea, vomiting, collapse, coma, and convulsions. As little as 2.25 g of some cationic agents have caused death in an adult. In four cases, 100–400 mg/kg of benzalkonium chloride caused death. Cationic detergents are rapidly inactivated by tissues and ordinary soap.
Because of the caustic potential and rapid onset of seizures, emesis is not recommended. Activated charcoal should be administered. Anticonvulsants may be needed.
Most common household detergents are anionic. Laundry compounds have water softener (sodium phosphate) added, which is a strong irritant and may reduce ionized calcium. Anionic detergents irritate the skin by removing natural oils. Although ingestion causes diarrhea, intestinal distention, and vomiting, no fatalities have been reported.
The only treatment usually required is to discontinue use if skin irritation occurs and replace fluids and electrolytes. Induced vomiting is not indicated following ingestion of automatic dishwasher detergent, because of its alkalinity. Dilute with water or milk.
C. Nonionic Detergents (Brij Products; Tritons X-45, X-100, X-102, and X-144)
These compounds include lauryl, stearyl, and oleyl alcohols and octyl phenol. They have a minimal irritating effect on the skin and are almost always nontoxic when swallowed.
HE: Pediatric poisonings from household products: hydrofluoric acid and methacrylic acid. Curr Opin Pediatr 2011;13(2):157–161
GA: Pediatric exposure to laundry detergent pods. Pediatrics Dec 2014;134(6):1127–1135. doi: 10.1542/peds.2014-0057.25384489.
Most medically important bites in the United States are caused by the black widow spider (Latrodectus mactans) and the North American brown recluse (violin) spider (Loxosceles reclusa). Positive identification of the spider is helpful, because many spider bites may mimic those of the brown recluse spider.
The black widow spider is endemic to nearly all areas of the United States. The initial bite causes sharp fleeting pain that spreads centripetally. Local and systemic muscular cramping, abdominal pain, nausea and vomiting, tachycardia, and hypertension are common. Systemic signs of black widow spider bite may be confused with other causes of acute abdomen. Although paresthesias, nervousness, and transient muscle spasms may persist for weeks in survivors, recovery from the acute phase is generally complete within 2–3 days. In contrast to popular opinion, death is extremely rare.
Initial pain control should be achieved with use of benzodiazepines and opioids or opiates. Antivenom is effective, but supplies are limited and should be reserved for severe cases in which the previously mentioned therapies have failed.
2. Brown Recluse Spider (Violin Spider)
The North American brown recluse spider is most commonly seen in the central and Midwestern areas of the United States. Its bite characteristically produces a localized reaction with progressively severe pain within 24 hours. The initial bleb on an erythematous ischemic base is replaced by a black eschar within 1 week. This eschar separates in 2–5 weeks, leaving an ulcer that heals slowly. Systemic signs (loxoscelism) include cyanosis, morbilliform rash, fever, chills, malaise, weakness, nausea and vomiting, joint pains, hemolytic reactions with hemoglobinuria, jaundice, and delirium and are more common in children. Fatalities are rare. Fatal disseminated intravascular coagulation has been reported.
Although of unproved efficacy, the following therapies have been used: dexamethasone, 4 mg IV four times a day, during the acute phase; polymorphonuclear leukocyte inhibitors, such as dapsone or colchicine. Supportive wound care is recommended, with possible reconstruction/debridement.
et al: Clinical presentation and treatment of black widow spider envenomation: a review of 163 cases. Ann Emerg Med 1992;21:782
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et al: Nineteen documented cases of Loxosceles reclusa
envenomation. J Am Acad Dermatol 2001;44:603
Accidental ingestion of excessive amounts of vitamins rarely causes significant problems. Very rare cases of hypervitaminosis A do occur, however, particularly in patients with poor hepatic or renal function. Hypervitaminosis A can result in increased intracranial pressure, ocular toxicity, and hepatotoxicity. However, chronic doses more than 50,000–100,000 IU are required for toxicity. The fluoride contained in many multivitamin preparations is not a realistic hazard, because a 2- or 3-year-old child could eat 100 tablets, containing 1 mg of sodium fluoride per tablet, without experiencing serious symptoms. Iron poisoning has been reported with multivitamin tablets containing iron; most gummy vitamins do not contain iron. Pyridoxine abuse has caused neuropathies; nicotinic acid can result in flushing, and rarely hypotension and hepatotoxicity.
et al: Risk of vitamin A toxicity from candy-like chewable vitamin supplements for children. Pediatrics 2006;118(2):820–824
WARFARIN (COUMADIN) & NEWER ORAL ANTICOAGULANTS (NOAC)
Warfarin is used as an anticoagulant and rodenticide. It causes hypoprothrombinemia and capillary injury. A dose of 0.5 mg/kg of warfarin may be toxic in a child. Long-acting anticoagulant rodenticides (brodifacoum, difenacoum, bromadiolone, diphacinone, pinene, valone, and coumatetralyl) can cause a more serious toxicologic problem than warfarin as the anticoagulant activity may persist for periods ranging from 6 weeks to several months. However, most unintentional ingestions can be watched at home without further evaluation. If there are concerns for large ingestions, a prothrombin time at 48 hours can determine extent of toxicity. Treatment with vitamin K1 at high doses may be needed for weeks for long-acting anticoagulant toxicity.
Refer to published American College of Chest Physicians guidelines on management of bleeding in patient receiving vitamin K antagonists. With evidence for bleeding, give fresh frozen plasma, prothrombin complex concentrated, or activated factor. Without significant bleeding, oral vitamin K is recommended. No clear therapy is available for the newer direct factor inhibitors. Therapy has been focused on using fresh frozen plasma, prothrombin complex concentrate, and activated factor.
Newer oral anticoagulants have been developed that have direct inhibition to specific clotting factors. Examples include direct Xa inhibitors (apixaban, edoxaban, rivaroxaban), and direct thrombin (IIa) inhibitors (dabigatran). Toxic doses have not been established, but accidental ingestions do not typically lead to significant toxicity. If available, chromogenic antifactor Xa assay can quantitate direct Xa inhibition, and ecarin clotting time (ECT) or dilute thrombin time (dTT) is the most the most sensitive coagulation parameter for direct thrombin inhibitors. Activated four-factor prothrombin complex concentrates or activated Factor VII should be used to treat potentially life-threatening bleeding. Reversal agents are being developed for NOAC-associated coagulopathy.
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DL: Evaluation of dabigatran exposures reported to poison control centers. Ann Pharmacother Mar 2014;48(3):354–360. doi: 10.1177/1060028013513883.24301686.
et al: Reversal of rivaroxaban
and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2012;125(16):1573–1579
S: Management of intentional super warfarin
poisoning with long-term vitamin K and brodifacoum levels. Clin Toxicol (Phila) 2011;49(5):385–390
et al: An observational study of the Factor Xa inhibitors Rivaroxaban
as reported to eight poison centers. Ann Emerg Med Feb 2016;67(2):189–195. doi: 10.1016/j.annemergmed.2015.07.014.26298448.