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Poisoning Kent R. Olson, MD
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INITIAL EVALUATION: POISONING OR OVERDOSE Patients with drug overdoses or poisoning may initially have no symptoms or they may have varying degrees of overt intoxication. The asymptomatic patient may have been exposed to or may have ingested a lethal dose but not yet exhibit any manifestations of toxicity. It is important to: (1) quickly assess the potential danger, (2) consider gut decontamination to prevent absorption, (3) treat complications if they occur, and (4) observe the asymptomatic patient for an appropriate interval.
``Assess the Danger If the drug or poison is known, its danger can be assessed by consulting a text or computerized information resource or by calling a regional poison control center. (In the United States, dialing 1-800-222-1222 will direct the call to the regional poison control center.) Assessment will usually take into account the dose ingested; the time since ingestion; the presence of any symptoms or clinical signs; preexisting cardiac, respiratory, kidney, or liver disease; and, occasionally, specific serum drug or toxin levels. Be aware that the history given by the patient or family may be incomplete or unreliable.
Immediate 24-Hour Toxicology Consultation Call your regional poison control center U.S. toll-free 1-800-222-1222
``Observation of the Patient Asymptomatic or mildly symptomatic patients should be observed for at least 4–6 hours. Longer observation is indicated if the ingested substance is a sustained-release preparation or is known to slow gastrointestinal motility or may cause a delayed onset of symptoms (such as acetaminophen, colchicine, or hepatotoxic mushrooms). After that time, the patient may be discharged if no symptoms
have developed. Before discharge, psychiatric evaluation should be performed to assess suicide risk. Intentional ingestions in adolescents should raise the possibility of unwanted pregnancy or sexual abuse. cc
THE SYMPTOMATIC PATIENT
In symptomatic patients, treatment of life-threatening complications takes precedence over in-depth diagnostic evaluation. Patients with mild symptoms may deteriorate rapidly, which is why all potentially significant exposures should be observed in an acute care facility. The following complications may occur, depending on the type of poisoning.
COMA ``Assessment & Complications Coma is commonly associated with ingestion of large doses of antihistamines (eg, diphenhydramine), benzodiazepines and other sedative-hypnotic drugs, ethanol, opioids, antipsychotic drugs, or antidepressants. The most common cause of death in comatose patients is respiratory failure, which may occur abruptly. Pulmonary aspiration of gastric contents may also occur, especially in victims who are deeply obtunded or convulsing. Hypoxia and hypoventilation may cause or aggravate hypotension, arrhythmias, and seizures. Thus, protection of the airway and assisted ventilation are the most important treatment measures for any poisoned patient.
``Treatment A. Emergency Management The initial emergency management of coma can be remembered by the mnemonic ABCD, for Airway, Breathing, Circulation, and Drugs (dextrose, thiamine, and naloxone or flumazenil), respectively. 1. Airway—Establish a patent airway by positioning, suction, or insertion of an artificial nasal or oropharyngeal airway. If the patient is deeply comatose or if airway
Poisoning reflexes are depressed, perform endotracheal intubation. These airway interventions may not be necessary if the patient is intoxicated by an opioid or a benzodiazepine and responds to intravenous naloxone or flumazenil (see below). 2. Breathing—Clinically assess the quality and depth of respiration, and provide assistance if necessary with a bagvalve-mask device or mechanical ventilator. Administer supplemental oxygen, if needed. The arterial blood CO2 tension is useful in determining the adequacy of ventilation. The arterial blood Po2 determination may reveal hypoxemia, which may be caused by respiratory arrest, broncho spasm, pulmonary aspiration, or noncardiogenic pulmonary edema. Pulse oximetry provides an assessment of oxygenation but is not reliable in patients with methemoglobinemia or carbon monoxide poisoning, unless a newer pulse oximetry device capable of detecting these forms of hemoglobin is used (eg, the Masimo pulse CO-oximeter). 3. Circulation—Measure the pulse and blood pressure and estimate tissue perfusion (eg, by measurement of urinary output, skin signs, arterial blood pH). Place the patient on continuous ECG monitoring. Insert an intravenous line, and draw blood for glucose, electrolytes, serum creatinine and liver tests, and possible quantitative toxicologic testing. 4. Drugs A. Dextrose and thiamine—Unless promptly treated, severe hypoglycemia can cause irreversible brain damage. Therefore, in all obtunded, comatose or convulsing patients, give 50% dextrose, 50–100 mL by intravenous bolus, unless a rapid bedside blood sugar test is available and rules out hypoglycemia. In alcoholic or very malnourished patients who may have marginal thiamine stores, give thiamine, 100 mg intramuscularly or in the intravenous fluids. B. Opioid antagonists—Naloxone, 0.4–2 mg intravenously, may reverse opioid-induced respiratory depression and coma. It is often given empirically to any comatose patient with depressed respirations. If opioid overdose is strongly suspected, give additional doses of naloxone (up to 5–10 mg may be required to reverse the effects of potent opioids). Note: Naloxone has a shorter duration of action (2–3 hours) than most common opioids; repeated doses may be required, and continuous observation for at least 3–4 hours after the last dose is mandatory. Nalmefene, a newer opioid antagonist, has a duration of effect longer than that of naloxone but still shorter than that of the opioid methadone. C. Flumazenil—Flumazenil, 0.2–0.5 mg intravenously, repeated as needed up to a maximum of 3 mg, may reverse benzodiazepine-induced coma. Caution: Flumazenil should not be given if the patient has coingested a tricyclic antidepressant or other potential convulsant, is a user of high-dose benzodiazepines, or has a seizure disorder because its use in these circumstances may precipitate seizures. In most circumstances, use of flumazenil is not advised as the potential risks outweigh its benefits. Note: Flumazenil has a short duration of effect (2–3 hours), and resedation requiring additional doses may occur.
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HYPOTHERMIA ``Assessment & Complications Hypothermia commonly accompanies coma due to opioids, ethanol, hypoglycemic agents, phenothiazines, barbiturates, benzodiazepines, and other sedative-hypnotics and central nervous system depressants. Hypothermic patients may have a barely perceptible pulse and blood pressure. Hypothermia may cause or aggravate hypotension, which will not reverse until the temperature is normalized.
``Treatment Treatment of hypothermia is discussed in Chapter 37. Gradual rewarming is preferred unless the patient is in cardiac arrest.
HYPOTENSION ``Assessment & Complications Hypotension may be due to poisoning by many different drugs and poisons, including antihypertensive drugs, β-blockers, calcium channel blockers, disulfiram (ethanol interaction), iron, trazodone, quetiapine, and other anti psychotic agents and antidepressants. Poisons causing hypotension include cyanide, carbon monoxide, hydrogen sulfide, aluminum phosphide, arsenic, and certain mushrooms. Hypotension in the poisoned or drug-overdosed patient may be caused by venous or arteriolar vasodilation, hypovolemia, depressed cardiac contractility, or a combination of these effects.
``Treatment Most hypotensive patients respond to empiric treatment with repeated 200 mL intravenous boluses of 0.9% saline or other isotonic crystalloid up to a total of 1–2 L; much larger amounts may be needed if the victim is profoundly volume depleted (eg, as with Amanita phalloides mushroom poisoning). Monitoring the central venous pressure (CVP) can help determine whether further fluid therapy is needed. If fluid therapy is not successful, give dopamine or norepinephrine by intravenous infusion. Consider bedside cardiac ultrasound or pulmonary artery catheterization (or both) if hypotension persists. Hypotension caused by certain toxins may respond to specific treatment. For hypotension caused by overdoses of tricyclic antidepressants or other sodium channel blockers, administer sodium bicarbonate, 50–100 mEq by intravenous bolus injection. Norepinephrine 4–8 mcg/min by intravenous infusion is more effective than dopamine in some patients with overdoses of tricyclic antidepressants or of drugs with predominantly vasodilating effects. For β-blocker overdose, glucagon (5–10 mg intravenously) may be of value. For calcium channel blocker overdose, administer calcium chloride, 1–2 g intravenously (repeated doses may be necessary; doses of 5–10 g and more have been given in some cases). High-dose insulin (0.5-1 units/ kg/h intravenously) euglycemic therapy may also be used (see the sections on β-Adrenergic Blockers and Calcium Channel Blockers, below). Intralipid 20% lipid emulsion
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has been reported to improve hemodynamics in human case reports or animal studies of intoxication by highly lipid-soluble drugs such as bupivacaine, bupropion, clomipramine, and verapamil. Jamaty C et al. Lipid emulsions in the treatment of acute poisoning: a systematic review of human and animal studies. Clin Toxicol (Phila). 2010 Jan;48(1):1–27. [PMID: 20095812]
Table 38–1. Common toxins or drugs causing arrhythmias.1 Arrhythmia Sinus bradycardia
β-Blockers, calcium channel blockers, clonidine, digitalis glycosides, organophosphates
Atrioventricular block
β-Blockers, calcium channel blockers, class Ia antiarrhythmics (including quinidine), carbamazepine, clonidine, digitalis glycosides, lithium
Sinus tachycardia
β-Agonists (eg, albuterol), amphetamines, anticholinergics, antihistamines, caffeine, cocaine, pseudoephedrine, tricyclic and other antidepressants
Wide QRS complex
Class Ia and class Ic antiarrhythmics, phenothiazines (eg, thioridazine), potassium (hyperkalemia), propranolol, tricyclic antidepressants, bupropion, lamotrigine, diphenhydramine (severe overdose)
QT interval prolongation and torsades de pointes
Arsenic, class Ia and class III antiarrhythmics, citalopram, droperidol, lithium, methadone, pentamidine, sertraline, sotalol, thioridazine, and many other drugs2
Ventricular premature beats and ventricular tachycardia
Amphetamines, cocaine, ephedrine, caffeine, chlorinated or fluorinated hydrocarbons, digoxin, aconite (found in some Chinese herbal preparations), fluoride, theophylline. QT prolongation can lead to atypical ventricular tachycardia (torsades de pointes)
HYPERTENSION ``Assessment & Complications Hypertension may be due to poisoning with amphetamines, anticholinergics, cocaine, performance-enhancing products (containing caffeine, phenylephrine, ephedrine, or yohimbine), monoamine oxidase (MAO) inhibitors, and other drugs. Severe hypertension (eg, diastolic blood pressure > 105–110 mm Hg in a person who does not have chronic hypertension) can result in acute intracranial hemorrhage, myocardial infarction, or aortic dissection.
``Treatment Treat hypertension if the patient is symptomatic or if the diastolic pressure is > 105–110 mm Hg—especially if there is no prior history of hypertension. Hypertensive patients who are agitated or anxious may benefit from a sedative such as lorazepam, 2–3 mg intravenously. For persistent hypertension, administer phentolamine, 2–5 mg intravenously, or nitroprusside sodium, 0.25–8 mcg/kg/min intravenously. If excessive tachycardia is present, add propranolol, 1–5 mg intravenously, or esmolol, 25–100 mcg/kg/min intravenously, or labetalol 0.2–0.3 mg/ kg intravenously. Caution: Do not give β-blockers alone, since doing so may paradoxically worsen hypertension as a result of unopposed α-adrenergic stimulation. Wang NE et al. Hypertensive crisis and NSTEMI after accidental overdose of sustained release pseudoephedrine: a case report. Clin Toxicol (Phila). 2008 Nov;46(9):922–3. [PMID: 18608273]
ARRHYTHMIAS ``Assessment & Complications Arrhythmias may occur with a variety of drugs or toxins (Table 38–1). They may also occur as a result of hypoxia, metabolic acidosis, or electrolyte imbalance (eg, hyperkalemia, hypokalemia, hypomagnesemia or hypocalcemia), or following exposure to chlorinated solvents or chloral hydrate overdose. Atypical ventricular tachycardia (torsades de pointes) is often associated with drugs that prolong the QT interval.
