- Patient may be asymptomatic early after acute ingestion or present with anorexia, nausea, and right upper quadrant pain
- Draw 4-hour postingestion levels, and use the nomogram (Figure 47–1) to predict severity following acute ingestion
- – Chronic toxicity should be assessed through clinical examination, an acetaminophen level, and liver function tests
- – N-Acetylcysteine (NAC) therapy is antidote if indicated
Nomogram for prediction of acetaminophen hepatotoxicity following acute overdosage. The upper line defines serum acetaminophen concentrations known to be associated with hepatotoxicity. The lower line defines serum levels 25% below those expected to cause hepatotoxicity. To give a margin for error, the lower line should be used as a guide to treatment. (Modified and reproduced, with permission, from Rumack BM, Matthew M: Acetaminophen poisoning and toxicity. Pediatrics 1975;55:871.)
Acetaminophen is a widely used ingredient in numerous over-the-counter and prescription preparations. One of the products of the normal metabolism of acetaminophen is hepatotoxic; at toxic levels, it saturates the glutathione detoxification system in the liver and accumulates, causing delayed hepatic injury (24–72 hours after ingestion). The toxic dose of acetaminophen is considered to be over 150 mg/kg in children and seven gin adults.
Caution: Shortly after ingestion of acetaminophen, there may be no symptoms or only anorexia, vomiting, or nausea; hepatic necrosis may not become clinically apparent until 24–48 hours later, when nausea, vomiting, abdominal pain, jaundice, and markedly elevated results on liver function tests may appear. Hepatic failure may follow.
Provide intensive supportive care and gastrointestinal decontamination as described previously. Administer activated charcoal regardless of the possibility that N-acetylcysteine may be administered.
Obtain a 4-hour postingestion acetaminophen serum concentration measurement, and use the Rumack-Matthew nomogram (see Figure 47–1) to predict the range of severity. If the 4-hour level is over 150 μg/mL, begin treatment with N-acetylcysteine. Because acetaminophen and salicylate are often ingested simultaneously, a measurement of serum salicylate concentration should also be obtained immediately. The nomogram is not helpful in determining the need for N-acetylcysteine for sustained-release product or chronic ingestions. If a sustained-released product has been ingested, two serum acetaminophen levels should be obtained 4–6 hours apart and treatment given if either level is above the possible toxicity line. For chronic toxicity or for those patients who present after 24 hours postingestion, treatment is based on clinical effects, liver function tests, and the acetaminophen level.
N-acetylcysteine substitutes for glutathione and binds the toxic metabolite of acetaminophen, thus inactivating and detoxifying it. It is available in both oral and intravenous dosage forms. Both the oral and intravenous routes have been demonstrated in multiple studies to be effective. Give 140 mg/kg orally of a 10 or 20% solution diluted to 5% with citrus juice or soda. Follow with 70 mg/kg orally every 4 hours for 72 hours. If the patient vomits a dose within 1 hour, it should be repeated; slow drip by nasogastric tube and administration of an antiemetic (eg, metoclopramide, 10–20 mg intravenously) may be helpful. Intravenous N-acetylcysteine dosing is 150 mg/kg in 200 mL of 5% dextrose for over 15 minutes. Maintenance dosing is 50 mg/kg in 500 mL of 5% dextrose over 4 hours followed by 100 mg/kg in 1-L 5% dextrose infused over 16 hours. Anaphylactoid reactions have been reported with the use of intravenous N-acetylcysteine.
To be effective, N-acetylcysteine must be given within 12–16 hours of ingestion of acetaminophen and preferably within 8 hours. Do not delay treatment if a serum acetaminophen level is not readily available and a toxic dose may have been taken. Treat with N-acetylcysteine empirically and reevaluate treatment after the acetaminophen level has returned. N-Acetylcysteine can also be safely given in pregnancy.
Use serum concentration of acetaminophen as a guide to the severity of poisoning, and hospitalize all patients requiring acetylcysteine therapy and those with evidence of hepatotoxicity.
Wolf SJ, Heard K, Sloan EP, Jagoda AS; American College of Emergency Physicians: Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen
overdose. Ann Emerg Med 2007;50:292–313
Dart RC, Erdman AR, Olson KR et al: Acetaminophen
poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2006;44:1–18
Amphetamines and Other Related Stimulants
- All drugs in this class are central nervous system stimulants
- Predominant symptom is sympathetic hyperactivity
- Treatment is supportive; no specific antidote is available
Amphetamines and other stimulants are easily abused because of their wide availability, primarily through street sales. Illicitly obtained stimulants frequently contain methamphetamine and may also contain PCP.
All of these drugs are central nervous system stimulants and cause sympathetic hyperactivity. Some may produce significant vasoconstriction causing hypertension. Most of these drugs have short half-lives and their peak effect and toxicity occur within 30 minutes after intravenous or intramuscular administration and 2–3 hours after oral ingestion. As a result, serum drug level measurements are of little value, and measures to enhance elimination generally do not alter the outcome.
Significant amphetamine poisoning is always accompanied by symptoms. Euphoria, mydriasis, and restlessness progress in severe cases to toxic psychosis and seizures. Hypertension can be severe and associated with palpitations or arrhythmias. Seizures and hyperthermia may produce rhabdomyolysis and myoglobinuria.
Provide intensive supportive care and gastrointestinal decontamination as described previously. For severe agitation or psychotic behavior, diazepam (5–10 mg in adults and 0.1–0.2 mg/kg in children) or lorazepam (2–4 mg in adults and 0.05–0.1 mg/kg in children) intravenously may be helpful; repeat every 5–10 minutes until sedation has been achieved.
Treat seizures with diazepam (5–10 mg in adults and 0.1–0.2 mg/kg in children) or lorazepam (2–4 mg in adults and 0.05–0.1 mg/kg in children) intravenously. May repeat every 5–10 minutes until seizures have ended. If seizures continue, administer phenobarbital (20 mg/kg intravenously over 20 minutes).
Treatment of Hypertension
Hypertension is generally transient and, unless severe, does not require treatment. Often the hypertension responds to benzodiazepine administration, but in severe cases (eg, diastolic blood pressure > 120 mm Hg, encephalopathy), intravenous nitroprusside, 0.5–1.0 μg/kg/min, is effective and easily titratable. Phentolamine, 0.1 mg/kg slowly intravenously, is an alternative drug.
Tachycardia and ventricular tachyarrhythmias rarely require treatment but may respond to administration of propranolol, 0.05–0.1 mg/kg intravenously.
Monitor temperature and start cooling measures if hyperthermia occurs. Check the urine for myoglobin. Acidification of the urine is not recommended.
If chest pain is present, perform an ECG and check for cardiac enzymes, and consider hospitalization to rule out myocardial ischemia or infarction. Patients with seizures may require computed tomography (CT) scanning to rule out intracranial hemorrhage.
Hospitalize patients with complications (psychotic behavior, hypertension, hyperthermia, chest pain, and arrhythmias) or those with prolonged symptoms.
Greene SL, Kerr F, Braitberg G: Review article: amphetamines and related drugs of abuse. Emerg Med Australas 2008;20:391–402
Scharman EJ, Erdman AR, Cobaugh DJ et al: Methylphenidate
poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2007;45:737–752
- Ingestion produces many symptoms prompting the phrase “blind as a bat, hot as Hades, red as a beet, dry as a bone, and mad as a hatter”
- Treatment is primarily supportive, although physostigmine can be used in life-threatening situations
Atropine, scopolamine, belladonna, many antihistamines, tricyclic antidepressants, and many plants (eg, jimsonweed [Datura stramonium], nightshade, Amanita muscaria mushrooms) have anticholinergic effects.
These drugs block cholinergic receptors both centrally and peripherally. Ingestion of a significant amount of an anticholinergic drug can produce many clinical effects. The popular phrase “blind as a bat, hot as Hades, red as a beet, dry as a bone, mad as a hatter” describes many of the manifestations of anticholinergic toxicity. Other signs and symptoms include tachycardia, gastrointestinal ileus, urinary retention, seizures, delirium, and hallucinations.
Provide intensive supportive care and gastrointestinal decontamination as described previously. Most patients can be managed with supportive measures alone, including sedation with benzodiazepines, cooling, and bladder emptying. If a patient develops life-threatening complications of anticholinergic toxicity (hemodynamically significant tachycardia, hyperthermia, or seizures resistant to benzodiazepines) that is refractory to conventional therapy, physostigmine, 1–2 mg intravenously over 2 minutes, can be given. Physostigmine works within minutes and the duration of effect is 30–60 minutes. It has been associated with severe complications, including bradycardia, heart block, and seizures. Atropine should be readily available if the antidote is used, and ECG monitoring is necessary. Physostigmine is contraindicated in patients with an overdose of tricyclic antidepressants.
Hospitalize patients who have incapacitating signs or symptoms of anticholinergic poisoning.
Krenzelok EP: Aspects of Datura poisoning and treatment. Clin Toxicol (Phila) 2010;48:104–110
- Average toxic dose is 5 mg/kg
- Anticholinergic symptoms range from mydriasis, agitation, and tachycardia to seizures and coma
- Cardiovascular manifestations are often lifethreatening and include QRS widening, profound hypotension, atrioventricular blocks, and ventricular arrhythmias
Major tricyclic antidepressants include amitriptyline (Elavil, many others), imipramine (Tofranil, many others), and doxepin (Adapin, Sinequan). Maprotiline (Ludiomil) is a tetracyclic antidepressant with similar properties.
The tricyclic antidepressants are analogs of phenothiazines, with complex effects, including anticholinergic, α-adrenergic-receptor blocking, and quinidine-like activity on the heart. They are well absorbed and highly tissue bound, with volumes of distribution of 10–40 L/kg. These drugs are eliminated primarily by metabolism in the liver, and the half-lives are 10–30 hours. The average toxic dose is more than 5 mg/kg, with severe poisoning occurring at doses of 10–20 mg/kg.
Other antidepressants include the selective serotonin reuptake inhibitors (SSRI): fluoxetine, paroxetine, sertraline, citralopram and escitralapam. Other antidresssants include serotonin/norepinephrine reuptake inhibitors (SNRI) (venlafaxine and duloxetine), buproprion (norepinephrine and dopamine reuptake inhibitor) and the antidepressant sedative trazodone.
The hallmark of tricyclic antidepressant toxicity is the rapid onset of life-threatening clinical effects. Many symptoms are the result of the anticholinergic activity of these drugs, for example, mydriasis, dry mouth, tachycardia, agitation, and hallucinations. The onset of coma may be rapid, even precipitous. Twitching and myoclonic jerking have been noted, and seizures occur frequently and may be difficult to treat.
Cardiovascular manifestations are the most dramatic and life-threatening (Figure 47–2). Quinidine-like slowing of conduction is reflected by widening of the QRS complex (>100 ms) and prolonged QT and PR intervals. Varying degrees of atrioventricular block and ventricular tachycardia are common. Atypical (torsades de pointes) ventricular tachycardia may occur. Profound hypotension resulting from decreased contractility and vasodilatation may occur and is a frequent cause of death. Hypoxemia and acidosis aggravate the cardiovascular toxicity of tricyclic antidepressants.
Supraventricular tachycardia with prolonged QTc and terminal right axis resulting from tricyclic antidepressant overdose.
Diagnosis is generally based on history, relevant physical findings, widened QRS complexes, and prolonged QT intervals (3 Cs: c ardiac abnormalities, c onvulsions, and c oma). The diagnosis may be confirmed by qualitative or quantitative tests for these drugs in the blood or urine. Plasma concentrations are rarely available and often lack sensitivity in detecting active metabolites. Prolongation of the QRS complex or the terminal axis in lead aVR is a better predictor of severity of poisoning than is the drug concentration.
Some cyclic antidepressants (amoxapine) and antipsychotics (loxapine) can cause seizures and coma without associated cardiovascular toxicity or electrocardiographic changes.
The SSRIs in combination with other serotonergic drugs, or when taken alone, may lead to the development of some degree of serotonin syndrome. Ingestion of the SNRI antidepressants as well as buproprion, may cause seizures.
Provide intensive supportive care and gastrointestinal decontamination as described previously. Do not induce emesis because of the well-established risk of seizures and coma. Administer activated charcoal if the patient has ingested a toxic amount and is seen within 1 hour. Consider multidose charcoal for symptomatic patients.
Constant monitoring of the ECG for at least 6 hours is mandatory. Progressive widening of the QRS complex indicates worsening toxicity.
Treat seizures with diazepam or phenobarbital. Do not use physostigmine to treat seizures, because it may cause seizures and other complications.
Sinus tachycardia is benign and usually does not require treatment. Physostigmine and propranolol may aggravate conduction abnormalities and should not be used.
Ventricular arrhythmias and conduction defects may respond to sodium bicarbonate, 50–100 mEq (1–2 mEq/kg) as an intravenous bolus. It is not clear whether the improvement is merely a result of correction of acidosis, a result of transient hypernatremia, or a result of a shift in the protein binding of the drug with alkalosis. Lidocaine, 1–2 mg/kg as an intravenous bolus, is frequently effective. Quinidine-like drugs (eg, quinidine, procainamide, and disopyramide) are contraindicated, because they worsen cardiotoxicity.
Treat hypotension initially with intravenous infusion of sodium bicarbonate, 50–100 mEq (1–2 mEq/kg), and crystalloid solutions. If the patient fails to respond after 1–2 L have been infused, further therapy should be guided by measurement of pulmonary artery wedge pressures and cardiac output. Norepinephrine and epinephrine have been found to be more effective than dopamine in refractory hypotension.