``Treatment Arrhythmias may be caused by hypoxia or electrolyte imbalance, and these conditions should be sought and treated. If
Common Causes
1 Arrhythmias may also occur as a result of hypoxia, metabolic acidosis, or electrolyte imbalance (eg, hyperkalemia or hypokalemia, hypocalcemia, hypomagnesemia). 2 http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm
ventricular arrhythmias persist, administer lidocaine or amiodarone at usual antiarrhythmic doses. Note: Wide QRS complex tachycardia in the setting of tricyclic antidepressant overdose (or diphenhydramine or class Ia antiarrhythmic drugs) should be treated with sodium bicarbonate, 50–100 mEq intravenously by bolus injection. (See discussion of tricyclic antidepressant poisoning.) Caution: Avoid class Ia antiarrhythmic agents (eg, procainamide, disopyramide), which may aggravate arrhythmias caused by tricyclic anti depressants. Torsades de pointes associated with prolonged QT interval may respond to intravenous magnesium (2 g intravenously over 2 minutes) or overdrive pacing. Treat digitalis-induced arrhythmias with digoxin-specific antibodies (see discussion of cardiac glycoside poisoning). For tachyarrhythmias induced by chlorinated solvents, chloral hydrate, Freons, or sympathomimetic agents, use propranolol or esmolol (see doses given above in Hypertension section). Barnes BJ et al. Drug-induced arrhythmias. Crit Care Med. 2010 Jun;38(6 Suppl):S188–97. [PMID: 20502173]
Poisoning
SEIZURES ``Assessment & Complications Seizures may be due to poisoning with many poisons and drugs, including amphetamines, antidepressants (especially tricyclic antidepressants, bupropion, and venlafaxine), antihistamines (especially diphenhydramine), antipsychotics, camphor, cocaine, isoniazid (INH), chlorinated insecticides, and theophylline. Massive overdose with acetaminophen has caused seizures. The onset of seizures may be delayed for up to 22 hours after sustained-released bupropion overdose. Seizures may also be caused by hypoxia, hypoglycemia, hypocalcemia, hyponatremia, withdrawal from alcohol or sedative-hypnotics, head trauma, central nervous system infection, or idiopathic epilepsy. Prolonged or repeated seizures may lead to hypoxia, metabolic acidosis, hyperthermia, and rhabdomyolysis.
``Treatment Administer lorazepam, 2–3 mg, or diazepam, 5–10 mg, intravenously over 1–2 minutes, or—if intravenous access is not immediately available—midazolam, 5–10 mg intramuscularly. If convulsions continue, administer phenobarbital, 15–20 mg/kg slowly intravenously over no less than 30 minutes. (For drug-induced seizures, phenobarbital is preferred over phenytoin.) Propofol infusion has also been reported effective for some resistant drug-induced seizures. Seizures due to a few drugs and toxins may require antidotes or other specific therapies (as listed in Table 38–2).
Table 38–2. Seizures related to toxins or drugs requiring special consideration.1 Toxin or Drug
1
Comments
Methylenedioxymethamphetamine (MDMA; “Ecstasy”)
Seizures may also be due to hyponatremia or hyperthermia.
Isoniazid
Administer pyridoxine.
Lithium
May indicate need for hemodialysis.
Organophosphates
Administer pralidoxime (2-PAM) and atropine in addition to usual anticonvulsants.
Strychnine
“Seizures” are actually spinally mediated muscle spasms and usually require neuromuscular paralysis and mechanical ventilation.
Theophylline
Seizures indicate need for hemodialysis.
Tricyclic antidepressants
Hyperthermia and cardiotoxicity are common complications of repeated seizures; paralyze early with neuromuscular blockers to reduce muscular hyperactivity.
See text for dosages.
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Heard K et al. Massive acetylcysteine overdose associated with cerebral edema and seizures. Clin Toxicol (Phila). 2011 Jun; 49(5):423–5. [PMID: 21740141] Young AC et al. Late-onset seizures associated with quetiapine poisoning. J Med Toxicol. 2009 Mar;5(1):24–6. [PMID: 19191211]
HYPERTHERMIA ``Assessment & Complications Hyperthermia may be associated with poisoning by amphetamines (especially methylenedioxymethamphetamine [MDMA; “Ecstasy”]), atropine and other anti-cholinergic drugs, cocaine, salicylates, strychnine, tricyclic antidepressants, and various other medications. Overdoses of serotonin reuptake inhibitors (eg, fluoxetine, paroxetine, sertraline) or their use in a patient taking an MAO inhibitor may cause agitation, hyperactivity, myoclonus, and hyperthermia (“serotonin syndrome”). Antipsychotic agents can cause rigidity and hyperthermia (neuroleptic malignant syndrome [NMS]). (See section on schizophrenia and other psychotic disorders in Chapter 25.) Malignant hyperthermia is a rare disorder associated with general anesthetic agents. Hyperthermia is a rapidly life-threatening complication. Severe hyperthermia (temperature > 40–41°C) can rapidly cause brain damage and multiorgan failure, including rhabdomyolysis, acute renal failure, and coagulopathy (see Chapter 37).
``Treatment Treat hyperthermia aggressively by removing the patient’s clothing, spraying the skin with tepid water, and fanning. If this is not rapidly effective, as shown by a normal rectal temperature within 30–60 minutes, or if there is significant muscle rigidity or hyperactivity, induce neuromuscular paralysis with a nondepolarizing neuromuscular blocker (eg, rocuronium, vecuronium). Once paralyzed, the patient must be intubated and mechanically ventilated and sedated. While the patient is paralyzed, the absence of visible muscular convulsive movements may give the false impression that brain seizure activity has ceased; bedside electroencephalography may be useful in recognizing continued nonconvulsive seizures. Dantrolene (2–5 mg/kg intravenously) may be effective for hyperthermia associated with muscle rigidity that does not respond to neuromuscular blockade (ie, malignant hyperthermia). Bromocriptine, 2.5–7.5 mg orally daily, has been recommended for neuroleptic malignant syndrome. Cyproheptadine, 4 mg orally every hour for three or four doses, or chlorpromazine, 25 mg intravenously or 50 mg intramuscularly, has been used to treat serotonin syndrome. Ables AZ et al. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010 May 1;81(9): 1139–42. [PMID: 20433130] Gallelli L et al. A case of neuroleptic malignant syndrome induced by risperidone in a schizophrenic woman. Curr Drug Saf. 2009 May;4(2):119–20. [PMID: 19442104]
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ANTIDOTES & OTHER TREATMENT
ANTIDOTES Give an antidote (if available) when there is reasonable certainty of a specific diagnosis (Table 38–3). Be aware that some antidotes themselves may have serious side effects. The indications and dosages for specific antidotes are discussed in the respective sections for specific toxins. Dart RC et al; Antidote Summit Authorship Group. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care. Ann Emerg Med. 2009;54(3): 386–94. [PMID: 19406507]
DECONTAMINATION OF THE SKIN Corrosive agents rapidly injure the skin and eyes and must be removed immediately. In addition, many toxins are readily absorbed through the skin, and systemic absorption can be prevented only by rapid action. Wash the affected areas with copious quantities of lukewarm water or saline. Wash carefully behind the ears, under the nails, and in skin folds. For oily substances (eg, pesticides), wash the skin at least twice with plain soap and shampoo the hair. Specific decontaminating solutions or
Table 38–3. Some toxic agents for which there are specific antidotes.1 Toxic Agent
1
Specific Antidote
solvents (eg, alcohol) are rarely indicated and in some cases may paradoxically enhance absorption. For exposure to chemical warfare poisons such as nerve agents or vesicants, some authorities recommend use of a dilute hypochlorite solution (household bleach diluted 1:10 with water), but not in the eyes.
DECONTAMINATION OF THE EYES Act quickly to prevent serious damage. Flush the eyes with copious amounts of saline or water. (If available, instill local anesthetic drops in the eye before beginning irrigation.) Remove contact lenses if present. Direct the irrigating stream so that it will flow across the eyes after running off the nasal bridge. Lift the tarsal conjunctiva to look for undissolved particles and to facilitate irrigation. Continue irrigation for 15 minutes or until each eye has been irrigated with at least 1 L of solution. If the toxin is an acid or a base, check the pH of the tears after irrigation, and continue irrigation until the pH is between 6 and 8. Special amphoteric solutions (Diphoterine, Previn) have been introduced in Europe for treatment of alkali injuries to the eye. After irrigation is complete, perform a careful examination of the eye, using fluorescein and a slit lamp or Wood lamp to identify areas of corneal injury. Patients with ser ious conjunctival or corneal injury should be immediately referred to an ophthalmologist.
GASTROINTESTINAL DECONTAMINATION
Acetaminophen
N-Acetylcysteine
Anticholinergics (eg, atropine)
Physostigmine
Anticholinesterases (eg, organophosphate pesticides)
Atropine and pralidoxime (2-PAM)
Benzodiazepines
Flumazenil (rarely used; see warning in text)
Carbon monoxide
Oxygen (hyperbaric oxygen of uncertain benefit)
Cyanide
Sodium nitrite, sodium thiosulfate; hydroxocobalamin
Digitalis glycosides
Digoxin-specific Fab antibodies
Heavy metals (eg, lead, mercury, iron) and arsenic
Specific chelating agents
Isoniazid
Pyridoxine (vitamin B6)
Removal of ingested poisons was a routine part of emergency treatment for decades. However, prospective randomized studies have failed to demonstrate improved clinical outcome after gastric emptying. For small or moderate ingestions of most substances, toxicologists generally recommend oral activated charcoal alone without prior gastric emptying; in some cases, when the interval after ingestion has been more than 1–2 hours and the ingestant is non–life-threatening, even charcoal is withheld. Exceptions are large ingestions of anticholinergic compounds and salicylates, which often delay gastric emptying, and ingestion of sustained-release or enteric-coated tablets, which may remain intact for several hours. Gastric emptying is not generally used for ingestion of corrosive agents or petroleum distillates, because further esophageal injury or pulmonary aspiration may result. However, in certain cases, removal of the toxin may be more important than concern over possible complications. Consult a medical toxicologist or regional poison control center (1-800-222-1222) for advice.
Methanol, ethylene glycol
Ethanol (ethyl alcohol) or fomepizole (4-methylpyrazole)
A. Emesis
Opioids
Naloxone, nalmefene
Snake venom
Specific antivenin
Sulfonylurea oral hypoglycemic drugs
Glucose, octreotide
See text for indications and dosages.
Emesis using syrup of ipecac can partially evacuate gastric contents if given very soon after ingestion (eg, at work or at home). However, it may increase the risk of pulmonary aspiration and delay or prevent the use of oral activated charcoal. Therefore, it is no longer used in the routine management of ingestions.
Poisoning B. Gastric Lavage Gastric lavage is more effective for liquid poisons or small pill fragments than for intact tablets or pieces of mushroom. It is most useful when started within 60 minutes after ingestion. However, the lavage procedure may delay administration of activated charcoal and may stimulate vomiting and pulmonary aspiration in an obtunded patient. 1. Indications—Gastric lavage is sometimes used after very large ingestions (eg, massive aspirin overdose), for collection and examination of gastric contents for identification of the poison, and make it easier to administer charcoal and oral antidotes. 2. Contraindications—Do not use lavage for stuporous or comatose patients with depressed airway protective reflexes unless they are endotracheally intubated beforehand. Some authorities advise against lavage when caustic material has been ingested; others regard it as essential to remove liquid corrosives from the stomach. 3. Technique—In obtunded or comatose patients, the danger of aspiration pneumonia is reduced by performing endotracheal intubation with a cuffed tube before the procedure. Gently insert a lubricated, soft but noncollapsible stomach tube (at least 37–40 F) through the mouth or nose into the stomach. Aspirate and save the contents, and then lavage repeatedly with 50- to 100-mL aliquots of fluid until the return fluid is clear. Use lukewarm tap water or saline.
C. Activated Charcoal Activated charcoal effectively adsorbs almost all drugs and poisons. Poorly adsorbed substances include iron, lithium, potassium, sodium, mineral acids, and alcohols. 1. Indications—Activated charcoal can be used for prompt adsorption of drugs or toxins in the stomach and intestine. Studies in volunteers show that activated charcoal given alone may be as effective as, or more effective, than ipecacinduced emesis or gastric lavage. However, evidence of benefit in clinical studies is lacking. Administration of charcoal, especially if mixed with sorbitol, can provoke vomiting, which could lead to pulmonary aspiration in an obtunded patient. 2. Contraindications—Activated charcoal should not be used for comatose or convulsing patients unless it can be given by gastric tube and the airway is first protected by a cuffed endotracheal tube. It is also contraindicated for patients with ileus or intestinal obstruction or those who have ingested corrosives for whom endoscopy is planned. 3. Technique—Administer activated charcoal, 60–100 g orally or via gastric tube, mixed in aqueous slurry. Repeated doses may be given to ensure gastrointestinal adsorption or to enhance elimination of some drugs (see below).
D. Catharsis 1. Indications—Cathartics are used by some toxicologists for stimulation of peristalsis to hasten the elimination of unabsorbed drugs and poisons and the activated charcoal
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slurry. There is no clinical evidence to support their use, and some agents (eg, sorbitol) can provoke vomiting, increasing the risk of pulmonary aspiration. 2. Contraindications and cautions—Do not give a cathartic to patients with suspected intestinal obstruction. Avoid sodium-based cathartics in patients with hypertension, advanced chronic kidney disease, and congestive heart failure and avoid magnesium-based cathartics in patients with advanced chronic kidney disease. Sorbitol (an osmotic cathartic found in some prepackaged activated charcoal slurry products) can cause hypotension and dehydration due to third-spacing and also causes intestinal cramping and vomiting.
E. Whole Bowel Irrigation Whole bowel irrigation uses large volumes of a balanced polyethylene glycol-electrolyte solution to mechanically cleanse the entire intestinal tract. Because of the composition of the irrigating solution, there is no significant gain or loss of systemic fluids or electrolytes. 1. Indications—Whole bowel irrigation is particularly effective for massive iron ingestion in which intact tablets are visible on abdominal radiographs. It has also been used for ingestions of lithium, sustained-release and entericcoated tablets, and swallowed drug-filled packets. 2. Contraindications—Do not use in patients with suspected intestinal obstruction. Use with caution in patients who are obtunded or have depressed airway protective reflexes. 3. Technique—Administer a balanced polyethylene glycolelectrolyte solution (CoLyte, GoLYTELY) into the stomach via gastric tube at a rate of 1–2 L/h until the rectal effluent is clear. This may take several hours. It is most effective when patients are able to sit on a commode to pass the intestinal contents.
F. Increased Drug Removal 1. Urinary manipulation—Forced diuresis is hazardous; the risk of complications (pulmonary edema, electrolyte imbalance) usually outweighs its benefits. Acidic drugs (eg, salicylates, phenobarbital) are more rapidly excreted with an alkaline urine. Acidification (sometimes promoted for amphetamines, phencyclidine) is not very effective and is contraindicated in the presence of rhabdomyolysis or myoglobinuria. 2. Hemodialysis—The indications for dialysis are as follows: (1) Known or suspected potentially lethal amounts of a dialyzable drug (Table 38–4); (2) Poisoning with deep coma, apnea, severe hypotension, fluid and electrolyte or acid-base disturbance, or extreme body temperature changes that cannot be corrected by conventional measures; or (3) Poisoning in patients with severe kidney, cardiac, pulmonary, or hepatic disease who will not be able to eliminate toxin by the usual mechanisms. Continuous renal replacement therapy (also known as continuous venovenous hemodiafiltration or venovenous hemodiafiltration) is of uncertain benefit for elimination
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Table 38–4. Recommended use of hemodialysis in poisoning. Poison
Common Indications1
directed physical examination and ordering common clinical laboratory tests, the clinician can often make a tentative diagnosis that may allow empiric interventions or may suggest specific toxicologic tests.
``Physical Examination
Carbamazepine
Seizures, severe cardiotoxicity; serum level > 60 mg/L
Ethylene glycol
Acidosis, serum level > 50 mg/dL
Lithium
Severe symptoms; level > 4 mEq/L more than 12 hours after last dose. Note: dialysis of uncertain value; CVVHD may be preferable; consult with medical toxicologist.
Methanol
Acidosis, serum level > 50 mg/dL
A. Sympathomimetic Syndrome
Phenobarbital
Intractable hypotension, acidosis despite maximal supportive care
Salicylate
Severe acidosis, CNS symptoms, level > 100 mg/ dL (acute overdose) or > 60 mg/dL (chronic intoxication)
Theophylline
Serum level > 90–100 mg/L (acute) or seizures and serum level > 40–60 mg/L (chronic)
The blood pressure and pulse rate are elevated, though with severe hypertension reflex bradycardia may occur. The temperature is often elevated, pupils are dilated, and the skin is sweaty, though mucous membranes are dry. Patients are usually agitated, anxious, or frankly psychotic. Examples: Amphetamines, cocaine, ephedrine and pseudoephedrine.
Valproic acid
Serum level > 900–1000 mg/L or deep coma, severe acidosis
1
See text for further discussion of indications. CNS, central nervous system; CVVHD, continuous venovenous hemodialysis.
of most poisons but has the advantage of slow removal of the toxin and any accompanying acidosis, and its use has been reported in the management of lithium intoxication. 3. Repeat-dose charcoal—Repeated doses of activated charcoal, 20–30 g orally or via gastric tube every 3–4 hours, may hasten elimination of some drugs (eg, phenytoin, carbamazepine, dapsone) by absorbing drugs excreted into the gut lumen (“gut dialysis”). However, clinical studies have failed to prove better outcome using multiple-dose charcoal. Sorbitol or other cathartics should not be used with each dose, or resulting large stool volumes may lead to dehydration or hypernatremia. Dohlman CH et al. Chemical burns to the eye: paradigm shifts in treatment. Cornea. 2011 Jun;30(6):613–4. [PMID: 21242777] Kumar VV et al. The effect of decontamination procedures on the pharmacokinetics of venlafaxine in overdose. Clin Pharmacol Ther. 2009 Oct;86(4):403–10. [PMID: 19606091] Olson KR. Activated charcoal for acute poisoning: one toxicologist’s journey. J Med Toxicol. 2010 Jun;6(2):190–8. [PMID: 20490748] Thanacoody RH. Extracorporeal elimination in acute valproic acid poisoning. Clin Toxicol (Phila). 2009 Aug;47(7):609–16. [PMID: 19656009]
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DIAGNOSIS OF POISONING
The identity of the ingested substance or substances is usually known, but occasionally a comatose patient is found with an unlabeled container or the patient is unable or unwilling to give a coherent history. By performing a
Important diagnostic variables in the physical examination include blood pressure, pulse rate, temperature, pupil size, sweating, and the presence or absence of peristaltic activity. Poisonings may present with one or more of the following common syndromes.
B. Sympatholytic Syndrome The blood pressure and pulse rate are decreased and body temperature is low. The pupils are small or even pinpoint. Patients are usually obtunded or comatose. Examples: Barbiturates, benzodiazepines and other sedative hypnotics, γ-hydroxybutyrate (GHB), clonidine and related antihypertensives, ethanol, opioids.
C. Cholinergic Syndrome Stimulation of muscarinic receptors causes bradycardia, miosis, sweating, and hyperperistalsis as well as bronchorrhea, wheezing, excessive salivation, and urinary incontinence. Nicotinic receptor stimulation may produce initial hypertension and tachycardia as well as fasciculations and muscle weakness. Patients are usually agitated and anxious. Examples: Carbamates, nicotine, organophosphates (including nerve agents), physostigmine.
D. Anticholinergic Syndrome Tachycardia with mild hypertension is common, and the body temperature is often elevated. Pupils are widely dilated. The skin is flushed, hot, and dry. Peristalsis is decreased, and urinary retention is common. Patients may have myoclonic jerking or choreoathetoid movements. Agitated delirium is frequently seen, and severe hyperthermia may occur. Examples: Atropine, scopolamine, other naturally occurring and pharmaceutical anticholinergics, antihistamines, tricyclic antidepressants.
``Laboratory Tests The following clinical laboratory tests are recommended for screening of the overdosed patient: measured serum osmolality and osmol gap, electrolytes and anion gap, glucose, creatinine, blood urea nitrogen (BUN), urinalysis (eg, oxalate crystals with ethylene glycol poisoning,
Poisoning
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myoglobinuria with rhabdomyolysis), and electrocardiography. Serum acetaminophen and ethanol quantitative levels should be determined in all patients with drug overdoses.
The osmol gap should also be checked; combined elevated anion and osmol gaps suggests poisoning by methanol or ethylene glycol, though this may also occur in patients with diabetic ketoacidosis and alcoholic ketoacidosis.
A. Osmol Gap
C. Toxicology Laboratory Testing
The osmol gap (see Table 38–5) is increased in the presence of large quantities of low-molecular-weight substances, most commonly ethanol. Common poisons associated with increased osmol gap are acetone, ethanol, ethylene glycol, isopropyl alcohol, methanol, and propylene glycol. Note: Severe alcoholic ketoacidosis and diabetic ketoacidosis can also cause an elevated osmol gap resulting from the production of ketones and other low-molecular-weight substances.
A comprehensive toxicology screen is of little value in the initial care of the poisoned patient because results do not return in time to influence clinical management. Specific quantitative levels of certain drugs may be extremely helpful (Table 38–6) however, especially if specific antidotes or interventions (eg, dialysis) would be indicated based on the results. If a toxicology screen is required, urine is the best specimen. Many hospitals can perform a quick but limited screen for “drugs of abuse” (typically these screens include
B. Anion Gap Metabolic acidosis associated with an elevated anion gap is usually due to an accumulation of lactic acid or other acids (see Chapter 21). Common causes of elevated anion gap in poisoning include carbon monoxide, cyanide, ethylene glycol, medicinal iron, INH, methanol, metformin, ibuprofen and salicylates. Massive acetaminophen overdose can cause early-onset anion gap metabolic acidosis. Table 38–5. Use of the osmol gap in toxicology. The osmol gap (∆osm) is determined by subtracting the calculated serum osmolality from the measured serum osmolality. Glucose BUN Calculated ( m g/dL) (mg/dL) + osmolality = 2[Na (mEq/L)] + + 18 2.8 (osm)
∆osm = Measured osmolality – Calculated osmolality Serum osmolality may be increased by contributions of circulating alcohols and other low-molecular-weight substances. Since these substances are not included in the calculated osmolality, there will be a gap proportionate to their serum concentration and inversely proportionate to their molecular weight: Molecular w e ight Serum conce ntration = ∆ osm × (mg/dL) 10
Molecular Weight
Toxic Concentration
Approximate Corresponding ∆osm (mosm/L)
46
300
65
Methanol
32
50
16
Ethylene glycol
60
100
16
Isopropanol
60
150
25
Ethanol
Note: The normal osmol gap may vary by as much as ± 10 mosm/L; thus, small osmol gaps may be unreliable in the diagnosis of poisoning. Adapted, with permission, from Stone CK, Humphries RL (editors): Current Emergency Diagnosis & Treatment, 5th ed. McGraw-Hill, 2004.