Hemodialysis and hemoperfusion have no role in tricyclic antidepressant poisoning.
Hospitalize all symptomatic patients with overdose of tricyclic antidepressants. Use serial ECGs along with the patient's clinical appearance to predict impending toxicity. Observe asymptomatic patients for a minimum of 6–8 hours, taking repeated measurements of the vital signs and QRS interval.
Flanagan RJ: Fatal toxicity of drugs used in psychiatry. Hum Psychopharmcol 2008;23:43–51
Howell C, Wilson AD, Waring WS: Cardiovascular toxicity due to venlafaxine
poisoning in adults: a review of 235 consecutive cases. Br J Clin Pharmacol 2007;64:192–197
Nelson LS, Erdman AR, Booze LL et al: Selective serotonin reuptake inhibitor poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2007;45:315–332
Woolf AD, Erdman AR, Nelson LS et al: Tricyclic antidepressant poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2007;45:203–233
β-Adrenergic Blocking Agents
- Ingestion of a large amount of β-blockers primarily affects the cardiac system
- Symptoms of ingestion include hypotension, bradycardia, and bronchoconstriction
- Glucagon can be used to treat hypotension if fluids are unsuccessful; glucagon can also be used to treat arrhythmias, but cardiac pacing may be required in severe cases
β-Adrenergic blocking agents are widely used in clinical medicine to treat hypertension, arrhythmias, angina pectoris, migraine headache, and thyrotoxicosis. β-Blockers act by competing with catecholamines for a finite number of β1 and β2 receptor sites. The β1-receptors are responsible for increasing the force and rate of cardiac contraction. The β2-receptors mediate vasodilatation; bronchial smooth muscle dilation; and a number of metabolic effects, including glycogenolysis. Excessive β-blockade can therefore cause hypoglycemia, bradycardia, bronchoconstriction, and hypoglycemia.
The main features of massive β-blocker overdose are hypotension and bradycardia. Pulmonary edema or bronchospasm may also occur, especially in patients with preexisting congestive heart failure or asthma. Hypoglycemia and hyperkalemia are sometimes seen. Convulsions are common with propranolol and other agents (eg, oxprenolol) with high lipid solubility and marked membrane-depressant effects. The ECG may show sinus bradycardia, atrioventricular blocks, or a prolonged QRS interval. In rare cases, ventricular tachyarrhythmias may occur, especially with sotalol overdose. Death is usually due to profound myocardial depression, with advanced atrioventricular block or asystole. Plasma levels of β-blockers are not clinically useful and are not routinely available.
General management of overdose, including airway protection, treatment of hypoglycemia, and gastrointestinal decontamination, should be undertaken as outlined earlier. Give multidose activated charcoal and initiate whole bowel irrigation in a patient who may have ingested a toxic amount of a sustained-release preparation.
Treat hypotension initially with fluids. If this is unsuccessful, use glucagon, 5–10 mg (100–150 μg/kg) as an intravenous bolus, followed by an infusion of 2–5 mg/h. Glucagon increases intracellular cyclic AMP by a mechanism different from that of β-receptors.
Advanced atrioventricular block or bradycardia resulting in hypotension can also be treated initially with glucagon, 100–150 μg/kg intravenously. If arrhythmia continues, atropine, 0.01–0.03 mg/kg intravenously, or isoproterenol, 0.05–0.3 μg/kg/min by intravenous infusion, may also be used. If these are unsuccessful, cardiac pacing may be necessary. The heart may not respond to attempts at pacing, even with high currents.
Because of the relatively large volume of distribution and extensive protein binding, dialysis is not likely to be of value for propranolol overdose. Less lipophilic agents (eg, atenolol, nadolol) have much smaller volumes of distribution and may be eliminated by dialysis or hemoperfusion, but they are less likely to cause profound toxicity.
Patients should remain under observation for at least 6–8 hours after ingestion. Patients with significant β-blocker intoxication (eg, profound bradycardia, conduction abnormalities, hypotension, and shock) should be hospitalized. Patients ingesting sustained-release products should be observed for 12–24 hours.
Kerns W: Management of beta-adrenergic blocker and calcium channel antagonist toxicity. Emerg Med Clin North Am 2007;25:309–331
Calcium Channel Blocking Agents
- Ingestion of a large amount of calcium channel blockers can cause hypotension, bradycardia, and central nervous system depression
- Treatment is primarily supportive, although both calcium and glucagon can be used to treat hypotension and bradycardia
Calcium channel blockers are being used with increasing frequency for supraventricular tachycardia, hypertension, rate control in atrial fibrillation or atrial flutter, angina, and vasospasm. These agents block the slow calcium channels and have the following cardiovascular effects: They depress sinus node activity, slow atrioventricular nodal conduction, cause coronary and peripheral vasodilatation, and depress myocardial contractility. Verapamil and diltiazem have the most marked myocardial effects and are especially dangerous in patients with sinus or atrioventricular nodal disease, Wolff–Parkinson–White syndrome, on digitalis therapy or in patients receiving β-blockers, quinidine, disopyramide, or other myocardial depressant drugs. Nifedipine is especially dangerous in patients receiving nitrates or β-blockers and in patients with obstructive valvular heart disease. Nifedipine is more likely than verapamil or diltiazem to be associated with increased heart rate and vasodilatation. Calcium channel blockers may also block insulin release, resulting in hyperglycemia.
The main manifestations of calcium channel blocker overdose are hypotension, bradycardia, and drowsiness. Bradydysrhythmias result from sinoatrial and atrioventricular nodal conduction dissociation. If the ingestion is that of a sustained-release preparation, toxicity and symptoms may be delayed for 6–8 hours. With regular-release preparations, toxicity is generally seen in 2–3 hours. Hyperkalemia and seizures, which are sometimes observed in overdoses of β-blockers, are not prominent in overdoses of calcium channel blockers. The ECG shows evidence of bradyarrhythmia with atrioventricular block. Death results from severe myocardial depression leading to asystole.
General management includes airway protection and gastrointestinal decontamination. Give multidose activated charcoal and initiate whole bowel irrigation in a patient who may have ingested sustained-release preparations.
Constant cardiac monitoring is essential. Appropriate pharmacologic management in seriously ill patients may require placement of central intravenous lines. Leg elevation, Trendelenburg positioning, and fluid management may be required. Advanced atrioventricular block and bradycardia resulting in hypotension may be treated initially with atropine, 0.01–0.03 mg/kg intravenously. Cardiac pacing may be required.
In hypotensive patients not responding to the therapy outlined above, calcium solutions have sometimes been successful. Administer 10% calcium chloride, 10–20 mL for adults (10–30 mg/kg for children) intravenously, or 10% calcium gluconate, 10–20 mL for adults (0.2–0.4 mL/kg for children), followed by repeated boluses or continuous intravenous infusion as necessary. Calcium administration improves the blood pressure more than the heart rate. As in β-blocker overdose, glucagon may improve both heart rate and blood pressure. An initial bolus of 2–5 mg intravenously may be given and followed by up to a total of 10 mg if no response is seen. If glucagon improves the patient's hemodynamics, then an infusion should be started. Isoproterenol, epinephrine, phenylephrine, or amrinone may be required for severe, unresponsive hypotension.
Asymptomatic patients should be observed for at least 8–10 hours. Patients with significant calcium channel blocker overdose should be hospitalized for monitoring and observation.
Lheureux PE, Zahir S, Gris M, Derrey AS, Penaloza A: Bench-to-bedside review: hyperinsulinaemia/euglycaemia therapy in the management of overdose of calcium-channel blockers. Crit Care 2006;10:212
Arroyo AM, Kao LW: Calcium channel blocker toxicity. Pediatr Emerg Care 2009;25:532–538
- Carbon monoxide is a colorless and odorless gas that binds with great affinity to hemoglobin
- Severe tissue hypoxia results
- Carbon monoxide levels correlate with severity of symptoms and should be used to guide treatment
- Treatment is with 100% oxygen; hyperbaric oxygen can also be used in certain circumstances
Carbon monoxide, a colorless, odorless, and tasteless gas, is produced by incomplete combustion of organic materials and is found in engine exhaust, kerosene heaters, burning charcoal briquettes, and from fireplaces. Any fire may also produce large quantities of carbon monoxide.
Carbon monoxide binds to hemoglobin with an affinity about 200 times greater than that of oxygen. The resulting carboxyhemoglobin complex cannot transport oxygen, causing tissue hypoxia that can lead to death or permanent neurologic damage if untreated. Hemoglobin saturation and blood oxygen content are dangerously low despite adequate (or elevated) arterial Po2 levels. Carbon monoxide also disrupts cellar respiration by binding to cytochrome oxidase.
The severity of symptoms usually correlates with carboxyhemoglobin levels (Table 47–11). The carboxyhemoglobin level can be obtained from either venous or arterial blood. The earliest reliable diagnostic symptom is headache. Usually, Po2 is normal, although metabolic acidosis due to tissue hypoxia may be present. Using oxygen saturation calculated from Po2 (based on assumption of normal hemoglobin) or measured by pulse oximetry will provide an incorrect estimate of oxygen-carrying capacity. Blood may be cherry-red, but the patient rarely appears pink. The ECG may show ischemia or infarction in a person with coronary disease. Delayed central nervous system effects such as Parkinsonism, memory loss, and personality changes can occur after recovery.
Table 47–11. Clinical Findings in Carbon Monoxide Poisoning. ||Download (.pdf)
Table 47–11. Clinical Findings in Carbon Monoxide Poisoning.
|Estimated Carbon Monoxide Concentration (Parts Per Million)||Carboxyhemoglobin (% of Total Hemoglobin)||Symptoms|
|Less than 35 ppm (cigarette smoking)||5||None, or mild headache|
|0.005% (50 ppm)||10||Slight headache, dyspnea on vigorous exertion|
|0.01% (100 ppm)||20||Throbbing headache, dyspnea with moderate exertion|
|0.02% (200 ppm)||30||Severe headache, irritability, fatigue, dimness of vision|
|0.03–0.05% (300–500 ppm)||40–50||Headache, tachycardia, confusion, lethargy, collapse|
|0.08–0.12% (800–1200 ppm)||60–70||Coma, convulsions|
|0.19% (1900 ppm)||80||Rapidly fatal|
Note: Act quickly. Delay in treatment may worsen neurologic damage.
Move the patient to fresh air immediately. Administer 100% oxygen by nonrebreathing face mask or endotracheal tube, not by nasal cannula or loose-fitting face mask. Oxygen competes with carbon monoxide for hemoglobin-binding sites. The half-life of carboxyhemoglobin in a person breathing room air is 5–6 hours; in 100% oxygen, it is only 1 hour. Hyperbaric 100% oxygen lowers the carboxyhemoglobin level even more rapidly (23 minutes), but it is seldom readily available and no studies have demonstrated a reduction in post carbon monoxide poisoning neurologic deficits in patients receiving hyperbaric oxygen versus 100% oxygen. Consider hyperbaric oxygen for patients with major symptoms of carbon monoxide intoxication such as loss of consciousness or myocardial ischemia or if the patient is pregnant.
Obtain arterial blood for measurement of carboxyhemoglobin content and arterial blood gases.
If carbon monoxide poisoning is associated with smoke inhalation, obtain a chest X-ray and consider hospitalization and monitoring for development of noncardiogenic pulmonary edema.
The use of corticosteroids and mannitol for cerebral edema has been recommended, but their value in preventing late neurologic sequelae remains unproved.
All patients with significant carbon monoxide poisoning (ie, with chest pain or other evidence of cardiac ischemia, neurologic signs, or carboxyhemoglobin concentrations above 25%) and pregnant patients must be hospitalized and given oxygen.
Juurlink DN, Buckley NA, Stanbrook MB et al: Hyperbaric oxygen
for carbon monoxide poisoning. Cochrane Database Syst Rev 2005:CD002041
Weaver LK: Clinical Practice: carbon monoxide poisoning. New Eng J Med 2009;360:1217–1225
- These cardiotoxic drugs result in rhythm and conduction disturbances in the heart and occasionally severe hyperkalemia
- Digoxin levels in combination with serum potassium are indicative of the degree of poisoning in the acute overdose
- Patients with severe arrhythmias or hyperkalemia may benefit from digitalis antibodies to reverse toxicity
Digoxin; digitoxin; and several plant digitalis derivatives including oleander, foxglove, and lily of the valley are the sources of digitalis and the cardiac glycosides. They are used therapeutically primarily for their ability to slow conduction through the atrioventricular node in disease states such as atrial fibrillation. They also increase the force of myocardial contractility and enhance automaticity. These therapeutic effects also mediate the severity of toxicity.
Digoxin has a large volume of distribution (6–10 L/kg) and a half-life of about 40 hours; for the most part, it is excreted unchanged in the urine. Digitoxin, by contrast, has a small volume of distribution, is highly protein bound, and undergoes extensive enterohepatic recirculation; its half-life is 7 days. In the elderly, the half-life may be increased owing to decreased creatinine clearance.
Blurred vision, color vision disturbance (especially with green or yellow vision), and neurologic symptoms may occur in a patient with chronic toxicity. The most serious toxic effects are those that cause rhythm and conduction disturbances in the heart, for example, third-degree atrioventricular block, bradycardia, ventricular ectopy, bidirectional ventricular tachycardia, and paroxysmal atrial tachycardia with atrioventricular block. In patients with chronic atrial fibrillation, digitalis toxicity may cause nonparoxysmal junctional tachycardia, which is characterized by a regular rhythm with narrow QRS complexes and a heart rate of 90–120 beats/min. Although hypokalemia may aggravate digitalis toxicity in the patient receiving chronic therapy, acute ingestion of an overdose is often associated with hyperkalemia. The plasma potassium level in digoxin overdose is indicative of the degree of poisoning of the Na+-K+-ATPase pump; if the potassium is elevated, the toxicity is severe. Therapeutic serum levels of digoxin are 0.5–2 ng/mL; for digitoxin, they are 18–22 ng/mL.