Table 38–6. Specific quantitative levels and potential therapeutic interventions.1 Drug or Toxin
Treatment
Acetaminophen
Specific antidote (N-acetylcysteine) based on serum level
Carbon monoxide
High carboxyhemoglobin level indicates need for 100% oxygen, consideration of hyperbaric oxygen
Carbamazepine
High level may indicate need for hemodialysis
Digoxin
On basis of serum digoxin level and severity of clinical presentation, treatment with Fab antibody fragments (eg, DigiFab) may be indicated
Ethanol
Low serum level may suggest nonalcoholic cause of coma (eg, trauma, other drugs, other alcohols). Serum ethanol may also be useful in monitoring ethanol therapy for methanol or ethylene glycol poisoning.
Iron
Level may indicate need for chelation with deferoxamine
Lithium
Serum levels can guide decision to institute hemodialysis
Methanol, ethylene glycol
Acidosis, high levels indicate need for hemodialysis, therapy with ethanol or fomepizole
Methemoglobin
Methemoglobinemia can be treated with methylene blue intravenously
Salicylates
High level may indicate need for hemodialysis, alkaline diuresis
Theophylline
Immediate hemodialysis or hemoperfusion may be indicated based on serum level
Valproic acid
Elevated levels may indicate need to consider hemodialysis or L-carnitine therapy, or both
1 Some drugs or toxins may have profound and irreversible toxicity unless rapid and specific management is provided outside of routine supportive care. For these agents, laboratory testing may provide the serum level or other evidence required for administering a specific antidote or arranging for hemodialysis.
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only opiates, amphetamines, and cocaine, and some add benzodiazepines, barbiturates, methadone, and tetrahydrocannabinol [marijuana]). There are numerous falsepositive and false-negative results. For example, synthetic opioids, such as fentanyl, oxycodone, and methadone are usually not detected by routine opiate screening. Blood samples may be saved for possible quantitative testing, but blood is not generally used for screening purposes since it is relatively insensitive for many common drugs, including psychotropic agents, opioids, and stimulants.
``Abdominal Radiographs A plain film of the abdomen may reveal radiopaque iron tablets, drug-filled condoms, or other toxic material. Studies suggest that few tablets are predictably visible (eg, ferrous sulfate, sodium chloride, calcium carbonate, and potassium chloride). Thus, the radiograph is useful only if abnormal.
``When to Refer Consultation with a regional poison control center (1-800222-1222) or a medical toxicologist is recommended when the diagnosis is uncertain; there are questions about what laboratory tests to order; when dialysis is being considered to remove the drug or poison; or when advice is needed regarding the indications, dose, and side effects of antidotes.
intermediate attacks other cell proteins, causing necrosis. Patients with enhanced P450 2E1 activity, such as chronic alcoholics and patients taking INH, are at increased risk of developing hepatotoxicity. Hepatic toxicity may also occur after long-term overuse of acetaminophen—eg, as a result of taking two or three acetaminophen-containing products concurrently or exceeding the recommended maximum dose of 4 g/d for several days.
``Clinical Findings Shortly after ingestion, patients may have nausea or vomiting, but there are usually no other signs of toxicity until 24–48 hours after ingestion, when hepatic aminotransferase levels begin to increase. With severe poisoning, fulminant hepatic necrosis may occur, resulting in jaundice, hepatic encephalopathy, advanced chronic kidney disease, and death. Rarely, massive ingestion (eg, serum levels > 500–1000 mg/L [33–66 mmol/L]) can cause early onset of acute coma, seizures, hypotension, and metabolic acidosis unrelated to hepatic injury. The diagnosis after acute overdose is based on measurement of the serum acetaminophen level. Plot the serum level versus the time since ingestion on the acetaminophen nomogram shown in Figure 38–1. Ingestion of sustainedrelease products or coingestion of an anticholinergic agent,
``When to Admit
Goldfrank LR (editor). Goldfrank’s Toxicologic Emergencies, 9th ed. McGraw-Hill, 2010. Olson KR (editor). Poisoning & Drug Overdose, 6th ed. McGrawHill, 2011.
cc
SELECTED POISONINGS
ACETAMINOPHEN Acetaminophen (paracetamol in the United Kingdom, Europe) is a common analgesic found in many nonprescription and prescription products. After absorption, it is metabolized mainly by glucuronidation and sulfation, with a small fraction metabolized via the P450 mixedfunction oxidase system (2E1) to a highly toxic reactive intermediate. This toxic intermediate is normally detoxified by cellular glutathione. With acute acetaminophen overdose (> 150–200 mg/kg, or 8–10 g in an average adult), hepatocellular glutathione is depleted and the reactive
300 200 at 4 hours
200 Plasma or serum acetaminophen concentration (mcg/mL)
• The patient has symptoms and signs of intoxication that are not expected to clear within a 6–8 hour observation period. • Delayed absorption of the drug might be predicted to cause a later onset of serious symptoms (eg, after ingestion of a sustained-release product). • Continued administration of an antidote is required (eg, N-acetylcysteine for acetaminophen overdose). • Psychiatric or social services evaluation is needed for suicide attempt or suspected drug abuse.
Probable toxicity
100 80 60 50 40 30
50 at 12 hours
20 No toxicity 10 8 6 5 4 3
0
5
10 15 20 Hours after ingestion
25
30
s Figure 38–1. Nomogram for prediction of acetaminophen hepatotoxicity following acute overdosage. The upper line defines serum acetaminophen concentrations associated with a risk of hepatotoxicity; the lower line defines serum levels 25% below those expected to cause hepatotoxicity. In uncomplicated cases, the upper line can be used as an indication for therapy with N-acetylcysteine. However, to provide a margin for error in the estimation of the time of ingestion and for patients at higher risk for hepatotoxicity, the lower line is usually used as a guide to treatment. (Adapted, with permission, from Rumack BH et al. Acetaminophen poisoning and toxicity. Pediatrics. 1975 Jun;55(6):871–6.)
Poisoning salicylate, or opioid drug may cause delayed elevation of serum levels and may render the nomogram useless. The nomogram is also not useful after chronic overdose.
``Treatment A. Emergency and Supportive Measures Administer activated charcoal (see p 1567) if it can be given within 1–2 hours of the ingestion. Although charcoal may interfere with absorption of the oral antidote acetylcysteine, this is not considered clinically significant.
B. Specific Treatment Although the risk is greatest if the serum acetaminophen level is above the upper line on the nomogram (Figure 38–1), many clinicians and published guidelines prefer to use the lower line as a guide to treatment, as it provides an added safety margin. If the precise time of ingestion is unknown or if the patient is at higher risk for hepato toxicity (eg, alcoholic, liver disease, long-term use of P450inducing drugs), then some clinicians use a lower threshold for initiation of N-acetylcysteine (in some case reports, a level of 100 mg/L [66 mmol/L] at 4 hours was suggested in very high-risk patients). The antidote N-acetylcysteine can be given orally or intravenously. Oral treatment begins with a loading dose of N-acetylcysteine, 140 mg/kg, followed by 70 mg/kg every 4 hours. Dilute the solution to about 5% with water, juice, or soda. If vomiting interferes with oral N-acetylcysteine administration, consider giving the antidote intravenously (see below). The conventional oral N-acetylcysteine protocol in the United States calls for 72 hours of treatment. However, other regimens have demonstrated equivalent success with 20–48 hours of treatment. The FDA-approved 21-hour intravenous regimen of acetylcysteine (Acetadote) calls for a loading dose of 150 mg/ kg given intravenously over 60 minutes, followed by a 4-hour infusion of 50 mg/kg, and a 16-hour infusion of 100 mg/kg. (If Acetadote is not available, the conventional oral formulation may also be given intravenously using a micropore filter and a slow rate of infusion. Call a regional poison control center or medical toxicologist for assistance.) Treatment with N-acetylcysteine is most effective if it is started within 8–10 hours after ingestion. Alhelail MA et al. Clinical course of repeated supratherapeutic ingestion of acetaminophen. Clin Toxicol (Phila). 2011 Feb;49(2):108–12. [PMID: 21370947] Chomchai S et al. Acetaminophen psi parameter: a useful tool to quantify hepatotoxicity risk in acute acetaminophen overdose. Clin Toxicol (Phila). 2011 Aug;49(7):664–7. [PMID: 21819286] Chun LJ et al. Acetaminophen hepatotoxicity and acute liver failure. J Clin Gastroenterol. 2009 Apr;43(4):342–9. [PMID: 19169150]
ACIDS, CORROSIVE The strong mineral acids exert primarily a local corrosive effect on the skin and mucous membranes. Symptoms include severe pain in the throat and upper gastrointestinal
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tract; bloody vomitus; difficulty in swallowing, breathing, and speaking; discoloration and destruction of skin and mucous membranes in and around the mouth; and shock. Severe systemic metabolic acidosis may occur both as a result of cellular injury and from systemic absorption of the acid. Severe deep destructive tissue damage may occur after exposure to hydrofluoric acid because of the penetrating and highly toxic fluoride ion. Systemic hypocalcemia and hyperkalemia may also occur after fluoride absorption, even following skin exposure. Inhalation of volatile acids, fumes, or gases such as chlorine, fluorine, bromine, or iodine causes severe irritation of the throat and larynx and may cause upper airway obstruction and noncardiogenic pulmonary edema.
``Treatment A. Ingestion Dilute immediately by giving a glass (4–8 oz) of water to drink. Do not give bicarbonate or other neutralizing agents, and do not induce vomiting. Some experts recommend immediate cautious placement of a small flexible gastric tube and removal of stomach contents followed by lavage, particularly if the corrosive is a liquid or has important systemic toxicity. In symptomatic patients, perform flexible endoscopic esophagoscopy to determine the presence and extent of injury. CT scan or plain radiographs of the chest and abdomen may also reveal the extent of injury. Perforation, peritonitis, and major bleeding are indications for surgery.
B. Skin Contact Flood with water for 15 minutes. Use no chemical antidotes; the heat of the reaction may cause additional injury. For hydrofluoric acid burns, soak the affected area in benzalkonium chloride solution or apply 2.5% calcium gluconate gel (prepared by adding 3.5 g calcium gluconate to 5 oz of water-soluble surgical lubricant, eg, K-Y Jelly); then arrange immediate consultation with a plastic surgeon or other specialist. Binding of the fluoride ion may be achieved by injecting 0.5 mL of 5% calcium gluconate per square centimeter under the burned area. (Caution: Do not use calcium chloride.) Use of a Bier-block technique or intra arterial infusion of calcium is sometimes required for extensive burns or those involving the nail bed; consult with a hand surgeon or poison control center (1-800-222-1222).
C. Eye Contact Anesthetize the conjunctiva and corneal surfaces with topical local anesthetic drops (eg, proparacaine). Flood with water for 15 minutes, holding the eyelids open. Check pH with pH 6.0–8.0 test paper, and repeat irrigation, using 0.9% saline, until pH is near 7.0. Check for corneal damage with fluorescein and slit lamp examination; consult an ophthalmologist about further treatment.
D. Inhalation Remove from further exposure to fumes or gas. Check skin and clothing. Treat pulmonary edema.
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Rauber-Lüthy C et al. Household chemicals: management of intoxication and antidotes. EXS. 2010;100:339–63. [PMID: 20358689] Vohra R et al. Recurrent life-threatening ventricular dysrhythmias associated with acute hydrofluoric acid ingestion: observations in one case and implications for mechanism of toxicity. Clin Toxicol (Phila). 2008 Jan;46(1):79–84. [PMID: 17906993]
Donoghue AM. Diphoterine for alkali chemical splashes to the skin at alumina refineries. Int J Dermatol. 2010 Aug; 49(8):894–900. [PMID: 21174372] Pace F et al. What is new in esophageal injury (infection, druginduced, caustic, stricture, perforation)? Curr Opin Gastroenterol. 2009 Jul;25(4):372–9. [PMID: 19530274] Schmidt SM et al. Corneal injury due to a calcium hydroxide containing food preparation product (“cal”). Pediatr Emerg Care. 2008 Jul;24(7):468–70. [PMID: 18633308]
ALKALIES
AMPHETAMINES & COCAINE
The strong alkalies are common ingredients of some household cleaning compounds and may be suspected by their “soapy” texture. Those with alkalinity above pH 12.0 are particularly corrosive. Disk (or “button”) batteries are also a source. Alkalies cause liquefactive necrosis, which is deeply penetrating. Symptoms include burning pain in the upper gastrointestinal tract, nausea, vomiting, and difficulty in swallowing and breathing. Examination reveals destruction and edema of the affected skin and mucous membranes and bloody vomitus and stools. Radiographs may reveal evidence of perforation or the presence of radiopaque disk batteries in the esophagus or lower gastrointestinal tract.
Amphetamines and cocaine are widely abused for their euphorigenic and stimulant properties. Both drugs may be smoked, snorted, ingested, or injected. Amphetamines and cocaine produce central nervous system stimulation and a generalized increase in central and peripheral sympathetic activity. The toxic dose of each drug is highly variable and depends on the route of administration and individual tolerance. The onset of effects is most rapid after intravenous injection or smoking. Amphetamine derivatives and related drugs include methamphetamine (“crystal meth,” “crank”), MDMA (“Ecstasy”), ephedrine (“herbal ecstasy”), and methcathinone (“cat” or “khat”). Methcathinone derivatives and related synthetic chemicals such as methylenedioxypyrovalerone (MDPV) have become popular drugs of abuse and are often sold as purported “bath salts.” Amphetamine-like reactions have also been reported after use of synthetic cannabinoids (eg, “Spice” and “K2”). Nonprescription medications and nutritional supplements may contain stimulant or sympathomimetic drugs such as ephedrine, yohimbine, or caffeine (see also Theophylline section).
``Treatment A. Ingestion Dilute immediately with a glass of water. Do not induce emesis. Some gastroenterologists recommend immediate cautious placement of a small flexible gastric tube and removal of stomach contents followed by gastric lavage after ingestion of liquid caustic substances to remove residual material. Prompt endoscopy is recommended in symptomatic patients to evaluate the extent of damage; CT scanning may also aid in assessment. If a radiograph reveals the location of ingested disk batteries in the esophagus, immediate endoscopic removal is mandatory. The use of corticosteroids to prevent stricture formation is of no proved benefit and is definitely contraindicated if there is evidence of esophageal perforation.
B. Skin Contact Wash with running water until the skin no longer feels soapy. Relieve pain and treat shock.
C. Eye Contact Anesthetize the conjunctival and corneal surfaces with topical anesthetic (eg, proparacaine). Irrigate with water or saline continuously for 20–30 minutes, holding the lids open. Amphoteric solutions may be more effective than water or saline and some are available in Europe (Diphoterine, Previn). Check pH with pH test paper, and repeat irrigation for additional 30-minute periods until the pH is near 7.0. Check for corneal damage with fluorescein and slit lamp examination; consult an ophthalmologist for further treatment.
``Clinical Findings Presenting symptoms may include anxiety, tremulousness, tachycardia, hypertension, diaphoresis, dilated pupils, agitation, muscular hyperactivity, and psychosis. Muscle hyperactivity may lead to metabolic acidosis and rhabdomyolysis. In severe intoxication, seizures and hyperthermia may occur. Sustained or severe hypertension may result in intracranial hemorrhage, aortic dissection, or myocardial infarction. Ischemic colitis has been reported. Hyponatremia has been reported after MDMA use; the mechanism is not known but may involve excessive water intake, syndrome of inappropriate antidiuretic hormone (SIADH), or both. The diagnosis is supported by finding amphetamines or the cocaine metabolite benzoylecgonine in the urine. Note that many drugs can give a false-positive result on the immunoassay for amphetamines.
``Treatment A. Emergency and Supportive Measures Maintain a patent airway and assist ventilation, if necessary. Treat seizures as described at the beginning of this chapter (see p 1565). Rapidly lower the body temperature (see hyperthermia, p 1565) in patients who are hyperthermic (temperature > 39–40°C).
Poisoning B. Specific Treatment Treat agitation, psychosis, or seizures with a benzodiazepine such as diazepam, 5-10 mg, or lorazepam, 2–3 mg intravenously. Add phenobarbital 15 mg/kg intravenously for persistent seizures. Treat hypertension with a vaso dilator drug such as phentolamine (1–5 mg intravenously) or a combined α- and β-adrenergic blocker such as labetalol (10–20 mg intravenously). Do not administer a pure β-blocker such as propranolol alone, as this may result in paradoxic worsening of the hypertension as a result of unopposed α-adrenergic effects. Treat tachycardia or tachyarrhythmias with a shortacting β-blocker such as esmolol (25–100 mcg/kg/min by intravenous infusion). Treat hyperthermia as described above (see p 1565). Treat hyponatremia as outlined in Chapter 21. Holubar SD et al. Methamphetamine colitis: a rare case of ischemic colitis in a young patient. Arch Surg. 2009 Aug;144(8): 780–2. [PMID: 19687384] Kiely E et al. A fatality from an oral ingestion of methamphetamine. J Anal Toxicol. 2009 Oct;33(8):557–60. [PMID: 19874669] Ross EA et al. “Bath salts” intoxication. N Engl J Med. 2011 Sep 8;365(10):967–8. [PMID: 21899474] Spiller HA et al. Clinical experience with and analytical confirmation of “bath salts” and “legal highs” (synthetic cathinones) in the United States. Clin Toxicol (Phila). 2011 Jul;49(6): 499–505. [PMID: 21824061]
ANTICOAGULANTS Warfarin and related compounds (including ingredients of many commercial rodenticides) inhibit the clotting mechanism by blocking hepatic synthesis of vitamin K–dependent clotting factors. Anticoagulants may cause hemoptysis, gross hematuria, bloody stools, hemorrhages into organs, widespread bruising, and bleeding into joint spaces. The prothrombin time is increased within 12–24 hours (peak 36–48 hours) after a single overdose. After ingestion of brodifacoum, difenacoum, and related rodenticides (so-called “superwarfarins”), inhibition of clotting factor synthesis may persist for several weeks or even months after a single dose.
``Treatment A. Emergency and Supportive Measures Discontinue the drug at the first sign of gross bleeding, and determine the prothrombin time (international normalized ratio, INR). If the patient has ingested an acute overdose, administer activated charcoal (see p 1567).
B. Specific Treatment Do not treat prophylactically with vitamin K—wait for evidence of anticoagulation (elevated prothrombin time). If the INR is elevated, give phytonadione (vitamin K1), 10–25 mg orally, and increase the dose as needed to restore the prothrombin time to normal. Doses as high as 200 mg/d have been required after ingestion of “superwarfarins.” Give
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fresh-frozen plasma, prothrombin complex concentrate, or activated Factor VII as needed to rapidly correct the coagulation factor deficit if there is serious bleeding. If the patient is chronically anticoagulated and has strong medical indications for being maintained in that status (eg, prosthetic heart valve), give much smaller doses of vitamin K (1 mg orally) and fresh-frozen plasma (or both) to titrate to the desired prothrombin time. If the patient has ingested brodifacoum or a related superwarfarin, prolonged observation (over weeks) and repeated administration of large doses of vitamin K may be required. Gunja N et al. Management of intentional superwarfarin poisoning with long-term vitamin K and brodifacoum levels. Clin Toxicol (Phila). 2011 Jun;49(5):385–90. [PMID: 21740137] Wiedermann CJ et al. Warfarin-induced bleeding complications— clinical presentation and therapeutic options. Thromb Res. 2008;122(Suppl 2):S13–8. [PMID: 18549907]
ANTICONVULSANTS Anticonvulsants (carbamazepine, phenytoin, valproic acid, and many newer agents) are widely used in the management of seizure disorders and some are also used for treatment of mood disorders or pain. Phenytoin can be given orally or intravenously. Rapid intravenous injection of phenytoin can cause acute myocardial depression and cardiac arrest owing to the solvent propylene glycol (fosphenytoin does not contain this diluent). Chronic phenytoin intoxication can occur following only slightly increased doses because of zeroorder kinetics and a small toxic-therapeutic window. Phenytoin intoxication can also occur following acute intentional or accidental overdose. The overdose syndrome is usually mild even with high serum levels. The most common manifestations are ataxia, nystagmus, and drowsiness. Choreoathetoid movements have been described. Carbamazepine is used for treatment of trigeminal neuralgia, temporal lobe epilepsy, and other seizure disorders. Intoxication causes drowsiness, stupor and, with high levels, atrioventricular block, coma, and seizures. Dilated pupils and tachycardia are common. Toxicity may be seen with serum levels > 20 mg/L (85 mcmol/L), though severe poisoning is usually associated with concentrations > 30–40 mg/L (127–169 mcmol/L). Because of erratic and slow absorption, intoxication may progress over several hours to days. Valproic acid intoxication produces a unique syndrome consisting of hypernatremia (from the sodium component of the salt), metabolic acidosis, hypocalcemia, elevated serum ammonia, and mild liver aminotransferase elevation. Hypoglycemia may occur as a result of hepatic metabolic dysfunction. Coma with small pupils may be seen and can mimic opioid poisoning. Encephalopathy and cerebral edema can occur. The newer anticonvulsants gabapentin, levetiracetam, vigabatrin, and zonisamide generally cause somnolence, confusion and dizziness; felbamate can cause crystalluria
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and kidney dysfunction after overdose, and may cause idiosyncratic aplastic anemia with therapeutic use; lamotrigine, topiramate, and tiagabine have been reported to cause seizures after overdose.
``Treatment A. Emergency and Supportive Measures For recent ingestions, give activated charcoal orally or by gastric tube (see p 1567). For large ingestions of carbamazepine or valproic acid—especially of sustained-release formulations—consider whole bowel irrigation (see p 1567). Multiple-dose activated charcoal and whole-bowel irrigation may be beneficial in ensuring gut decontamination for selected large ingestions.