Provide intensive supportive care and gastrointestinal decontamination as described previously. Gastric lavage may worsen bradycardia by enhancing vagal tone.
If hypokalemia is present, replace potassium. For severe hyperkalemia, measures to reduce the potassium level may be necessary in order to reduce the cardiotoxic effects of digitalis. Because the total body potassium is not high, potassium-binding resins (ie, Kayexalate) should not be used. Other measures such as insulin, glucose, and sodium bicarbonate can be attempted in addition to specific antidotal therapy. Avoid the use of calcium, which may potentiate the cardiac toxicity of digitalis. Magnesium replacement may be beneficial.
For symptomatic bradycardia or second- or third-degree atrioventricular block, atropine, 0.5–1.0 mg intravenously, repeated every 5 minutes if there is no response, may be helpful. The total dose should not exceed 2 mg. A transcutaneous pacemaker may be used.
For ventricular ectopic beats, both lidocaine and phenytoin are effective, although lidocaine is easier to use. Give 1 mg/kg as an intravenous bolus, followed by 1–4 mg/min by continuous infusion. Phenytoin and the new prodrug fosphenytoin are also effective at suppressing atrial and ventricular ectopy.
Avoid direct current countershock, because it may cause serious conduction and rhythm disturbances including asystole or ventricular fibrillation in patients with digitalis toxicity. If countershock is unavoidable, use the lowest voltage that is effective.
Dialysis or hemoperfusion is of no value for digoxin because of its large volume of distribution. Digitoxin may be effectively removed by hemoperfusion and by repeated doses of activated charcoal or cholestyramine, which interrupt enterohepatic recirculation.
The treatment of choice for cardiac glycoside toxicity is digitalis-specific Fab fragments. Digitalis-specific Fab fragment antibodies are extremely effective and are indicated for patients with serious arrhythmias or severe hyperkalemia. Each vial binds 0.6 mg of digoxin. Toxicity usually is reversed within 5–10 minutes, and the digoxin–antibody complex is excreted in the urine. After administration of the Fab fragment antibodies (Table 47–12), serum digoxin levels are elevated owing to cross-reaction of the complex in the assay. When the ingested amount is unknown, 5–10 vials may be given initially.
Table 47–12. Digoxin Immune Fab Dosing.
All patients with digitalis and other cardiac glycoside poisoning require hospitalization in a cardiac-monitored unit for observation and treatment. Onset of cardiac toxicity may be delayed for 6–12 hours after acute ingestion.
Bauman JL, Didomenico RJ, Galanter WL: Mechanisms, manifestations, and management of digoxin
toxicity in the modern era. Am J Cardiovasc Drugs 2006;6:77–86
- Includes both acids and alkalis
- Ingestion can result in coagulative (acids) or liquefactive (alkalis) necrosis of tissue
- Treatment is supportive and includes dilution of the material with water, milk, or normal saline
- Endoscopy is recommended to assess degree of damage in symptomatic patients
Corrosive agents include strong agents, alkalis (caustics), oxidizing agents, and other chemicals. They are commonly used in household cleaners (Table 47–13).
Table 47–13. Common Corrosive Agents. ||Download (.pdf)
Table 47–13. Common Corrosive Agents.
- Clinitest tablets
- Drain cleaners
- Oven cleaners
- Denture cleaners
|Penetrating liquefaction necrosis|
- Pool disinfectants
- Toilet bowl cleaners
|Weaker cleaning agents|
- Cationic detergents (dishwasher detergents)
- Household bleach
|Superficial burns and irritation; deep burns (rare)|
Toilet bowl cleaners, bleaches, battery acid, soldering flux (zinc chloride), and many industrial sources contain acids.
Lye (drain cleaners, reagent tablets used to detect glucose in urine [Clinitest, many others]), ammonia, and industrial-grade detergents contain caustic alkalis. The mechanism of toxicity is tissue destruction resulting from coagulative (acids) and liquefactive (alkali) necrosis and heat injury during neutralization of the chemical by water in body tissues. Most household bleaches and detergents are dilute and do not cause severe corrosive burns. Concentrated alkalis are common in the household, especially in granular form or strongly concentrated liquids (pH > 12.5), and these cause severe tissue damage. Corrosive burns may lead to airway or intestinal edema and obstruction, mucosal perforation, and (later) stricture formation.
Symptoms are almost always present with significant ingestion and include mouth and throat pain, dysphagia, drooling, and substernal or abdominal pain. However, significant gastric or esophageal burns may be present without oral lesions. Skin and eye burns may also occur.
Dilute the corrosive material with water, normal saline, or milk (8 ounces for adults, 4 ounces for children). Do not give neutralizers, because they may increase the heat of hydration and worsen subsequent tissue destruction. Do not induce vomiting, because this may produce further tissue damage. Activated charcoal is contraindicated because it can interfere with endoscopy.
Diagnostic endoscopy should be performed in any symptomatic patient with or without oral burns. Endoscopy may not be necessary in asymptomatic patients.
No studies support the efficacy of corticosteroids in preventing stricture formation, and they are no longer recommended. Esophageal or gastric perforation is a contraindication to their use. Antibiotics are indicated for suspected perforation or infection.
Hospitalize all patients known to have ingested or inhaled (aspirated) caustic or corrosive agents with a potential for tissue damage. Skin burns may be managed on an outpatient basis if they are of mild to moderate severity. Eye injuries should be copiously irrigated and evaluated by an ophthalmologist.
Bauman JL, Didomenico RJ, Galanter WL: Mechanisms, manifestations, and management of digoxin
toxicity in the modern era. Am J Cardiovasc Drugs 2006;6:77–86
Salzman M, O'Malley RN: Updates on the evaluation and management of caustic exposures. Emerg Med Clin North Am 2007;25:459–476
Cocaine and Local Anesthetics
- Overdose of local anesthetics causes initial central nervous system excitement and seizures, followed by central nervous system depression
- Cocaine intoxication causes sympathetic hyperactivity and can result in severe hypertension, hyperthermia, myocardial ischemia, and even aortic dissection
- Treatment is supportive and should address any resulting cardiac or central nervous system symptoms
Cocaine is a natural extract from coca leaves. It is a local anesthetic that also has sympathomimetic effects. Overdoses of all local anesthetics are manifested by initial excitement and seizures, followed by central nervous system depression. Peak effects occur rapidly, usually in less than 1 hour.
All significant overdoses are associated with symptoms. Intravenous injection of cocaine and inhalation (smoking) of freebase, or crack, cocaine may result in very high levels. Cocaine causes euphoria, excitement, and restlessness; toxic psychosis, seizures, hypertension, tachycardia, dysrhythmias, and hyperthermia are common. Chest pain, myocardial ischemia and infarction, and aortic dissection have occurred. Blood cocaine and metabolite concentrations vary widely and do not predict the development of clinical findings.
Common local anesthetics such as lidocaine, mepiva-caine, and procaine have no toxic effects in usual doses. With excessive doses, they cause tremors, anxiety, and restlessness, followed by seizures and then cardiorespira-tory depression. Toxic doses for these drugs vary and depend on the route and duration of administration. Maximum recommended doses for infiltration anesthesia in adults are lidocaine, 4.5 mg/kg; bupivacaine, 2 mg/kg; and procaine, 7 mg/kg. Larger doses may be tolerated if epinephrine has been included in the preparation.
Provide intensive supportive care and gastrointestinal decontamination as described previously.
Treatment of Cocaine Overdose
Treat manifestations of sympathetic hyperactivity in the same way as for amphetamine overdose. Because effects peak rapidly, measures to enhance elimination of the drug from the body are unnecessary. The exception is those patients who ingest packets of cocaine to avoid arrest. If a patient is thought to have ingested packets of cocaine (body packers), whole bowel irrigation should be instituted immediately to hasten removal of the packets.
Patients with chest pain suggestive of ischemia should be evaluated with a 12-lead ECG and considered for admission to rule out myocardial infarction. Myocardial infarction may be present even with a normal ECG. Patients with a new onset of seizures may need CT scanning to rule out intracranial hemorrhage.
Treatment of Overdose with Common Local Anesthetics
Treatment consists of supportive measures with particular attention to respiratory depression and hypotension. Seizures are usually brief and easily treatable with benzodiazepines and usually do not require other anticonvulsant therapy. Recently, successful case reports have been documented in humans with the use of lipid infusion in significant local anesthetic toxicity. A 20% lipid infusion has been used to resuscitate a patients from cardiac arrest following the use of anesthetics.
Hospitalize patients with cocaine or local anesthetic poisoning manifested by multiple seizures, hyperthermia, ischemic chest pain, or severe hypertension.
- Cyanide acts as a cellular asphyxiant that inhibits the use of oxygen by the body's tissues
- Symptom onset is rapid and ultimately results in hypotension
- In mild cases, supportive care including 100% oxygen is adequate
- If poisoning is severe, a cyanide antidote kit of sodium nitrite, amyl nitrite, and sodium thiosulfate should be used
- Cyanide levels are not readily available and should not be used to determine treatment
- All patients with cyanide intoxication should be hospitalized
Fumigants, hydrocyanic acid gas used in industry, and burning plastics and fabrics are sources of cyanide. Sodium nitroprusside used to treat severe hypertension undergoes a biotransformation to methemoglobin and cyanide and can be a source of poisoning. Cyanide poisoning has also resulted from metabolism of ingested acetonitrile in an artificial nail-removing solution.
Cyanide is a rapidly absorbed cellular asphyxiant that inhibits the cytochrome oxidase system for oxygen utilization in cells. The inability of the body's tissues to use oxygen leads to anaerobic metabolism and a profound metabolic acidosis. Death may occur within minutes after a dose of 200 mg. In fatal poisoning, blood levels usually exceed 1–2 mg/mL. Cyanide gas is much more toxic than salt forms because of its rapid absorption, and its effects are usually immediate.
Significant poisoning is associated with rapidly developing symptoms, including headache, nausea and vomiting, anxiety, confusion, and collapse. Initial hypertension and tachycardia progress to hypotension, bradycardia, and apnea. The smell of bitter almonds is present occasionally. The skin may appear pink. The measured oxygen saturation of venous blood may be elevated as a result of failure of oxygen uptake by the tissues.
Note: Act quickly. To be successful, treatment must be started within 5–10 minutes in cases of severe poisoning. In witnessed cases of cyanide poisoning, begin therapy without waiting for symptoms.
Supportive care only, including 100% oxygen, may be given to asymptomatic patients as well as those with mild to moderate symptoms. Close observation is needed because the antidote may need to be administered if the patient deteriorates. If activated charcoal is available, administer it at once. Although its binding affinity for cyanide is low, it can adsorb a lethal dose.
Every emergency department should have a prepackaged cyanide antidote kit containing sodium nitrite, 300 mg in 10-mL ampules (2); sodium thiosulfate, 12.5 g in 50-mL ampules (2); amyl nitrite inhalant, 0.3 mL (12 Aspirols); and syringes and stomach tube (Table 47–14).
Table 47–14. Prepackaged Cyanide Antidote Kit.a ||Download (.pdf)
Table 47–14. Prepackaged Cyanide Antidote Kit.a
|Amyl nitrite||0.3 mL (aspirol inhalant)|
- Break 1–2 aspirols under patient's nose
- Sodium nitrite
|Sodium nitrite||3 g/dL (300 mg in 10 mL [vials])||300 mg intravenously|
|Sodium thiosulfate||25 g/dL (12.5 g in 50 mL [vials])||500 mg intravenously|
Nitrites produce methemoglobin, which binds free cyanide.
Break a capsule of amyl nitrite under the patient's nose for deep inhalation while starting an intravenous infusion of sodium nitrite and thiosulfate. A new ampule should be used every 3 minutes until intravenous medication has begun.
Give sodium nitrite, 300 mg (10-mL ampule) intravenously for adults; for children, 0.12–0.33 mL/kg up to 10 mL with a normal hemoglobin concentration (for alternate dosing in a child with abnormal hemoglobin, consult Poisindex). Caution: Do not over treat; fatal methemoglobinemia has resulted from overzealous use of nitrites. After initial therapy, guide subsequent treatment by monitoring symptoms and signs. The goal of nitrite therapy is a methemoglobin level of 25–30%.
Sodium thiosulfate is a cofactor in the rhodanese enzyme conversion of cyanide to thiocyanate, which is less toxic and readily excreted. Give thiosulfate, 50 mL of a 25% solution to adults and 1.65 mL/kg of a 25% solution to children, intravenously.
Vitamin B12A (hydroxocobalamin) has been successfully used in Europe. Hydroxocobalamin reverses cyanide toxicity by combining with cyanide to form cyanocobalamin (Vitamin B12A). The usual dose is 50 mg/kg; a single dose of 5 g is usually sufficient.
All patients with suspected or documented cyanide poisoning should be hospitalized.
Hall AH, Saiers J, Baud F: Which cyanide antidote? Crit Rev Toxicol 2009;39:541–552
- Methemoglobin cannot bind oxygen or carbon dioxide
- Symptoms correlate with the degree of methemoglobinemia and can include asymptomatic cyanosis, dyspnea, and severe central nervous system depression
- Treatment includes methylene blue, which can reduce methemoglobin levels in less than 1 hour
Hemoglobin becomes methemoglobin when iron is oxidized from the ferrous to the ferric form. Methemoglobin is dark chocolate like in color and can no longer bind to oxygen or carbon dioxide. Conversion of hemoglobin to methemoglobin decreases both delivery of oxygen to the tissues and removal of carbon dioxide, and tissue hypoxia may result.
Methemoglobin is produced endogenously in small quantities and is reduced by methemoglobin reductase; normally, less than 1–2% of hemoglobin is methemoglobin. Methemoglobinemia is caused by various oxidant drugs and poisons, including nitrites, some well water, nitrous gases, chloroquine and primaquine, phenazopyridine, sulfonamides, sulfones, aniline dye derivatives, phenacetin, dapsone, local anesthetics, and nitrobenzenes.
Symptoms correlate with the degree of methemoglobinemia. At concentrations of 1.5 g/dL (about 10% of the total hemoglobin), patients may seek care for cyanosis without any shortness of breath. When the level of methemoglobin exceeds 15% of total hemoglobin, blood appears chocolate brown when it is dripped onto filter paper. The exact concentration of methemoglobin in the blood may be determined spectrophotometrically. However, the Po2 and calculated oxyhemoglobin on routine test of arterial blood gases are falsely normal, and the measured saturation by pulse oximetry is unreliable.
Conversion of up to 25% of normal hemoglobin to methemoglobin is usually not associated with clinical findings other than peripheral and perioral cyanosis, although anxiety, headache, weakness, and lightheadedness can develop. At conversion levels of 35–40%, patients experience lassitude, fatigue, and dyspnea. At conversion levels exceeding 60%, coma and death may occur as a result of severe central nervous system depression. Anemia, acidosis, respiratory compromise (eg, chronic obstructive pulmonary disease), and cardiac disease may make patients more symptomatic than expected for a given methemoglobin level.
Provide intensive supportive care and gastrointestinal decontamination as described previously.
Oxygen per se does not affect the methemoglobin level, but it should be given to improve tissue oxygenation pending the start of specific therapy. Give oxygen, 5–10 L/min by mask; in comatose or severely acidotic patients, give 100% oxygen by rebreathing mask or endotracheal tube. Continue oxygen therapy for 1–2 hours after giving methylene blue (see below). Always give oxygen if the percentage of methemoglobin is higher than 40% or if the patient has severe symptoms.
Methylene blue is a specific antidote for methemoglobinemia. The dose is 1–2 mg/kg, or 0.1 mL/kg of a 1% solution, given intravenously over 5 minutes. The dose may be repeated at 1 mL/kg once after 1 hour, but the amount specified should not be exceeded, because an overdose of methylene blue can also cause methemoglobinemia. Methylene blue should reduce methemoglobin levels significantly in less than 1 hour. Patients with glucose-6-phosphate dehydrogenase deficiency may not respond to methylene blue and may experience hemolysis. Exchange transfusions may be required in these patients. Note: Methylene blue is contraindicated in patients with methemoglobinemia associated with nitrite treatment of cyanide poisoning because it may cause release of cyanide, resulting in toxic concentrations.
Discontinue the offending drug or chemical.
Symptomatic patients with methemoglobinemia should be hospitalized for treatment. Some agents (eg, dapsone) may produce prolonged or recurrent methemoglobinemia over several days.
Guay J: Methemoglobinemia related to local anesthetics: a summary of 242 episodes. Anesth Analg 2009;108:837–845
Ethanol and Other Alcohols
- Ethanol, methanol, ethylene glycol, and isopropanol are all central nervous system depressants. Levels of all alcohols should be obtained, although the level may not predict the severity of the intoxication
- Treatment of ethanol intoxication is supportive and includes glucose and thiamine
- Treatment of methanol and ethylene glycol ingestions includes either fomepizole or an ethanol drip to inhibit the formation of toxic metabolites
- Treatment of isopropanol ingestion is supportive and may include dialysis if the level is greater than 400 mg/dL
Methanol, ethylene glycol, and even isopropanol have been used as cheap substitutes for ethanol, although this practice is less common now than formerly. These alcohols may also be ingested accidentally or in suicide attempts. All are capable of causing intoxication similar to that produced by ethanol, and all can widen the osmolar gap (see Table 47–4). Additional toxic effects and death can occur as a result of the metabolism of ethylene glycol and methanol.
Ethanol is a central nervous system depressant. It is metabolized by alcohol dehydrogenase (in most cases by fixed-rate, zero-order kinetics) at a rate of about 7–10 g/h, resulting in a decrease in blood alcohol concentration of 20–30 mg/dL/h. The rate of elimination among individuals varies, as does tolerance. In the United States, legal impairment for purposes of driving is generally defined as blood (or breath) ethanol concentrations above 80–100 mg/dL; coma usually occurs with levels exceeding 300 mg/dL, except in chronic ethanol abusers who have developed tolerance.
Symptoms of alcohol intoxication include ataxia, dysarthria, depressed sensorium, and nystagmus. The breath may smell of alcohol, but this finding is neither sensitive nor specific. Alcohol intoxication is frequently seen with trauma and can contribute significantly to morbidity and mortality. Coma and respiratory depression with subsequent pulmonary aspiration due to intoxication are also common causes of illness and death. Laboratory diagnosis may be aided by direct determination of the blood ethanol concentration or by its estimation from the calculated osmolar gap (see Table 47–4).
Provide intensive supportive care and gastrointestinal decontamination as described previously. Supportive care is the primary mode of therapy. Special care should be taken to prevent aspiration.
Give thiamine and glucose as needed. Give thiamine, 100 mg intramuscularly or intravenously, to prevent Wernicke's syndrome. Check for hypoglycemia, because ethanol inhibits gluconeogenesis, and give glucose, 50 mL of a 50% solution (25 g of glucose) intravenously over 3–4 minutes, if needed.
Diagnose and correct disorders such as hypovolemia, hypothermia, infection, trauma, or gastrointestinal tract bleeding. Do not use fructose therapy or forced diuresis.
Hospitalize patients with ethanol poisoning if ethanol intoxication has caused abnormalities that would by themselves require hospitalization (eg, obtundation, seizures, and refractory hypoglycemia).
Methanol is a highly toxic alcohol found in a variety of commercial products, including paint stripper, antifreeze, automobile windshield washer fluid, and solid alcohols (Sterno Canned Heat, and many others). It is metabolized by alcohol dehydrogenase to formaldehyde and formic acid. An osmolar gap and profound metabolic acidosis with an anion gap result. Optic neuritis (caused by formate) that results in blindness has been described after overdose. Early diagnosis is essential, because permanent blindness or death may result if methanol intoxication is left untreated.
The major clinical effect of methanol before it is metabolized is central nervous system depression. As the methanol is metabolized to formic acid (this may be delayed 6–18 hours if ethanol has also been ingested), visual disturbances invariably occur (blurred vision or hazy and snow-like patterns), along with hyperemia of the optic disk, headache, dizziness, and breathlessness. In severe toxicity, seizures and coma may occur.
Examination shows variable degrees of central nervous system dysfunction (agitation and intoxication to coma). Pupillary dysfunction has been shown to be a strong predictor of mortality. The retinas may appear suffused and bright red. Early after ingestion, the only finding may be inebriation with an elevated osmolar gap. Later, severe metabolic acidosis occurs.
If serious intoxication is suspected, begin therapy even before receiving the results of blood methanol concentration determination.
Provide intensive supportive care and gastrointestinal decontamination as described previously. The main objective of treatment is to limit the accumulation of formate by blocking the metabolism of methanol by alcohol dehydrogenase. Two drugs have been shown to be effective, fomepizole (Antizol) and ethanol.
Fomepizole is the treatment of choice. It is approved by the FDA for the treatment of ethylene glycol and methanol poisoning. Fomepizole, like ethanol, inhibits alcohol dehydrogenase and the formation of toxic metabolites. Give a loading dose of 15 mg/kg intravenously, followed by 10 mg/kg every 12 hours for 48 hours. After 48 hours the dose is increased to 15 mg/kg every 12 hours until the level of methanol is undetectable or both symptoms and acidosis resolve and the level is less than 20 mg/dL. Fomepizole has several advantages over ethanol infusion, including ease of dosing, lack of central nervous system depression, and no requirement for constant serum monitoring because of its reliable therapeutic concentration. Ethanol infusion can also be used if fomepizole is unavailable.
In the absence of fomepizole ethanol may be used. Ethanol is metabolized in preference to methanol by alcohol dehydrogenase, thus blocking further metabolism of methanol. The loading dose of ethanol for an average 70-kg adult is 0.7 g/kg (2 mL/kg of 100-proof [50%] ethanol orally; or 7 mL/kg of 10% ethanol intravenously). Maintain continuous infusion of 0.07–0.1 g/kg/h to keep blood concentration of ethanol between 100 and 200 mg/dL. These levels are sufficient to produce clinically evident intoxication. Ethanol may be given intravenously or orally, but intravenous solutions must be at concentrations of 10% or less to prevent hypertonicity of the solution. Monitor and maintain adequate ventilation during the infusion of ethanol.
Correct metabolic acidosis with sodium bicarbonate; keep the pH at 7.2 or higher. Because folate deficiency increases the toxicity of methanol (in animals), folate replacement may be helpful. It can be given as a 50-mg intravenous dose every 4 hours for five doses, then once a day.
Hemodialysis is indicated for methanol blood concentrations higher than 50 mg/dL and in patients with severe acidosis, high formate levels, seizures, optic changes, or mental status changes; it should be started as soon as possible. The ethanol infusion must be adjusted to replace ethanol lost in dialysis (increase ethanol to 0.15–0.2 g/kg/h). Fomepizole is also dialyzed, and dosing should be increased to every 4 hours during dialysis.
Hospitalize all patients with suspected or documented methanol poisoning. If the osmolar gap and anion gap are both normal 1 hour after suspected ingestion, serious intoxication is unlikely.
Ethylene glycol is a common ingredient of deicers and antifreeze products. It is sweet tasting, and some preparations are attractively colored. Following ingestion, it is metabolized by alcohol dehydrogenase to glycolate and ultimately to oxalate, which precipitates with calcium to form calcium oxalate crystals. Symptoms may occur within 30 minutes or after a delay of several hours. Severe toxicity has resulted from the inhalation of ethylene glycol containing carburetor cleaner.
The clinical course of ethylene glycol intoxication can be divided into three phases. The first phase occurs less than 1 hour after ingestion and is characterized by central nervous system depression. The second phase affects the cardiopulmonary system, and heart failure or pulmonary edema can occur approximately 12 hours after ingestion. The final phase occurs 24–72 hours after ingestion and is characterized by renal tubule necrosis, flank pain, hematuria, and renal failure. Visual symptoms are usually not present, and the ocular fundi appear normal (as distinguished from their appearance in methanol poisoning). An osmolar gap is present, and after metabolism to toxic products, a severe acidosis usually occurs, and crystals of calcium oxalate may be seen in the urine. The urine may be fluorescent under an ultraviolet lamp owing to the fluorescence often added to commercial antifreeze products.
Fomepizole is the treatment of choice, although ethanol can be used if fomepizole is unavailable. The dosing is the same as in methanol poisoning. Hemodialysis is now indicated only in patients with severe acidosis or abnormal renal function; the ethylene glycol level by itself does not determine the need for dialysis.
Hospitalize all patients with suspected or documented ethylene glycol intoxication.
Isopropanol is a common ingredient in many household products, especially rubbing alcohol. It causes intoxication with central nervous system and cardiac depression; blood concentrations of 150 mg/dL are frequently associated with deep coma. It is metabolized by alcohol dehydrogenase to acetone, although most of the clinical effects of isopropanol intoxication are due to the parent compound. Both the alcohol and acetone cause an elevated osmolar gap, but acidosis is rare. The odor and acetonemia without acidosis is characteristic of isopropanol intoxication.
Treatment is primarily supportive and similar to that for ethanol intoxication. Hemodialysis is indicated for patients with an isopropanol level greater than 400 mg/dL and significant central nervous system depression.
Hospitalize patients with isopropanol intoxication who have significant signs (eg, stupor, coma, or hypotension).
- Choking, gagging, or gasping following ingestion
- Delayed (4–6 hours) physical findings
- Infiltrates on chest X-ray (chemical pneumonitis)
Hydrocarbons—a large group of compounds that includes petroleum distillates—exert various toxic effects. They are classified by two characteristics: viscosity (lowviscosity products are more likely to cause chemical aspiration pneumonia) and their potential for systemic toxicity (central nervous system or cardiac toxicity). These properties are summarized in Table 47–15.
Table 47–15. Clinical Features of Hydrocarbon Poisoning. ||Download (.pdf)
Table 47–15. Clinical Features of Hydrocarbon Poisoning.
|Type||Examples||Risk of Pneumonia||Risk of Systemic Toxicity||Treatment|
|High-viscosity||Vaseline, motor oil, gasoline||Low||Low||None|
|Low-viscosity, nontoxic||Furniture polish, mineral spirits, kerosene, lighter fluid||High||Low||Observe for pneumonia. Do not induce emesis|
|Low-viscosity, unknown systemic toxicity||Turpentine, pine oil||High||Variable||Observe for pneumonia. Do not induce emesis if less than 1–2 mL/kg was ingested|
|Low-viscosity, known systemic toxicity||CHAMP: Camphor, Halogenated or Aromatic hydrocarbons (benzene, toluene), Metals, Pesticides||High||High||Gastric aspiration followed by activated charcoal|
The major complication following ingestion of petroleum distillates is aspiration pneumonitis, which may occur with poisoning caused by any of the lowviscosity compounds. Most cases of poisoning are accidental, and exposure is rarely more than a taste (5–10 mL). As little as 1–2 mL of low-viscosity compounds may produce severe chemical pneumonitis if aspirated into the tracheobronchial tree.