B. Specific Treatment There are no specific antidotes. Naloxone was reported to have reversed valproic acid overdose in one anecdotal case. Carnitine may be useful in patients with valproic acid– induced hyperammonemia. Consider hemodialysis for massive intoxication with valproic acid or carbamazepine (eg, carbamazepine levels > 60 mg/L [254 mcmol/L] or valproic acid levels > 800 mg/L [5544 mcmol/L]). French LK et al. Complete heart block and death following lamotrigine overdose. Clin Toxicol (Phila). 2011 Apr;49(4):330–3. [PMID: 21563910] Thanacoody RH. Extracorporeal elimination in acute valproic acid poisoning. Clin Toxicol (Phila). 2009 Aug;47(7):609–16. [PMID: 19656009] Wade JF et al. Emergent complications of the newer anticonvulsants. J Emerg Med. 2010 Feb;38(2):231–7. [PMID: 18762404]
ANTIPSYCHOTIC DRUGS Promethazine, prochlorperazine, chlorpromazine, haloperidol, droperidol, risperidone, olanzapine, ziprasidone, quetiapine, and aripiprazole are used as antipsychotic agents, and sometimes as antiemetics and potentiators of analgesic and hypnotic drugs. Phenothiazines (particularly chlorpromazine) induce drowsiness and mild orthostatic hypotension in as many as 50% of patients. Larger doses can cause obtundation, miosis, severe hypotension, tachycardia, convulsions, and coma. Abnormal cardiac conduction may occur, resulting in prolongation of QRS or QT intervals (or both) and ventricular arrhythmias. Among the newer agents, quetiapine is more likely to cause coma and hypotension. With therapeutic or toxic doses, an acute extrapyramidal dystonic reaction may develop in some patients, with spasmodic contractions of the face and neck muscles, extensor rigidity of the back muscles, carpopedal spasm, and motor restlessness. This reaction is more common with haloperidol and other butyrophenones and less common with newer atypical antipsychotics such as ziprasidone, olanzapine, aripiprazole, and quetiapine. Severe rigidity accompanied by hyperthermia and metabolic acidosis (“neuroleptic malignant syndrome”) may occasionally occur and is lifethreatening (see Chapter 25).
``Treatment A. Emergency and Supportive Measures Administer activated charcoal (see p 1567) for large or recent ingestions. For severe hypotension, treatment with intravenous fluids and vasopressor agents may be necessary. Treat hyperthermia as outlined on p 1565. Maintain cardiac monitoring.
B. Specific Treatment Hypotension and cardiac arrhythmias associated with widened QRS intervals on the ECG in a patient with thioridazine poisoning may respond to intravenous sodium bicarbonate as used for tricyclic antidepressants. Prolongation of the QT interval and torsades de pointes is usually treated with intravenous magnesium or overdrive pacing. For extrapyramidal signs, give diphenhydramine, 0.5–1 mg/kg intravenously, or benztropine mesylate, 0.01–0.02 mg/kg intramuscularly. Treatment with oral doses of these agents should be continued for 24–48 hours. Bromocriptine (2.5–7.5 mg orally daily) may be effective for mild or moderate neuroleptic malignant syndrome. Dantrolene (2–5 mg/kg intravenously) has also been used for muscle rigidity but is not a true antidote. For severe hyperthermia, rapid neuromuscular paralysis (see p 1565) is preferred. Caroff SN et al. Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial. Neurol Clin. 2011 Feb;29(1):127–48. [PMID: 21172575] Morris E et al. Neuroleptic malignant syndrome developing after acute overdose with olanzapine and chlorpromazine. J Med Toxicol. 2009 Mar;5(1):27–31. [PMID: 19191213] Page CB et al. Promethazine overdose: clinical effects, predicting delirium and the effect of charcoal. QJM. 2009 Feb;102(2): 123–31. [PMID: 19042969]
ARSENIC Arsenic is found in some pesticides and industrial chemicals, and arsenic trioxide has recently been reintroduced as a chemotherapeutic agent. A massive epidemic of chronic arsenic poisoning has occurred in Bangladesh due to naturally occurring arsenic in deep aquifers used for drinking water. Symptoms of acute poisoning usually appear within 1 hour after ingestion but may be delayed as long as 12 hours. They include abdominal pain, vomiting, watery diarrhea, and skeletal muscle cramps. Profound dehydration and shock may occur. In chronic poisoning, symptoms can be vague but often include pancytopenia, painful peripheral sensory neuropathy, and skin changes including melanosis, keratosis, and desquamating rash. Urinary arsenic levels may be falsely elevated after certain meals (eg, seafood) that contain large quantities of a nontoxic form of organic arsenic.
``Treatment A. Emergency Measures After recent ingestion (within 1–2 hours), perform gastric lavage. Activated charcoal is of uncertain benefit because it
Poisoning binds arsenic poorly. Administer intravenous fluids to replace losses due to vomiting and diarrhea.
B. Antidote For patients with severe acute intoxication, give dimercaprol injection (British anti-Lewisite, BAL), 10% solution in oil, 3–5 mg/kg intramuscularly every 4–6 hours for 2 days. The side effects include nausea, vomiting, headache, and hypertension. Follow dimercaprol with oral succimer (dimercaptosuccinic acid, DMSA), 10 mg/kg every 8 hours, for 1 week. Consult a medical toxicologist or regional poison control center (1-800-222-1222) for advice regarding chelation. Balakumar P et al. Arsenic exposure and cardiovascular disorders: an overview. Cardiovasc Toxicol. 2009 Dec;9(4):169–76. [PMID: 19787300] Pimparkar BD et al. Arsenicosis: review of recent advances. J Assoc Physicians India. 2010 Oct;58:617–9. [PMID: 21510113] Rahman MM et al. Chronic exposure of arsenic via drinking water and its adverse health impacts on humans. Environ Geochem Health. 2009 Apr;31(Suppl 1):189–200. [PMID: 19190988]
ATROPINE & ANTICHOLINERGICS Atropine, scopolamine, belladonna, diphenoxylate with atropine, Datura stramonium, Hyoscyamus niger, some mushrooms, tricyclic antidepressants, and antihistamines are antimuscarinic agents with variable central nervous system effects. The patient complains of dryness of the mouth, thirst, difficulty in swallowing, and blurring of vision. The physical signs include dilated pupils, flushed skin, tachycardia, fever, delirium, myoclonus, ileus, and flushed appearance. Antidepressants and antihistamines may induce convulsions. Antihistamines are commonly available with or without prescription. Diphenhydramine commonly causes delirium, tachycardia, and seizures. Massive overdose may mimic tricyclic antidepressant poisoning.
``Treatment A. Emergency and Supportive Measures Administer activated charcoal (see p 1567). Tepid sponge baths and sedation, or neuromuscular paralysis in rare cases, are indicated to control high temperatures (see p 1565).
B. Specific Treatment For severe anticholinergic syndrome (eg, agitated delirium), give physostigmine salicylate, 0.5–1 mg slowly intravenously over 5 minutes, with ECG monitoring; repeat as needed to a total dose of no more than 2 mg. Caution: Bradyarrhythmias and convulsions are a hazard with physostigmine administration, and the drug should be avoided in patients with cardiotoxic effects from tricyclic antidepressants or other sodium channel blockers.
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Irioka T et al. Opsoclonus caused by diphenhydramine selfpoisoning. J Neuroophthalmol. 2009 Mar;29(1):72–3. [PMID: 19458581] Mateo Montoya A et al. Acute anticholinergic syndrome from Atropa belladonna mistaken for blueberries. Eur J Ophthalmol. 2009 Jan–Feb;19(1):170–2. [PMID: 19123171]
a-ADRENERGIC
BLOCKERS
There are a wide variety of β-adrenergic blocking drugs, with varying pharmacologic and pharmacokinetic properties (see Table 11–7). The most toxic β-blocker is propranolol. Propranolol competitively blocks β1 and β2 adrenoceptors and also has direct membrane-depressant and central nervous system effects.
``Clinical Findings The most common findings with mild or moderate intoxication are hypotension and bradycardia. Cardiac depression from more severe poisoning is often unresponsive to conventional therapy with β-adrenergic stimulants such as dopamine and norepinephrine. In addition, with propranolol and other lipid-soluble drugs, seizures and coma may occur. Propranolol, oxprenolol, acebutolol, and alprenolol also have membrane-depressant effects and can cause conduction disturbance (wide QRS interval) similar to tricyclic antidepressant overdose. The diagnosis is based on typical clinical findings. Routine toxicology screening does not usually include β-blockers.
``Treatment A. Emergency and Supportive Measures Attempts to treat bradycardia or heart block with atropine (0.5–2 mg intravenously), isoproterenol (2–20 mcg/ min by intravenous infusion, titrated to the desired heart rate), or an external transcutaneous cardiac pacemaker are often ineffective, and specific antidotal treatment may be necessary (see below). For drugs ingested within an hour of presentation (or longer after ingestion of an extended-release formulation), administer activated charcoal (see p 1567).
B. Specific Treatment For persistent bradycardia and hypotension, give glucagon, 5–10 mg intravenously, followed by an infusion of 1–5 mg/h. Glucagon is an inotropic agent that acts at a different receptor site and is therefore not affected by β-blockade. High-dose insulin (0.5-1 units/kg/h intravenously) along with glucose supplementation has been used to reverse severe cardiotoxicity. Membrane-depressant effects (wide QRS interval) may respond to boluses of sodium bicarbonate (50–100 mEq intravenously) as for tricyclic anti depressant poisoning. Intravenous lipid emulsion (Intralipid 20%, 1.5 mL/kg) has been used successfully in severe propranolol overdose.
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Jovic-Stosic J et al. Severe propranolol and ethanol overdose with wide complex tachycardia treated with intravenous lipid emulsion: a case report. Clin Toxicol (Phila). 2011 Jun; 49(5):426–30. [PMID: 21740142] Page C et al. The use of high-dose insulin-glucose euglycemia in beta-blocker overdose: a case report. J Med Toxicol. 2009 Sep; 5(3):139–43. [PMID: 19655287]
CALCIUM CHANNEL BLOCKERS Calcium channel blockers are used to treat angina pectoris, hypertension, supraventricular tachycardia, migraine, and other disorders. In therapeutic doses, nifedipine, nicardipine, amlodipine, felodipine, isradipine, nisoldipine, and nimodipine act mainly on blood vessels, while verapamil and diltiazem act mainly on cardiac contractility and conduction. However, these selective effects can be lost after acute overdose. Patients may present with bradycardia, atrioventricular (AV) nodal block, hypotension, or a combination of these effects. Hyperglycemia is common due to blockade of insulin release. With severe poisoning, cardiac arrest may occur.
``Treatment A. Emergency and Supportive Measures For ingested drugs, administer activated charcoal (see p 1567). In addition, whole bowel irrigation (see p 1567) should be initiated as soon as possible if the patient has ingested a sustained-release product.