A coincidental or intentional inhalation of hydrocarbon vapors may produce irritation, nausea, and headache. Exposure to volatile vapors in an enclosed area may result in hypoxia owing to displacement of oxygen from the atmosphere. Inhalation of aromatic (eg, toluene) or halogenated (eg, freon and trichloroethylene) hydrocarbon solvents may cause euphoria, confusion, hallucinations, coma, and cardiac arrhythmias. Chronic exposure to toluene may cause myopathy, hypokalemia, renal tubular acidosis, and neuropathy.
Symptoms suggesting aspiration are choking, coughing, or gasping immediately following ingestion of a toxic compound. Physical signs of aspiration are often present but may be delayed for up to 4–6 hours. For example, chest X-ray may reveal infiltrates before physical signs appear. Systemic signs of toxicity include narcosis, delirium, and for certain compounds, seizures. Some of these effects may result from hypoxemia due to pneumonitis. Hydrocarbons may sensitize the myocardium to the arrhythmogenic effects of endogenous catecholamines.
Gastric decontamination is controversial. Activated charcoal does not absorb hydrocarbons very well. Gastric lavage should be considered in hydrocarbon ingestion for substances that cause significant systemic toxicity. These include camphor, halogenated hydrocarbons, and aromatic hydrocarbons. The risk of aspiration may outweigh the benefit of decreasing toxicity with gastric lavage. Perform endotracheal intubation to protect the airway before performing gastric lavage.
No treatment is required.
Low-Viscosity Compounds with No Known Systemic Toxicity
If there are unequivocal signs of aspiration pneumonitis, protect the airway if necessary to prevent further aspiration, and give oxygen. If the patient is asymptomatic and has no history of coughing or choking after ingestion, aspiration is unlikely. Do not induce emesis or perform gastric lavage, because it may increase the risk of aspiration. Observe the patient closely for 4–6 hours to detect signs of possible aspiration. Obtain a chest X-ray even in asymptomatic patients.
Low-Viscosity Compounds with Unknown or Unproved Toxicity
It is unclear whether these compounds have inherent systemic toxic effects apart from chemical pneumonitis, and controversy exists regarding the use of lavage to clear a compound of this group from the body. Evaluate the patient, and give treatment for possible pulmonary aspiration, as described above.
Low-Viscosity Compounds with Known Systemic Toxicity
Consider gastric emptying for ingestions of more than 30 mL of hydrocarbons with systemic toxicity, intentional overdoses, and mixed overdoses with other toxins. In the absence of the above scenarios, avoid gastric emptying. Activated charcoal should also be initiated under the same pretenses. Activated charcoal is especially useful if the toxin (eg, camphor) is known to produce coma or seizures abruptly. If lethargy, coma, or seizures are present, intubate the patient with a cuffed endotracheal tube and perform gastric lavage. Evaluate the patient for possible pulmonary aspiration.
Hospitalize patients who have ingested low-viscosity petroleum distillates if symptoms or signs of systemic toxicity (lethargy and seizures) or pneumonitis (coughing, choking, and abnormal findings on chest X-ray) are present. Because delayed onset of pulmonary complications may occur after hydrocarbon poisoning, it is prudent to observe patients for 4–6 hours before discharging them from the emergency department.
Lin CY et al: Toxicity and metabolism of methylnaphthalenes: comparison with naphthalene and 1-nitronaphthalene. Toxicology 2009:16;260:16–27
Manoguerra AS, Erdman AR, Wax PM et al: Camphor
Poisoning: an evidence-based practice guideline for out of hospital management. Clin Toxicol (Phila) 2006;44(4):357–370
Inhalants (Toxic Gases and Vapors)
- Irritation of upper airway and conjunctiva
- Chemical pneumonitis and pulmonary edema
Many toxic inhalants (eg, carbon monoxide and phosgene) are produced by combustion of household or industrial products in accidental fires or as byproducts of work activity (eg, welding). Many toxic chemicals exist in gaseous form (eg, chlorine, arsine) and exposure occurs during an accidental spill or leak. Toxic gases can be classified as (1) simple asphyxiants, (2) chemical asphyxi-ants and systemic poisons, and (3) irritants or corrosives (Table 47–16).
Table 47–16. Clinical Features of Toxic Gases and Fumes. ||Download (.pdf)
Table 47–16. Clinical Features of Toxic Gases and Fumes.
|Class of Toxin||Toxin||Source||Clinical Features||Treatment|
- Carbon dioxide
- Inert gases (nitrogen, argon)
- Cooking gas
- Cooking gas
- All fires
- Industry (especially welding)
|All displace normal air and lower Fio2, Symptoms of hypoxemia, without airway irritation||Remove patient from source; give oxygen|
|Chemical asphyxiants||Carbon monoxide||Fires||Forms carboxyhemoglobin; inhibits oxygen transport. Headache is earliest symptom||100% oxygen|
|Hydrocyanic acid||Industry; burning plastics, furniture, fabrics||Highly toxic cellular asphyxiant (see section on cyanide).||Use cyanide antidote (Table 47–14)|
|Hydrogen sulfide||Liquid manure pits, decaying organic materials||Highly toxic cellular asphyxiant similar to cyanide; sudden collapses; ability to smell characteristic odor of rotten eggs is rapidly fatigued|
- Use sodium nitrite as for cyanide (makes sulmethemoglobin).
- Do not use thiosulfate
|Irritants: High solubility in water|
- Chlorine gas
- Hydrochloric acid
- Industry; swimming pool chemical; bleach mixed with acid at home
- Industry, burning fabrics
|Early onset of lacrimation, sore throat, stridor, tracheobronchitis; with heavy exposure, may progress to pulmonary edema in 2–6 h||Humidified oxygen; bronchodilators; airway management|
|Low solubility in water|
- Nitrogen dioxide
- Burning cellulose; fabrics.
- Grain silos (acid red gas)
- Inert gas arc welding industry
- Burning of chlorinated organic material
|Has sweet “electric” smell. Delayed onset (12–24 h) of tracheobronchitis, pneumonitis, and pulmonary edema. Late chronic bronchitis||Oxygen; observation for 24–48 h; steroids (controversial)|
|Allergenic||Toluene diisocyanate||Manufacture of polyurethanes||Reactive bronchoconstriction; may have long-term effects (chronic obstructive pulmonary disease) in susceptible persons||Bronchodilators.|
|Metal fumes||Welding (especially galvanized metal welding)|
- “Metal fumes fever.”
- Chills, fever, myalgias, headache, nonproductive cough, leukocytosis (4–8 h after exposure)
|Self-limited (12–24 h)|
|Arsine||Burning arsenic-containing ores; electronics industry|
- Highly toxic.
- Hemolysis, pulmonary edema, renal failure; chronic arsenic toxicity
|Exchange transfusion; use dimercaprol (BAL) for chronic arsenic toxicity only|
|Mercury Lead||Industry, welding||See specific metals|
Methane, propane, and inert gases cause toxicity by lowering the ambient oxygen concentration.
Chemical Asphyxiants and Systemic Poisons
Examples include carbon monoxide, cyanide, and hydrogen sulfide. These substances possess intrinsic systemic toxicity manifested after absorption into the circulation.
These substances cause cellular destruction and inflammation when they come in contact with the tracheobronchial tree, usually by producing acids or alkali upon contact with moisture. Gases that are highly water soluble (eg, chlorine and ammonia) cause immediate irritation, mainly of the upper airway and conjunctiva, whereas gases that are poorly soluble in water (eg, nitrogen dioxide) may be more deeply inhaled, producing delayed lower airway destruction with chemical pneumonitis and pulmonary edema.
Symptoms and signs vary depending on the toxin. In an accidental fire, combinations of all classes of toxic inhalants may be responsible for symptoms of toxicity, for example, a burning sensation in the eyes and mouth, sore throat, brassy cough, dyspnea, and headache. Look for singed nasal hairs, carbonaceous deposits on the nose and face, upper airway swelling or obstruction, wheezing or signs of pulmonary edema, and manifestations of systemic toxicity. Obtain arterial blood gas determinations, carboxyhemoglobin level measurements, and chest X-ray.
Remove the patient from the source of toxic gases, and begin supplemental oxygen, 10 L/min, by mask. For victims of smoke inhalation or carbon monoxide poisoning, give 100% oxygen.
Treatment of poisoning caused by chemical asphyxiants and systemic toxins depends on the specific toxin. For cyanide, see previous discussion; for hydrogen sulfide poisoning, use sodium nitrate and hyperbaric oxygen, as outlined in the Cyanide section. Although unproved, nitrite therapy may decrease sulfide toxicity by binding it with methemoglobin. Do not give thiosulfate for hydrogen sulfide intoxication, because the enzyme rhodanese is not involved in elimination of sulfide.
For upper airway irritation, humidified oxygen is often effective. Carefully observe the patient for stridor and other signs of progressive airway obstruction that would require endotracheal intubation. For bronchospasm, give nebulized bronchodilators.
Hospitalize for observation and treatment all patients with significant symptoms or signs of poisoning caused by inhalation of toxic gases. Patients exposed briefly to high-solubility irritant gases whose symptoms have resolved can be safely discharged; however, those exposed to low-solubility irritants such as nitrogen oxides or phosgene may experience delayed-onset pulmonary edema or chemical pneumonitis and should be admitted for 16–24 hours' observation.
Yalamanchili C: Acute hydrogen sulfide toxicity due to sewer gas exposure. Am J Emerg Med 2008;26:518.e5–7
- Signs and symptoms of iron poisoning can vary widely and include all major organ systems
- Levels can be obtained and in many cases guide treatment
- Chelation therapy is available for iron poisoning
Iron poisoning results primarily from ingestion of mineral supplements containing divalent iron: ferrous sulfate (20% elemental iron), ferrous fumarate (33%), and ferrous gluconate (12%).
Absorption of iron is dose related and may increase dramatically with overdose levels, especially when the corrosive action of iron has damaged the intestinal mucosal barrier. Iron also causes vasodilatation and disruption of cellular electron transport. The elemental iron equivalent should be used when toxic doses are being estimated; an amount higher than 40 mg/kg causes toxicity, and amounts over 60 mg/kg are potentially lethal. Blood concentrations of iron may assist in the diagnosis of acute toxicity but may be unreliable owing to concurrent absorption of iron and distribution in the tissues. A peak concentration in serum often occurs 4–6 hours after ingestion. Serum concentrations over 500 μg/dL are potentially toxic, and levels over 1000 μg/dL are associated with severe poisoning.
Four stages of intoxication are commonly described:
Severe nausea and vomiting and abdominal pain occur within 1–4 hours. Hyperglycemia and leukocytosis are common. In severe cases, hemorrhagic gastroenteritis, shock, acidosis, and coma may follow. A plain film of the abdomen may show radiopaque iron tablets.
During the next period, which lasts 6–12 hours and sometimes up to 24 hours, the patient may appear relatively well or may even improve. Patients with significant ingestions, however, can still have progressive, silent systemic deterioration.
A stage of shock, acidosis, coagulopathy, and hypoglycemia may occur 12–24 hours after ingestion of significant amounts of iron and reflects a severe course and poor outlook. Serum iron concentration at this stage may be deceptively low, because most absorbed iron has been taken up by tissues.
The last stage is characterized by hepatic poisoning with possible progression to hepatic injury.
Provide intensive supportive care and gastrointestinal decontamination as described previously. For serious or massive ingestion, enhance removal of iron from the gastrointestinal tract with whole bowel irrigation. Activated charcoal is not effective.
Intravenous chelation with deferoxamine is the treatment of choice when symptoms of iron poisoning are evident or when the serum iron level is over 500 μg/dL. The iron–deferoxamine complex is excreted in the urine and has a pink color. If urinary output is inadequate, the complexes may be removed with hemodialysis. The deferoxamine intramuscular challenge is no longer recommended, and any patient with a significant ingestion who appears toxic or has a serum iron level greater than 500 mg/dL should receive treatment. The dose of deferoxamine is 10–15 mg/kg until serum iron levels fall to less than 400 μg/dL or until urine no longer has characteristic pink color. Rapid IV administration may cause hypotension.
Observe the patient for several hours when ingestion of significant amounts of iron is suspected, because symptoms in the initial phase may be deceptively mild.
Hospitalize all patients with suspected or documented cases of iron poisoning. If patients remain asymptomatic, with a negative abdominal X-ray and no elevation of white blood cell count or blood glucose 6 hours after ingestion, they may be discharged to home care.
Madiwale T, Liebelt E: Iron: not a benign therapeutic drug. Curr Opin Pediatr 2006;18:174–179
- Seizures, metabolic acidosis, and coma
- Seizures may be refractory to standard management (benzodiazepines)
- Estimated acute toxic dose is 80–100 mg/kg
Isoniazid is a common antituberculosis drug often prescribed as a 3–6-month supply. The principal manifestations of isoniazid overdose are seizures, metabolic acidosis, and coma. Seizures may be due to depression of γ-aminobutyric acid levels in the central nervous system. Severe metabolic acidosis accompanies recurrent seizure activity. The estimated acute toxic dose is 80–100 mg/kg, although this range may be lower in patients with preexisting seizure disorders, vitamin B6 deficiency, or chronic alcoholism.