B. Specific Treatment If bradycardia and hypotension are not reversed with atropine (0.5–2 mg intravenously), isoproterenol (2–20 mcg/ min by intravenous infusion), or a transcutaneous cardiac pacemaker, administer calcium intravenously. Start with calcium chloride 10%, 10 mL, or calcium gluconate 10%, 20 mL. Repeat the dose every 3–5 minutes. The optimum (or maximum) dose has not been established, but many toxicologists recommend raising the ionized serum calcium level to as much as twice the normal level. Calcium is most useful in reversing negative inotropic effects and is less effective for AV nodal blockade and bradycardia. Epinephrine infusion (1–4 mcg/min initially) and glucagon (5–10 mg intravenously) have also been recommended. In addition, high doses of insulin (0.5–1 units/kg intravenous bolus followed by 0.5–1 units/kg/h infusion) along with sufficient dextrose to maintain euglycemia have been reported to be beneficial but there are no controlled studies. Infusion of Intralipid 20% lipid emulsion has been reported to improve hemodynamics in animal models and case reports of calcium channel blocker poisoning. Abeysinghe N et al. Diltiazem overdose: a role for high-dose insulin. Emerg Med J. 2010 Oct;27(10):802–3. [PMID: 20660906] Cave G et al. Intravenous lipid emulsion as antidote: a summary of published human experience. Emerg Med Australas. 2011 Apr;23(2):123–41. [PMID: 21489160] Engebretsen KM et al. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol (Phila). 2011 Apr;49(4):277–83. [PMID: 21563902]
CARBON MONOXIDE Carbon monoxide is a colorless, odorless gas produced by the combustion of carbon-containing materials. Poisoning may occur as a result of suicidal or accidental exposure to automobile exhaust, smoke inhalation in a fire, or accidental exposure to an improperly vented gas heater, generator, or other appliance. Carbon monoxide avidly binds to hemoglobin, with an affinity approximately 250 times that of oxygen. This results in reduced oxygen-carrying capacity and altered delivery of oxygen to cells (see also Smoke Inhalation in Chapter 9).
``Clinical Findings At low carbon monoxide levels (carboxyhemoglobin saturation 10–20%), victims may have headache, dizziness, abdominal pain, and nausea. With higher levels, confusion, dyspnea, and syncope may occur. Hypotension, coma, and seizures are common with levels > 50–60%. Survivors of acute severe poisoning may develop permanent obvious or subtle neurologic and neuropsychiatric deficits. The fetus and newborn may be more susceptible because of high carbon monoxide affinity for fetal hemoglobin. Carbon monoxide poisoning should be suspected in any person with severe headache or acutely altered mental status, especially during cold weather, when improperly vented heating systems may have been used. Diagnosis depends on specific measurement of the arterial or venous carboxyhemoglobin saturation, although the level may have declined if high-flow oxygen therapy has already been administered, and levels do not always correlate with clinical symptoms. Routine arterial blood gas testing and pulse oximetry are not useful because they give falsely normal Pao2 and oxyhemoglobin saturation determinations, respectively. (A specialized pulse oximetry device, the Masimo pulse CO-oximeter, is capable of distinguishing oxyhemoglobin from carboxyhemoglobin.)
``Treatment A. Emergency and Supportive Measures Maintain a patent airway and assist ventilation, if necessary. Remove the victim from exposure. Treat patients with coma, hypotension, or seizures as described at the beginning of this chapter (see pp 1562, 1563, 1565).
B. Specific Treatment The half-life of the carboxyhemoglobin (CoHb) complex is about 4–5 hours in room air but is reduced dramatically by high concentrations of oxygen. Administer 100% oxygen by tight-fitting high-flow reservoir face mask or endotracheal tube. Hyperbaric oxygen (HBO) can provide 100% oxygen under higher than atmospheric pressures, further shortening the half-life; it may also reduce the incidence of subtle neuropsychiatric sequelae. Randomized controlled studies disagree about the benefit of HBO, but commonly recommended indications for HBO in patients with carbon monoxide poisoning include a history of loss of
Poisoning consciousness, CoHb > 25%, metabolic acidosis, age over 50 years, and cerebellar findings on neurologic examination. Annane D et al. Hyperbaric oxygen therapy for acute domestic carbon monoxide poisoning: two randomized controlled trials. Intensive Care Med. 2010 Mar;37(3):486–9. [PMID: 21125215] Buckley NA et al. Hyperbaric oxygen for carbon monoxide poisoning. Cochrane Database Syst Rev. 2011 Apr 13;(4): CD002041. [PMID: 21491385]
CLONIDINE & OTHER SYMPATHOLYTIC ANTIHYPERTENSIVES Overdosage with these agents (clonidine, guanabenz, guanfacine, methyldopa) causes bradycardia, hypotension, miosis, respiratory depression, and coma. (Transient hypertension occasionally occurs after acute overdosage, a result of peripheral α-adrenergic effects in high doses.) Symptoms are usually resolved in < 24 hours, and deaths are rare. Similar symptoms may occur after ingestion of topical nasal decongestants chemically similar to clonidine (oxymetazoline, tetrahydrozoline, naphazoline). Brimonidine and apraclonidine are used as ophthalmic preparations for glaucoma. Tizanidine is a centrally acting muscle relaxant structurally related to clonidine; it produces similar toxicity in overdose.
``Treatment A. Emergency and Supportive Measures Give activated charcoal (see p 1567). Maintain the airway and support respiration if necessary. Symptomatic treatment is usually sufficient even in massive overdose. Maintain blood pressure with intravenous fluids. Dopamine can also be used. Atropine is usually effective for bradycardia.
B. Specific Treatment There is no specific antidote. Although tolazoline has been recommended for clonidine overdose, its effects are unpredictable and it should not be used. Naloxone has been reported to be successful in a few anecdotal and poorly substantiated cases. Farooqi M et al. Toxicity from a clonidine suspension. J Med Toxicol. 2009 Sep;5(3):130–3. [PMID: 19655285] Fernandez MA et al. Pediatric systemic poisoning resulting from brimonidine ophthalmic drops. Pediatr Emerg Care. 2009 Jan; 25(1):59. [PMID: 19148021]
COCAINE See Amphetamines & Cocaine.
CYANIDE Cyanide is a highly toxic chemical used widely in research and commercial laboratories and many industries. Its gaseous form, hydrogen cyanide, is an important component of smoke in fires. Cyanide-generating glycosides are also found in the pits of apricots and other related plants.
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Cyanide is generated by the breakdown of nitroprusside, and poisoning can result from rapid high-dose infusions. Cyanide is also formed by metabolism of acetonitrile, a solvent found in some over-the-counter fingernail glue removers. Cyanide is rapidly absorbed by inhalation, skin absorption, or ingestion. It disrupts cellular function by inhibiting cytochrome oxidase and preventing cellular oxygen utilization.
``Clinical Findings The onset of toxicity is nearly instantaneous after inhalation of hydrogen cyanide gas but may be delayed for minutes to hours after ingestion of cyanide salts or cyanogenic plants or chemicals. Effects include headache, dizziness, nausea, abdominal pain, and anxiety, followed by confusion, syncope, shock, seizures, coma, and death. The odor of “bitter almonds” may be detected on the victim’s breath or in vomitus, though this is not a reliable finding. The venous oxygen saturation may be elevated (> 90%) in severe poisonings because tissues have failed to take up arterial oxygen.
``Treatment A. Emergency and Supportive Measures Remove the victim from exposure, taking care to avoid exposure to rescuers. For suspected cyanide poisoning due to nitroprusside infusion, stop or slow the rate of infusion. (Metabolic acidosis and other signs of cyanide poisoning usually clear rapidly.) For cyanide ingestion, administer activated charcoal (see p 1567). Although charcoal has a low affinity for cyanide, the usual doses of 60–100 g are adequate to bind typically ingested lethal doses (100–200 mg).
B. Specific Treatment In the United States, there are two available cyanide antidote regimens. The conventional cyanide antidote package (Taylor Pharmaceuticals) (Table 38–7) contains nitrites (to induce methemoglobinemia, which binds free cyanide) and thiosulfate (to promote conversion of cyanide to the less toxic thiocyanate). Administer amyl nitrite by crushing an ampule under the victim’s nose or at the end of the endotracheal tube, and administer 3% sodium nitrite solution, 10 mL intravenously. Caution: Nitrites may induce hypotension and dangerous levels of methemoglobin. Also administer 25% sodium thiosulfate solution, 50 mL intravenously (12.5 g). The other approved cyanide treatment in the United States is hydroxocobalamin (Cyanokit, EMD Pharmaceuticals), a newer and potentially safer antidote. The adult dose of hydroxocobalamin is 5 g intravenously (children’s dose is, 70 mg/kg). Barillo DJ. Diagnosis and treatment of cyanide toxicity. J Burn Care Res. 2009 Jan–Feb;30(1):148–52. [PMID: 19060738] Cigolini D et al. Hydroxocobalamin treatment of acute cyanide poisoning from apricot kernels. Emerg Med J. 2011 Sep;28(9):804–5. [PMID: 21856998] Lawson-Smith P et al. Cyanide intoxication as part of smoke inhalation—a review on diagnosis and treatment from the emergency perspective. Scand J Trauma Resusc Emerg Med. 2011 Mar 3;19:14. [PMID: 21371322]
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Table 38–7. Currently available cyanide (CN) antidote kits. Antidote
Contents
Action
Conventional cyanide antidote kit1
Amyl nitrite, 0.3 mL aspirol for inhalation; sodium nitrite 300 mg in a 10-mL vial; sodium thiosulfate 12.5 g in a 50-mL vial
Nitrites induce methemoglobinemia, which binds CN; thiosulfate hastens CN conversion to less toxic thiocyanate
Cyanokit2
Hydroxocobalamin 5 g in two 2.5-g vials
Converts CN to cyanocobalamin (vitamin B12)
1 In 2
the United States, manufactured by Taylor Pharmaceuticals. Manufactured by EMD Pharmaceuticals.
DIETARY SUPPLEMENTS & HERBAL PRODUCTS Following passage of the Dietary Supplement Health and Education Act (DSHEA) in 1994, there has been an increase in the use of dietary supplements and herbal medicines in the United States. Unlike prescription and over-the-counter pharmaceuticals, dietary supplements do not require FDA approval, do not undergo the same premarketing evaluation of safety and efficacy as drugs, and purveyors may or may not adhere to good manufacturing practices and quality control standards. Supplements may cause illness as a result of intrinsic toxicity, misidentification or mislabeling, drug-herb reactions, or adulteration with pharmaceuticals. If you suspect a dietary supplement or herbal product may be the cause of an otherwise unexplained illness, contact the FDA (1-888-463-6332) or the regional poison control center (1-800-222-1222), or consult one of the following online databases: http://www. naturaldatabase.therapeuticresearch.com and, http://www. fda.gov/food/dietarysupplements/default.htm.
Table 38–8 lists selected examples of clinical toxicity from some of these products. Ashar BH. The Dietary Supplement Health and Education Act: time for a reassessment: comment on “acute selenium toxicity associated with a dietary supplement”. Arch Intern Med. 2010 Feb 8;170(3):261–3. [PMID: 20142571] Shaw D. Toxicological risks of Chinese herbs. Planta Med. 2010 Dec;76(17):2012–8. [PMID: 21077025]
DIGITALIS & OTHER CARDIAC GLYCOSIDES Cardiac glycosides are derived from a variety of plants and are widely used to treat heart failure and supraventricular arrhythmias. These drugs paralyze the Na+-K+-ATPase pump and have potent vagotonic effects. Intracellular effects include enhancement of calcium-dependent contractility and shortening of the action potential duration. A number of plants (eg, oleander, foxglove, lily-of-the-valley)
Table 38–8. Examples of potential toxicity associated with some dietary supplements and herbal medicines. Product
Common Use
Possible Toxicity
Azarcon (Greta)
Mexican folk remedy for abdominal pain, colic
Contains lead (see p 1581)
Comfrey
Gastric upset, diarrhea
Contains pyrrolizidine alkaloids, can cause hepatic veno-occlusive disease
Creatine
Athletic performance enhancement
Nausea, diarrhea, abdominal cramps; elevated serum creatinine
Ginkgo
Memory improvement, tinnitus
Antiplatelet effects, hemorrhage; abdominal pain, diarrhea
Ginseng
Immune system; stress
Decreased glucose; increased cortisol
Guarana
Athletic performance enhancement, appetite suppression
Contains caffeine: can cause tremor, tachycardia, vomiting
Kava
Anxiety, insomnia
Drowsiness, hepatitis, skin rash
Ma huang
Stimulant; athletic performance enhancement
Contains ephedrine: anxiety, insomnia, hypertension, tachycardia, seizures
Spirulina
Body building
Niacin-like flushing reaction
Yohimbine
Sexual enhancement
Hallucinations, hypertension, tachycardia
Zinc
Cold/flu symptoms
Nausea, oral irritation, anosmia
Adapted, with permission, from Table II-30 by Haller C in “Herbal and Alternative Products,” In: Olson KR (ed.) Poisoning & Drug Overdose, 5th edition, McGraw Hill, 2007.