Symptoms occur 30 minutes to 3 hours following ingestion and include nausea and vomiting, slurred speech, dizziness, lethargy progressing to stupor, hyperreflexia, seizures, metabolic acidosis, hyperglycemia, and cardiovascular and respiratory depression. Symptoms and signs occur promptly after significant poisoning.
Provide intensive supportive care and gastrointestinal decontamination as described previously.
Treat seizures with lorazepam or diazepam, as described in Chapter 17. If these medications are not effective, continue benzodiazepines and give pyridoxine (vitamin B6) in doses equivalent to the amount ingested (gram for gram). If the amount ingested is unknown, start with 5 g (0.1 g/kg) intravenously given over 3–5 minutes, and repeat every 10–15 minutes until seizures are controlled. If the intravenous form of pyridoxine is not available, pyridoxine can be given as a slurry in a similar dose via a nasogastric tube.
Consider hemodialysis for patients unresponsive to conventional therapy.
Hospitalize all patients who have ingested more than 80 mg/kg of isoniazid and those who have signs or symptoms suggesting isoniazid poisoning.
Menzies D, Long R, Trajman A et al: Adverse events with 4 months of rifampin
therapy or 9 months of isoniazid
therapy for latent tuberculosis infection: a randomized trial. Ann Intern Med 2008;18;149:689–697
Forget EJ, Menzies D: Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf 2006;5:231–249.
- Apathy, lethargy, tremor, slurred speech, and ataxia
- In severe overdose, choreoathetosis, seizures, and coma
- Toxicity often accidental and seen with diuretic therapy and dehydration
- Lithium levels >2 mEq/L are usually toxic
Lithium is frequently used to treat bipolar disorder and other psychiatric disorders. It is a monovalent cation like sodium and potassium; unlike these cations, however, it has only a small gradient of distribution across cell membranes and cannot maintain membrane potentials. It is rapidly absorbed into extracellular fluid, with an initial volume of distribution of 0.1–0.2 L/kg. Its distribution into selected tissues then occurs slowly over several hours. Its final volume of distribution is about 1 L/kg. It is excreted unchanged in the urine and actively reabsorbed, with a half-life of approximately 22 hours (with normal renal function). Sodium and water depletion lead to marked increases in the reabsorption of lithium and to elevation of blood concentrations of lithium.
Symptoms of lithium overdose include apathy, lethargy, tremor, slurred speech, ataxia, and fasciculations, which may progress in severe overdose to choreoathetosis, seizures, coma, and death. Persistent neurologic sequelae may occur. Toxicity is frequently accidental and occurs secondary to chronic sodium depletion, diuretic therapy, and dehydration. In these cases, the serum lithium level is a more reliable index to the severity of overdose, because adequate time has passed for distribution into the central nervous system. In such circumstances, blood concentrations of lithium greater than 2 mEq/L are usually associated with toxicity.
In acute overdose, in contrast, initially elevated serum lithium concentrations may be misleading, because distribution into tissues occurs over several hours. For example, an initial toxic level of 4 mEq/L may easily fall to 1 mEq/L with final distribution. Thus, in acute overdose, repeated measurements of serum lithium levels and assessment of mental status (eg, every 4 hours) are more helpful than a single assessment in evaluating toxicity.
General Management and Prevention of Absorption
Provide intensive supportive care. Whole bowel irrigation is an effective means of increasing lithium removal. Activated charcoal does not adsorb lithium.
The treatment of choice for serious intoxication is hemodialysis. Specific indications for hemodialysis have not been well defined by careful studies, but dialysis should be considered for any patient with obtundation, seizures, or coma. Dialysis is the only route of elimination in patients with renal failure. Hemoperfusion is not effective.
Because lithium is reabsorbed in the kidney when sodium and fluids are depleted, sodium levels should be followed closely. Administration of intravenous saline may prevent reabsorption of lithium. Normal urine flow rates are adequate.
Prevention of Accidental Toxicity
To prevent chronic (accidental) toxicity, frequent assessment of fluid and sodium balance and lithium levels is recommended for patients taking lithium.
Hospitalize all patients with serum lithium concentrations above 2–3 mEq/L and those who show objective signs of lithium intoxication.
- Sedation, hypotension, bradycardia, hypothermia, and respiratory depression
- Diagnosis is confirmed if patient regains consciousness after naloxone
Codeine, heroin, hydrocodone, oxycodone, and other opiates with varying potencies and durations of action are found in a wide range of prescription analgesic preparations. Some opiates, such as dextromethorphan, are found in nonprescription drugs.
The opiates act on central nervous system receptors and cause sedation, hypotension, bradycardia, hypothermia and respiratory depression. Most opiates have a half-life of 3–6 hours; the major exceptions are methadone (15–20 hours) and propoxyphene (12–15 hours).
Consider opiate intoxication in any comatose or lethargic patient, especially when the clinical findings listed above are present. Pinpoint pupils are a typical sign, although in mixed overdoses, pupils may be in middle position. Signs of parenteral drug abuse may or may not be apparent. Pulmonary edema may occur. The diagnosis is confirmed if toxic concentrations of opiates are found in blood or urine or if the patient regains consciousness after administration of naloxone.
Provide intensive supportive care and gastrointestinal decontamination as described previously. Maintain adequate airway and ventilation.
Give naloxone (a specific narcotic antagonist) to all patients with suspected opiate overdose. Start with 0.4–2 mg intravenously. Repeat 2 mg every 2–3 minutes three or four times if no response occurs and narcotic overdose is suspected. Some authorities recommend up to 10–20 mg to treat suspected narcotic overdose. Naloxone may also be administered intramuscularly or intranasal. Because naloxone has a half-life of 1 hour and effects lasting only 2–3 hours (shorter than many opiates), its effects may wear off before those of the narcotic, permitting the patient to lapse into coma again. If relapse occurs after the first response to naloxone, a naloxone continuous infusion may be started, using approximately two-thirds of the dose required to initially awaken the patient given over each hour.
Another option in the busy emergency department is a long-acting opioid antagonist such as nalmefene. Nalmefene (2 mg) has been shown to last for as long as 8 hours, thereby reducing the need for any drips or repeated doses of naloxone. Naloxone is still the preferred initial antidote for comatose patients when the cause is uncertain because it will produce a shorter period of withdrawal in the chronically opioid-dependent patient.
Prevention of Narcotic Withdrawal Symptom
Watch carefully for withdrawal symptoms caused by naloxone or nalmefene. Chronic narcotic abusers who have developed tolerance to opiates may develop acute narcotic withdrawal when these agents are given. Although this syndrome is not life-threatening, it is a management problem in the emergency department if the patient becomes combative or uncooperative or signs out of the hospital before adequate treatment can be given. Careful titration of the naloxone dose may help to prevent narcotic withdrawal syndrome.
Hospitalize and observe all patients thought or known to have ingested significant amounts of opiates and those who relapse after the initial response to naloxone. Patients with heroin overdose who respond to naloxone may be safely discharged if they are asymptomatic 3 hours after the last dose.
Merlin MA, Saybolt M, Kapitanyan R et al: Intranasal naloxone
delivery is an alternative to intravenous naloxone
for opioid overdoses. Am J Emerg Med 2010;28:296–303
Aquina CT, Marques-Baptista A, Bridgeman P, Merlin MA: OxyContin abuse and overdose. Postgrad Med 2009;121:163–167
Organophosphates and Other Cholinesterase Inhibitors
- Toxicity and potency vary widely
- DUMBELS (diarrhea; urination; miosis; bronchorrhea; excitation with muscle fasciculation, emesis; lacrimation; and salivation, seizures). Death is usually from respiratory depression
- Diagnosis usually confirmed with low plasma or red blood cell cholinesterase level
Cholinesterase inhibitors are found in a variety of insecticides (organophosphates and carbamates) available for home and commercial use (eg, crop sprays, bug bombs, and flea collars). Some chemical warfare agents (nerve gases) are also cholinesterase inhibitors.
These compounds inhibit acetylcholinesterase and therefore allow accumulation of acetylcholine at muscarinic and nicotinic receptors in nerve endings. Organophosphates bind irreversibly with the enzyme, whereas carbamates are considered reversible inhibitors. All are rapidly absorbed from the skin, gastrointestinal tract, and respiratory tract. Toxicity and potency vary widely. Workers chronically exposed to organophosphates and infants with underdeveloped cholinesterase activity are at greater risk for intoxication.
Miosis, excessive salivation, bronchospasm, hyperactive bowel sounds, and lethargy typically occur shortly after exposure. Either bradycardia (muscarinic effect) or tachycardia (nicotinic effect) may be observed. QT-interval prolongation and pleomorphic ventricular tachyarrhythmias are a late consequence of poisoning. Symptoms of toxicity are easily remembered with the mnemonic DUMBELS. (diarrhea; urination; miosis; bronchorrhea; emesis, excitation with muscle fasciculation; lacrimation; and salivation).
Measurement of the plasma or red blood cell cholinesterase level is helpful in confirming acute toxicity; cholinesterase levels become low soon after exposure.
Provide intensive supportive care and gastrointestinal decontamination as described previously. Careful management of the airway is important, because significant bronchial secretions, bronchospasm, and hypoventilation may occur. Position the patient so as to avoid aspiration, and provide suction and oxygen as required. Early recognition of respiratory distress and subsequent intubation may decrease the mortality among these patients. Remove and isolate the patient's clothing, and carefully wash the skin with soap and water. Medical personnel should be careful to avoid cross-contamination.
Atropine is a symptomatic treatment for muscarinic signs (salivation, bronchorrhea, bronchospasm, and sweating). Large doses may be required. Start with 1–2 mg intravenously (0.5 mg in children), followed by repeated doses of 2–4 mg every 5–10 minutes until signs of atropinization occur (ie, flushing, mydriasis, drying of secretions, and tachycardia). The use of up to 50 mg in 24 hours is not unusual.
Pralidoxime (Protopam, 2-PAM) competitively inhibits binding of organophosphates to acetylcholinesterase and should be given to all patients with significant intoxication. It is not required for carbamate poisoning, because carbamate toxicity is transient. The dose is 1–2 g (25–50 mg/kg in children) in saline intravenously over 5–10 minutes. Continuous pralidoxime infusion has also been shown to improve the outcome in organophosphate poisoning. Adequate renal function is a prerequisite for use of pralidoxime, because it is excreted in the urine.
Other experimental treatments include magnesium, fresh frozen plasma and hemoperfusion.
Patients who receive prompt treatment usually recover from acute toxicity. However, two neurologic sequelae of severe intoxication—organophosphate-induced delayed neuropathy and intermediate syndrome—may occur after significant exposure.
Hospitalize all patients with clinical effects of organophosphate poisoning. Carbamate poisoning is usually transient, and patients who recover rapidly may be discharged.
Eddleston M, Buckley NA, Eyer P, Dawson AH: Management of acute organophosphorus pesticide poisoning. Lancet 2008;371:597–607
Peter JV, Moran JL, Graham PL: Advances in the management of organophosphate poisoning. Expert Opin Pharmacother 2007;8:1451–1464
- Rapid onset of action
- Vertical and horizontal nystagmus are common
- Symptomsmayfluctuate, unpredictably, fromsevere agitation to quiet stupor
- Hyperthermia and rhabdomyolysis may lead to myoglobinuria and renal failure
Phencyclidine is a common adulterant of marijuana, amphetamines, and street hallucinogens. PCP is also called angel dust, crystal, supergrass, ozone, whack, rocket fuel, and peace pill by its users. It may be smoked, snorted, ingested, or injected.
PCP is a sympathomimetic, hallucinogenic, dissociative anesthetic agent originally used in veterinary practice. It has a rapid onset of action when smoked or snorted, causing euphoria and hallucinations. Serious overdose does not usually occur with smoking, because users can titrate the dose to achieve the desired effect. Ingestion of 20–25 mg of PCP can cause severe intoxication. PCP has a large volume of distribution (2–4 L/kg) and a half-life of several hours to days.
Symptoms typically fluctuate, with patients alternating unpredictably from severe agitation to quiet stupor. Bizarre, paranoid behavior and extreme violence may occur unexpectedly. Both vertical and horizontal nystagmus is common. The pupils may be large or small. Hypertension, tachycardia, and hyperthermia are common. Marked muscle rigidity, dystonias, and seizures may occur. Hyperthermia and rhabdomyolysis resulting in myoglobinuria and renal failure are a major cause of subsequent illness. The diagnosis is made primarily on clinical grounds but may be confirmed by demonstrating PCP in urine or gastric aspirate. Serum PCP concentrations are not of value in emergency management.
Provide intensive supportive care and gastrointestinal decontamination as described previously. Most instances of PCP intoxication are mild and self-limited, and patients need no specific treatment other than to be in a quiet and supportive environment.
Treatment of Moderate to Severe Poisoning
Diazepam, 2–5 mg intravenously every 10 minutes until sedation is achieved, is effective in controlling moderate agitation or anxiety.
Treatment of Rhabdomyolysis or Myoglobinuria
If the patient has rhabdomyolysis or myoglobinuria, maintain urine output with intravenous fluids and mannitol.
Hospitalize patients who have moderate to severe PCP poisoning, particularly if hyperthermia, severe muscular rigidity, or evidence of rhabdomyolysis is an accompanying manifestation.
Moeller KE: Urine drug screening: practical guide for clinicians. Mayo Clin Proc 2008;83:66–76
Phenothiazines and Atypical Antipsychotics
- Extrapyramidal side effects (eg, dystonia, orofacial spasms)
- Sedation, miosis, and hypotension are common
- Coma, seizures, and ventricular arrhythmias may occur with large doses
Antipsychotic drugs include chlorpromazine (Thorazine, many others), prochlorperazine (Compazine), haloperidol (Haldol, others), and many other phenothiazines and butyrophenones. More recent antipsychotics do not have the same adverse effects of these older medications and are called “atypical.” These include aripiprazole, quetiapine, risperidone, olanzapine, and ziprasidone.
The mechanism of toxicity of the antipsychotics is complex. Antiadrenergic properties cause sedation and hypotension, anticholinergic effects are manifested by dry mouth and tachycardia, and antidopaminergic properties may produce extrapyramidal side effects (most commonly seen with haloperidol). The contribution of each of these effects in drug overdose depends on the specific drug and on the individual patient. Most of these compounds have large volumes of distribution (10–30 L/kg) and long half-lives (12–30 hours); dialysis is not effective.
With acute overdose, sedation, miosis, and hypotension are common. Coma and seizures may occur with very large ingestions. Prolongation of the QT interval and ventricular arrhythmias may occur. Disruption of the temperature-regulating mechanism may lead to hyperthermia or hypothermia. Extrapyramidal side effects may occur even at therapeutic doses and include dystonic posturing, spasm of orofacial muscles, cogwheel rigidity, and spasticity. Clinical effects following atypical antipsychotic overdose include sedation, anticholinergic effects, QT prolongation and rarely extrapyramidal effects.
Provide intensive supportive care and gastrointestinal decontamination as described previously. Treat hypotension with intravenous crystalloid solution; if a vasopressor is needed, norepinephrine is preferable.
Treatment of Extrapyramidal Reactions
Diphenhydramine (Benadryl, many others), 0.5–1 mg/kg intravenously slowly, or benztropine (Cogentin), 1–2 mg intramuscularly for adults, is recommended for extrapyramidal reactions. Relapse may occur; dispense oral anticholinergics for 2–3 days.
Treatment of Atypical Antipsychotic Overdose
Patients who overdose on atypical antipsychotics present in a manner similar to patients who overdose on the high-potency antipsychotics and should be managed similarly including close cardiac monitoring.
Hospitalize patients with clinically significant poisoning due to antipsychotics. In the acute period, close cardiac monitoring for arrhythmias and hypotension is warranted. Indications of significant poisoning include (1) rapidly worsening clinical findings and (2) obtundation. Patients with extrapyramidal reactions who respond to anticholinergic therapy may be discharged.
Tan HH, Hoppe J, Heard K: A systemic review of cardiocascular effects after atypical antipsychotic medication overdose. Am J Emerg Med 2009;27:607–616
Isbister GK, Balit CR, Kilham HA: Antipsychotic poisoning in young children: a systemic review. Drug Saf 2005;28:1029–1044
- Delayed onset of symptoms (gastrointestinal irritation) of 6–12 hours suggests a toxic mushroom ingestion
- Mushrooms containing amatoxin may produce fatal hepatic necrosis
Of the over 5000 varieties of mushrooms found in the United States, about 100 can be toxic. Most poisonous mushrooms act as gastrointestinal irritants. Table 47–17 lists several types of poisonous mushrooms, symptoms, and treatment. The most significant are Amanita phalloides and other mushrooms containing amatoxin, which may produce fatal hepatic necrosis.
Table 47–17. Mushrooms: Symptoms, Toxicity, and Treatment. ||Download (.pdf)
Table 47–17. Mushrooms: Symptoms, Toxicity, and Treatment.
- Chlorophyllum molybdites
- Omphalotus illudens
- Cantharellus cibarius
- Amanita caesarea
- Nausea, vomiting, diarrhea (occasional bloody).
- Initial: Nausea, vomiting, diarrhea
- IV hydration
- IV hydration, glucose, monitor, AST, ALT, PT, PTT, bilirubin, BUN, creatinine
|Onset 6–24 h|
- Gyromitro esculenta: fall season
- Amanita phalloides, Amanita verna, and Amanita virosa: spring season
|Day 2: Rise in AST, ALT; day 3: hepatic failure|
- For Amanita: activated charcoal
- Penicillin G, 300,000–1,000,000 U/kg/d
- Silymarin, 20–40 mg/kg/d.
- Consider cimetidine, 4–10 g/d
|Muscarinic (SLUDGE) syndrome||Salivation, lacrimation, diarrhea, gastrointestinal distress, emesis|
- Hyperbaric oxygen
- Supportive atropine, 0.01 mg/kg, repeated as needed for severe secretions.
- Amanita muscaria
- Amanita pantherina
|Intoxication, dizziness, ataxia, visual disturbances, seizures, tachycardia, hypertension, warm dry skin, dry mouth, mydriasis (anticholinergic effects)||Supportive sedation with phenobarbital, 30 mg IV, or diazepam, 2–5 mg IV, as needed for adults|
|Hallucinations||Visual hallucinations, ataxia||Supportive sedation with phenobarbital, 0.5 mg/kg, or, for adults, 30–60 mg IV, or diazepam, 0.1 mg/kg or 5 mg IV, for adults|
|Disulfiram 2–72 h after mushroom, and < 30 min after alcohol||Coprinus||Headache, flushing, tachycardia, hyperventilation, shortness of breath, palpitations|
Assistance with identification of specimens can often be obtained from a university biology department or mycology society. The regional poison control centers may also help with identification. However, because accurate identification of mushrooms is difficult without an experienced mycologist and impractical because many types of mushrooms are often ingested at one time, the best approach to mushroom ingestion is to assume that the most toxic types have been consumed. Delayed onset (6–12 hours) of gastrointestinal symptoms suggests amatoxin or monomethylhydrazine poisoning.
Provide intensive supportive care and gastrointestinal decontamination as described previously. Unintentional pediatric ingestion of unknown “little brown mushrooms” rarely requires treatment or admission. If poisoning with amatoxin is suspected, perform gastric decontamination in the emergency department. Activated charcoal should be administered every 2–4 hours. Hospitalize the patient for observation and obtain baseline hepatic and renal function measurements. A variety of potential antidotes have been recommended, including corticosteroids, penicillin G, thioctic acid, silymarin, and N-Acetylcysteine. Currently silymarin (Legalon, Madaus Inc.) is in phase III clinical trial. More important than specific antidotes is supportive care, including aggressive fluid replacement for massive gastroenteritis, supplemental glucose, and supportive treatment for hepatic encephalopathy. Early charcoal hemoperfusion or dialysis may be beneficial. Liver transplant has been successful in several patients with massive hepatic necrosis. Table 47–17 describes specific treatment for various kinds of mushroom poisoning.
Hospitalize patients thought or known to have ingested mushrooms known to cause serious poisoning (see Table 47–17).
Saller R, Brignoli R, Melzer J, Meier R: An updated systemic review with meta-analysis for the clinical evidence of silymarin. Forsch Komplementmed 2008;15:9–20
- Identification of plant is often difficult but essential to diagnosis of toxicity
- Symptoms are dependent on the planttoxin ingested (eg, cyanide, cardiac glycosides, anticholinergics)
Several hundred species of plants in the United States contain toxic compounds. Tables 47–18 and 47–19 give examples of nontoxic and toxic plants. Details about identification, mechanism of toxicity, and treatment are best obtained from a local poison control center. If the identity of a plant is unknown, it is helpful to send a sample to a local nursery or university botanist.
Table 47–18. Some Nontoxic Plants. ||Download (.pdf)
Table 47–18. Some Nontoxic Plants.
- African violet (Saintpaulia ionantha)
- Baby tears (Helxine soleirolii)
- Bridal veil (Genista monosperma pendula)
- Coleus species
- Fuchsia species
- Gardenia (Gardenia radicans)
- Jade plant (Crassula argentea)
- Piggyback Begonia (Begonia hispida var. cucullifera)
- Piggyback plant (Tolmiea menziesii)
- Rubber plant (Ficus elastica “Decora”)
- Spider plant (Chlorophytum comosum)
- Swedish ivy (Plectranthus australis)
- Wandering Jew (Tradescantia albiflora, T. fluminensis, Zebrina pendula)
- Zebra plant (Calathea zebrina)
Table 47–19. Some Poisonous Plants.a ||Download (.pdf)
Table 47–19. Some Poisonous Plants.a
|Plant Name||Type of Toxin|
|Azalea (Rhododendron species)||Andromedotoxin (nicotine-like and cardiotoxic)|
|Black nightshade (Solanum nigrum)||Solanine|
|Castor bean (Ricinus communis)||Toxalbumin (ricin)|
|Deadly nightshade (Atropa belladonna)||Anticholinergic|
|Dumb cane (Dieffenbachia)||Oxalates|
|Elderberry (Sambucus)||Cyanogenic (ripe berries nontoxic)|
|Foxglove (Digitalis purpurea)||Cardiac glycosides|
|Jequirity bean, rosary bean (Abrus precatorius)||Toxalbumin (a lectin)|
|Jerusalem cherry (Solanum pseudocapsicum)||Solanine|
|Jimsonweed (Datura stramonium)||Anticholinergic|
|Lily of the valley (Convallaria majalis)||Cardiac glycosides|
|Mistletoe (Viscum album, Phoradendron flavescens)||Tyramine (hypertension; gastroenteritis)|
|Mountain laurel (Kalmia latifolia)||Andromedotoxin (nicotine-like and cardiotoxic)|
|Oleander (Nerium oleander)||Cardiac glycosides|
|Pits (of cherry, apricot, peach)||Cyanogenic (amygdalin)|
|Poison hemlock (Conium maculatum)||Nicotine-like|
|Poinsettia (Euphorbia pulcherrima)||Oxalate-like|
|Tobacco (Nicotiana tabacum)||Nicotine|
|Water hemlock (Cicuta maculata)||Cicutoxin (seizures)|
|Yew (Taxus species)||Taxine (gastroenteritis, cardiac toxicity)|
Treat the specific symptoms manifested by the patient, not those thought to be associated with the type of poisonous plant believed to have been ingested. Many similar species of plants have widely varying potencies and combinations of toxins; the plant's age, the soil conditions, and other factors influence the severity of toxic symptoms.
Some of the more common plant toxins are described below. The list is not complete.
Insoluble calcium oxalate crystals in the leaves and stems of some plants irritate the mucous membranes and can cause edema of the mouth, throat, and tongue. In rare severe reactions, drooling, dysphagia, and airway obstruction may occur. Renal failure may occur if sufficient amounts of oxalates are absorbed.
Amygdalin and Cyanogenic Glycosides
Cyanide is produced by the gastrointestinal hydrolysis of chewed-up fruit pits or seeds (Prunus species: cherry, apricot, peach) or leaves and stems (Hydrangea, elder-berry). Severe poisoning is uncommon. See Cyanide section for symptoms and therapy.
Digitalis and similar compounds are present in varying amounts in certain plants. Serious clinically effects after consumption of only one oleander leaf, or oleander tea, have been reported (see Cardiac Glycosides section).
The typical anticholinergic syndrome of dry mouth, tachycardia, delirium, urinary retention, and mydriasis is seen. Most poisonings are mild, and supportive treatment is sufficient. Abuse of anticholinergic plants has been frequently reported. (see Anticholinergics section).
These toxins include nicotine and aconitine. Symptoms include nausea and vomiting, salivation, diarrhea, restlessness, and seizures. Mydriasis may also occur. Following an initial phase of excitement, respiratory depression and hypotension may occur.
Solanine produces gastrointestinal symptoms similar to those of nicotine. In addition, plants containing solanine often have significant amounts of atropinic alkaloids, so that the net effect is unpredictable. Onset of symptoms may be delayed several hours.
These highly toxic compounds (eg, abrin, ricin, and phallin) can cause acute gastroenteritis, dehydration, and shock. Convulsions, hemolysis, and renal and hepatic injury can also occur. Oral and esophageal irritation or burns may be seen.
In general, observation is recommended after ingestion of plants with known potentially serious toxic effects and activated charcoal may be beneficial in such cases. Begin specific treatment as indicated for the specific toxins involved.
Disposition depends on the plant ingested and the symptoms experienced.
Schep LJ, Slaughter RJ, Becket G, Beasley DM: Poisoning due to water hemlock. Clin Toxicol 2009;47:270–278
Froberg B, Ibrahim D, Furbee RB: Plant poisoning. Emerg Med Clin North Am 2007;25:375–433
- Toxicity generally occurs at levels >150 mg/kg
- Early manifestations include nausea, vomiting, and hyperventilation
- Initial respiratory alkalosis is often followed by a severe metabolic acidosis, creating a mixed acid–base status
- Hypoglycemia is prominent in children
Salicylates are present in numerous prescription and nonprescription medications, for example, analgesics, bismuth subsalicylate (Pepto-Bismol, many others), or oil of wintergreen (methyl salicylate).
The mechanism of toxicity with salicylate poisoning is complex and includes direct central nervous system stimulation, uncoupling of oxidative phosphorylation, inhibition of Krebs cycle enzymes, and interference with hemostatic mechanisms. The volume of distribution is dose dependent and usually small; with significant ingestion, however, the drug is redistributed into the central nervous system. Because salicylate is a weak acid, acidemia increases its penetration of the central nervous system. The half-life may increase from 2 to 20 hours at overdose levels as a result of saturation of liver metabolism. The elimination of salicylate is increased in alkaline urine. The minimum acute toxic dose is 150 mg/kg, with severe toxicity occurring at doses over 300–500 mg/kg. However, many cases of toxicity are a result of prolonged excessive treatment of minor illnesses (subacute or accidental overdose). The chronically ill and the elderly are at greater risk for subacute toxicity because of relative hypoalbuminemia and renal insufficiency.
Early manifestations of overdose include nausea and vomiting, tinnitus, listlessness, and hyperventilation. Loss of fluid and electrolytes is common. Initial respiratory alkalosis is followed by severe metabolic acidosis, hypokalemia, and hypoglycemia. Seizures, hyperpyrexia, and coma occur as toxicity becomes more severe. Measurement of the blood salicylate concentration is essential for effective management, although it is not as reliable an indicator of the severity of illness if subacute toxicity is present. In cases of acute salicylate ingestion the prognosis and patient management should not be based solely on an aspirin level. Consider the patient's clinical presentation, age, aspirin level, and acid–base status in making treatment decisions. In the presence of acidosis, toxicity occurs with considerably lower levels. Salicylate determinations should be repeated every 4–5 hours. Repeated measurements are especially important for ingestion of sustained-release or enteric-coated preparations, which are absorbed slowly and may result in delayed peak levels.
With subacute (accidental) toxicity, severity of poisoning does not correlate well with serum salicylate concentration, but levels above 30 mg/dL (300 mg/L) are significant. Patients with subacute toxicity are frequently very young or very old and they usually present with dehydration, obtundation, and acidosis. The diagnosis is often missed while the physician concentrates on the more prominent secondary complications. Cerebral and pulmonary edema and death are more common in patients with subacute toxicity.
Provide intensive supportive care and gastrointestinal decontamination as described previously. After acute overdose, give adequate charcoal to bind ingested salicylate. Multidose activated charcoal may be beneficial. For enteric-coated aspirin, toxicologists recommend multidose activated charcoal and possibly even whole bowel irrigation if the salicylate level is rising.
Correction of Acid–Base Status
Correct dehydration, hypoglycemia, hypokalemia, and acidosis. Fluid resuscitation is imperative. For significant dehydration, start with 20 mL/kg of an intravenous crystalloid solution given over 1–2 hours, and then give 3–5 mL/kg/h to maintain the urine output at 2–3 mL/kg/h. To correct acidosis and promote excretion of salicylate in the urine, give sodium bicarbonate, 1 mEq/kg/h. Concurrent correction of potassium deficit is mandatory. Urine pH should be maintained at 7–7.5. Alkalization of the urine is often unsuccessful in critically ill patients (especially the elderly), and it may aggravate pulmonary and cerebral edema.
Hemodialysis is recommended for critically ill patients with persistent seizures, acidosis that fails to respond to treatment, or cerebral or pulmonary edema. Although high salicylate concentrations (eg, > 120 mg/dL [1200 mg/L] at 6 hours) generally represent severe toxicity, hemodialysis should be based on the patient's complications and not the drug level. Hemodialysis is efficient in removing salicylate and can help to correct pH and electrolyte abnormalities. Consider early hemodialysis in ill patients with subacute overdose. Although there are no proved guidelines, elderly patients with serum salicylate levels over 60 mg/dL, and those with significant neurologic toxicity, should probably receive immediate hemodialysis. If the patient is hemodynamically unstable or hemodialysis is unavailable, continuous hemodiafiltration has been reported to be a viable alternative.
Obtain measurements of serum salicylate every 4–6 hours to monitor adequacy of treatment. If evidence of salicylate-induced hypoprothrombinemia is present, give vitamin K, 10 mg intramuscularly.
Rehydration, control of hyperthermia, and rapid correction of acidemia are essential. Give glucose, and replace potassium deficits.
Hospitalize all patients with known or suspected severe salicylate poisoning.
Pearlman BL, Gambhir R: Salicylate intoxication: a clinical review. Postgrad Med 2009;121;162–168
- Symptoms include nystagmus, atonia, lethargy, somnolence, respiratory depression, hypotension, and hypothermia
- Sedative–hypnotics such as γ-hydroxybutyric acid may be associated with symptoms ranging from respiratory depression and coma to seizure-like activity with aggressive behavior
Sedative–hypnotics include a broad range of drugs used to treat anxiety or insomnia. Included are benzodiazepines, zolpidem, and a variety of medications for insomnia. They can induce tolerance and can cause a withdrawal syndrome similar to that associated with ethanol withdrawal (except for the time of onset and duration). These agents are found singly and in various drug combinations. Of note, one sedative–hypnotic, γ-hydroxybutyric acid (GHB), has become a common drug of abuse. Effects range from respiratory depression, apnea, and coma to seizure-like activity along with aggressive behavior.
Absorption, distribution, and elimination of sedative–hypnotics vary. In general, the mechanism of toxicity of these drugs is central nervous system depression similar to that caused by ethanol.
Clinical manifestations of overdose include nystagmus, ophthalmoplegia, ataxia, dysarthria, lethargy, somnolence, respiratory depression, hypotension, and hypothermia. With the onset of deep coma, oculocephalic reflexes are lost and the pupils become nonreactive to light. The initial electroencephalogram may be flat, although the patient may subsequently recover completely. Serum drug levels may be misleading because levels of intoxication and rates of elimination vary enormously from person to person, depending on prior drug use and the patient's physical state.
Provide intensive supportive care and gastrointestinal decontamination as described previously. Treat shock and hypotension with an initial bolus of 200–1000 mL of intravenous crystalloid solution (Chapter 9). Restore the patient's core temperature to normal levels, because hypothermia will worsen hypotension. Monitoring the pulmonary capillary wedge pressure is helpful in avoiding fluid overload and determining the need for pressor agents. Vasopressors should be used only if adequate fluid replacement is ineffective (as determined by pulmonary capillary wedge pressure measurements).
Reserve hemodialysis or hemoperfusion for patients who remain hypotensive or otherwise unstable despite aggressive supportive care. These measures successfully remove only a few sedative–hypnotics (eg, phenobarbital, meprobamate, and ethchlorvynol).
The benzodiazepine antagonist flumazenil (Romazicon) should be used with extreme caution, if at all. The dose is 0.2 mg intravenously slowly repeated every 5–10 minutes as needed, up to a maximum 3–5 mg. Effects wear off in 1–3 hours, and repeated sedation is common. Contraindications include known seizure disorder, coingestion of drugs known to cause seizures, benzodiazepine addiction, and tricyclic antidepressant overdose. General supportive care usually suffices.
Hospitalize patients with sedative–hypnotic drug poisoning resulting in depression of vital reflexes (eg, respiration and gag reflex).
Charlson F, Degenhardt L, McLaren J, Hall W, Lynskey M: A systematic review of research examining benzodiazepine-related mortality. Pharmacoepidemiol Drug Saf 2009;18:93–103
- Minimum acute toxic dose is 10 mg/kg
- Mild symptoms include nausea and vomiting, tremor, anxiety, and abdominal cramping
- Severe symptoms include arrhythmias and seizures
Theophylline, caffeine, and other methylxanthines cause bronchodilatation; gastric, central nervous system, and cardiac stimulation; and vasodilatation. The half-life is 4–8 hours and is shortened in chronic smokers and prolonged in patients with congestive heart failure or cirrhosis. In acute overdose, the half-life may be markedly prolonged (up to 50 hours).
The minimum acute toxic dose is over 10 mg/kg, or 700 mg, in the average adult. Because drug metabolism varies markedly depending on the patient's clinical status, careful monitoring of patients receiving therapeutic doses is necessary to avoid iatrogenic toxicity.
Mild symptoms of toxicity are nausea and vomiting, abdominal cramps, tremor, and anxiety. Arrhythmias and seizures occur with more serious intoxication. Seizures are often refractory to treatment with standard anticonvulsants. The characteristics of acute single overdose differ from those of chronic, subacute overmedication. Acute overdose is characterized by hypotension, tachycardia, and hypokalemia. Seizures and serious arrhythmias are common with levels over 100 mg/L but rare with levels under 90 mg/L. By contrast, chronic intoxication more commonly results in seizures and arrhythmias with much lower serum levels (ie, 20–70 mg/L). Hypotension and hypokalemia are uncommon. The elderly are at highest risk for fatal outcome.
Sustained-release theophylline preparations are now commonly used, so that after acute overdose, early blood concentrations of the drug may be low and gastrointestinal symptoms absent. Obtain serial blood levels until the theophylline level begins to fall.
Provide intensive supportive care and gastrointestinal decontamination as described previously.
Consider activated charcoal if a significant dose has been ingested within 1 hour of arrival at the emergency department. Administer multidose activated charcoal and consider whole bowel irrigation for sustained-release preparations.
Seizures are usually difficult to control with standard drugs. Start with diazepam, 0.1–0.2 mg/kg as an intravenous bolus, followed by phenobarbital, 15 mg/kg intravenously over 20–30 minutes. Perform hemoperfusion immediately if seizures are not controlled.
Treat hypotension with intravenous fluids. Propranolol, 0.02–0.05 mg/kg, or esmolol, 25–50 μg/kg/min, intravenously, may reverse hypotension associated with tachycardia, both of which are mediated by excessive β-adrenergic stimulation.
Ventricular tachyarrhythmias and rapid atrial fibrillation may be controlled with propranolol or esmolol intravenously or with standard antiarrhythmics.
Charcoal hemoperfusion, hemofiltration, or hemodialysis is the treatment of choice for severe poisoning. Hemoperfusion is the treatment of choice for severe poisoning (intractable seizures, acute overdose with serum level over 80–100 mg/L, and hemodynamic instability). Repeated doses of activated charcoal may be effective at lowering theophylline levels, obviating extracorporeal treatment.
Hospitalize patients with significant theophylline poisoning (serum concentrations above 30 μg/mL or signs or symptoms of toxicity).
Dhar R, Stout CW, Link MS et al: Cardiovascular toxicities of performance-enhancing substances in sports. Mayo Clin Proc 2005;80:1307–-1315
Warfarin and Other Anticoagulants
- A single overdose with warfarin usually does not cause significant bleeding
- May see ecchymosis, hematuria, melena, epistaxis, gingival bleeding, hematoma, and hematemesis
- Life-threatening cardiac tamponade and intracranial hemorrhage may occur
Dicumarol and other natural anticoagulants are found in sweet clover. Warfarin and other synthetic coumarin-like anticoagulants are used therapeutically and as rodenticides.
Warfarin and other coumarin-like compounds inhibit blood clotting by interfering with the synthesis of vitamin K dependent clotting factors (II, VII, IX, X). Only the synthesis of new factors is affected, and the anticoagulation effect is delayed until currently circulating factors have degraded. Thus, effects may be seen within 8–12 hours after ingestion because factor II has only a 6-hour half-life, but peak effects are usually not observed until 1–2 days after ingestion because of the longer half-lives (24–60 hours) of the other clotting factors.
The potency and pharmacokinetics of the different coumarin anticoagulants vary. Warfarin is highly bound to albumin and has a half-life of 35 hours. It is metabolized by the liver. Multiple drug interactions are known to increase or decrease the anticoagulation effect (Table 47–20).
Table 47–20. Interactions of Warfarin and Oral Anticoagulants with Selected Drugs.
A single overdose with warfarin does not usually cause significant bleeding, because the half-life of warfarin is shorter than that of some of the clotting factors. Chronic warfarin administration carries a greater risk of excessive anticoagulation and bleeding. However, some extremely potent and long-acting anticoagulants, also known as super-warfarins (brodifacoum, indanediones), may produce severe bleeding disturbance for several weeks to months.
Excessive anticoagulation may result in ecchymoses, hematuria, uterine bleeding, melena, epistaxis, gingival bleeding, hemoptysis, or hematemesis. Hematomas may result in compression neuropathy or compartment syndrome. Life-threatening cardiac tamponade and intracranial hemorrhage have been reported. Such complications can be prevented if the international normalized ratio (INR) is carefully monitored and kept within the desired therapeutic range, if interacting drugs are avoided, and if antidotal therapy is begun promptly when necessary.
Provide intensive supportive care and gastrointestinal decontamination as described previously. Treatment is rarely required for acute single overdose of warfarin, because the dose involved (eg, from typical rodenticide) is small, and any anticoagulation effect is usually brief and mild. However, caution and careful follow-up are indicated after ingestion of the super-warfarins. Obtain a baseline prothrombin time and repeat the measurement after 24 and 48 hours. Children who ingest a rodenticide rarely require treatment.
Treatment of Major Hemorrhage
For major hemorrhage (eg, intracranial hemorrhage, aortic dissection, and shock), control bleeding with fluid resuscitation and withhold further doses of warfarin. Vitamin K, 5–10 mg intravenously, should be given along with fresh-frozen plasma, 15 mL/kg, or prothrombin complex concentrates. For patients with asymptomatic prolongation of the INR (>10), give vitamin K, 2–5 mg orally, without fresh-frozen plasma. Recheck the INR in 6–12 hours. If the INR is between 6 and 10, give vitamin K, 2 mg, orally without fresh-frozen plasma and recheck the INR in 12–24 hours. In all the above cases, vitamin K should be given intravenously or orally, not intramuscularly, because of the risk of erratic absorption and hematoma formation.
Hospitalize all patients with significantly prolonged prothrombin times, evidence of bleeding, or history of ingestion of massive amounts of anticoagulants. Patients who have documented anticoagulant effect after ingestion of the super-warfarin rodenticides will need close follow-up and repeated vitamin K dosing for up to several weeks.
Watt BE, Proudfoot AT, Bradberry SM, Vale JA: Anticoagulant rodenticides. Toxicol Rev 2005;24:259–269