Poisoning contain cardiac glycosides. Bufotenin, a cardiotoxic steroid found in certain toad secretions and used as an herbal medicine and a purported aphrodisiac, has pharmacologic properties similar to cardiac glycosides.
``Clinical Findings Intoxication may result from acute single exposure or chronic accidental overmedication. After acute overdosage, nausea and vomiting, bradycardia, hyperkalemia, and AV block frequently occur. Patients in whom toxicity develops gradually during long-term therapy may be hypokalemic and hypomagnesemic owing to concurrent diuretic treatment and more commonly present with ventricular arrhythmias (eg, ectopy, bidirectional ventricular tachycardia, or ventricular fibrillation). Digoxin levels may be only slightly elevated in patients with intoxication from cardiac glycosides other than digoxin because of limited crossreactivity of immunologic tests.
``Treatment A. Emergency and Supportive Measures After acute ingestion, administer activated charcoal (see p 1567). Monitor potassium levels and cardiac rhythm closely. Treat bradycardia initially with atropine (0.5–2 mg intravenously) or a transcutaneous external cardiac pacemaker.
B. Specific Treatment For patients with significant intoxication, administer digoxin-specific antibodies (digoxin immune Fab [ovine]; Digibind or DigiFab). Estimation of the Digibind dose is based on the body burden of digoxin calculated from the ingested dose or the steady-state serum digoxin concentration, as described below. More effective binding of digoxin may be achieved if the dose is given partly as a bolus and the remainder as an infusion over a few hours. 1. From the ingested dose—Number of vials = approximately 1.5–2 × ingested dose (mg). 2. From the serum concentration—Number of vials = serum digoxin (ng/mL) × body weight (kg) × 10–2. Note: This is based on the equilibrium digoxin level; after acute overdose, serum levels may be falsely high before tissue distribution is complete, and overestimation of the Digibind or DigiFab dose is likely. 3. Empiric dosing—Empiric titration of Digibind or DigiFab may be used if the patient’s condition is relatively stable and an underlying condition (eg, atrial fibrillation) favors retaining a residual level of digitalis activity. Start with one or two vials and reassess the patient’s clinical condition after 20–30 minutes. For cardiac glycosides other than digoxin or digitoxin, there is no formula for estimation of vials needed and treatment is entirely based on response to empiric dosing. Note: After administration of digoxin-specific Fab antibody fragments, serum digoxin levels may be falsely elevated depending on the assay technique.
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Bandara V et al. A review of the natural history, toxinology, diagnosis and clinical management of Nerium oleander (common oleander) and Thevetia peruviana (yellow oleander) poisoning. Toxicon. 2010 Sep 1;56(3):273–81. [PMID: 20438743] Eyer F et al. Free and total digoxin in serum during treatment of acute digoxin poisoning with Fab fragments: case study. Am J Crit Care. 2010 Jul;19(4):391–87. [PMID: 19875723] Rajapakse S. Management of yellow oleander poisoning. Clin Toxicol (Phila). 2009 Mar;47(3):206–12. [PMID: 19306191]
ETHANOL, BENZODIAZEPINES, & OTHER SEDATIVE-HYPNOTIC AGENTS The group of agents known as sedative-hypnotic drugs includes a variety of products used for the treatment of anxiety, depression, insomnia, and epilepsy. Besides common benzodiazepines, such as lorazepam, alprazolam, clonazepam, diazepam, oxazepam, chlordiazepoxide, and triazolam, this group includes the newer benzodiazepinelike hypnotics zolpidem and zaleplon, and the muscle relaxant carisoprodol. Ethanol and other selected agents are also popular recreational drugs. All of these drugs depress the central nervous system reticular activating system, cerebral cortex, and cerebellum.
``Clinical Findings Mild intoxication produces euphoria, slurred speech, and ataxia. Ethanol intoxication may produce hypoglycemia, even at relatively low concentrations, in children and in fasting adults. With more severe intoxication, stupor, coma, and respiratory arrest may occur. Carisoprodol (Soma) commonly causes muscle jerking or myoclonus. Death or serious morbidity is usually the result of pulmonary aspiration of gastric contents. Bradycardia, hypotension, and hypothermia are common. Patients with massive intoxication may appear to be dead, with no reflex responses and even absent electroencephalographic activity. Diagnosis and assessment of severity of intoxication are usually based on clinical findings. Ethanol serum levels > 300 mg/ dL (0.3 g/dL; 65 mmol/L) can produce coma in persons who are not chronically abusing the drug, but regular users may remain awake at much higher levels.
``Treatment A. Emergency and Supportive Measures Administer activated charcoal if the patient has ingested a massive dose and the airway is protected (see p 1567). Repeat-dose charcoal may enhance elimination of phenobarbital, but it has not been proved to improve clinical outcome. Hemodialysis may be necessary for patients with severe phenobarbital intoxication.
B. Specific Treatment Flumazenil is a benzodiazepine receptor-specific antagonist; it has no effect on ethanol, barbiturates, or other sedative-hypnotic agents. If used, flumazenil is given slowly intravenously, 0.2 mg over 30–60 seconds, and repeated in
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0.2-0.5 mg increments as needed up to a total dose of 3–5 mg. Caution: Flumazenil may induce seizures in patients with preexisting seizure disorder, benzodiazepine addiction, or concomitant tricyclic antidepressant or other convulsant overdose. If seizures occur, diazepam and other benzodiazepine anticonvulsants will not be effective. As with naloxone, the duration of action of flumazenil is short (2–3 hours) and resedation may occur, requiring repeated doses. Cantrell FL et al. Death on the doorstep of a border community— intentional self-poisoning with veterinary pentobarbital. Clin Toxicol (Phila). 2010 Oct;48(8):849–50. [PMID: 20738183] Kuzniar TJ et al. Coma with absent brainstem reflexes resulting from zolpidem overdose. Am J Ther. 2010 Sep–Oct;17(5): e172–4. [PMID: 20862780] Lakhal K et al. Protracted deep coma after bromazepam poisoning. Int J Clin Pharmacol Ther. 2010 Jan;48(1):79–83. [PMID: 20040343]
f -HYDROXYBUTYRATE
(GHB)
GHB has become a popular drug of abuse. It originated as a short-acting general anesthetic and is occasionally used in the treatment of narcolepsy. It gained popularity among bodybuilders for its alleged growth hormone stimulation and found its way into social settings, where it is consumed as a liquid. It has been used to facilitate sexual assault (“date-rape” drug). Symptoms after ingestion include drowsiness and lethargy followed by coma with respiratory depression. Muscle twitching and seizures are sometimes observed. Recovery is usually rapid, with patients awakening within a few hours. Other related chemicals with similar effects include butanediol and γ-butyrolactone (GBL). A prolonged withdrawal syndrome has been described in some heavy users.
``Treatment Monitor the airway and assist breathing if needed. There is no specific treatment. Most patients recover rapidly with supportive care. GHB withdrawal syndrome may require very large doses of benzodiazepines. Galicia M. Liquid ecstasy intoxication: clinical features of 505 consecutive emergency department patients. Emerg Med J. 2011 Jun;28(6):462–6. [PMID: 21602168] Zvosec DL et al. Case series of 226 γ-hydroxybutyrate-associated deaths: lethal toxicity and trauma. Am J Emerg Med. 2011 Mar;29(3):319–32. [PMID: 20825811]
HYPOGLYCEMIC DRUGS Medications used for diabetes mellitus include insulin, sulfonylureas and other insulin secretagogues, α-glucosidase inhibitors (acarbose, miglitol), biguanides (metformin), thiazolidinediones (pioglitazone, rosiglitazone), and newer peptide analogs (pramlintide, exenatide) or enhancers (sitagliptin) (see Chapter 27). Of these, insulin and the insulin secretagogues are the most likely to cause hypoglycemia. Metformin can cause lactic acidosis, especially in
patients with renal insufficiency or after intentional drug overdose. Table 27–7 lists the duration of hypoglycemic effect of oral hypoglycemic agents and Figure 27–3 the extent and duration of various types of insulins.
``Clinical Findings Hypoglycemia may occur quickly after injection of shortacting insulins or may be delayed and prolonged, especially if a large amount has been injected into a single area, creating a “depot” effect. Hypoglycemia after sulfonylurea ingestion is usually apparent within a few hours but may be delayed several hours, especially if food or glucosecontaining fluids have been given.
``Treatment Give sugar and carbohydrate-containing food or liquids by mouth, or intravenous dextrose if the patient is unable to swallow safely. For severe hypoglycemia, start with D50W, 50 mL intravenously (25 g dextrose); repeat, if needed. Follow up with dextrose-containing intravenous fluids (D5W or D10W) to maintain a blood glucose > 70–80 mg/dL. For hypoglycemia caused by sulfonylureas and related insulin secretagogues, consider use of octreotide, a synthetic somatostatin analog that blocks pancreatic insulin release. A dose of 50–100 mcg octreotide subcutaneously every 6–12 hours can reduce the need for exogenous dextrose and prevent rebound hypoglycemia from excessive dextrose dosing. Admit all patients with symptomatic hypoglycemia after sulfonylurea overdose. Observe asymptomatic overdose patients for at least 12 hours. Dougherty PP et al. Octreotide’s role in the management of sulfonylurea-induced hypoglycemia. J Med Toxicol. 2010 Jun; 6(2):199–206. [PMID: 20352540] Fasano CJ et al. Quantitative insulin and C-peptide levels among ED patients with sulfonylurea-induced hypoglycemia—a prospective case series. Am J Emerg Med. 2010 Oct;28(8):952–5. [PMID: 20887914]
IRON Iron is widely used therapeutically for the treatment of anemia and as a daily supplement in multiple vitamin preparations. Most children’s preparations contain about 12–15 mg of elemental iron (as sulfate, gluconate, or fumarate salt) per dose, compared with 60–90 mg in most adult-strength preparations. Iron is corrosive to the gastrointestinal tract and, once absorbed, has depressant effects on the myocardium and on peripheral vascular resistance. Intracellular toxic effects of iron include disruption of Krebs cycle enzymes.
``Clinical Findings Ingestion of < 30 mg/kg of elemental iron usually produces only mild gastrointestinal upset. Ingestion of > 40–60 mg/kg
Poisoning may cause vomiting (sometimes with hematemesis), diarrhea, hypotension, and acidosis. Death may occur as a result of profound hypotension due to massive fluid losses and bleeding, metabolic acidosis, peritonitis from intestinal perforation, or sepsis. Fulminant hepatic failure may occur. Survivors of the acute ingestion may suffer permanent gastrointestinal scarring. Serum iron levels > 350–500 mcg/dL are considered potentially toxic, and levels > 1000 mcg/dL are usually associated with severe poisoning. A plain abdominal radiograph may reveal radiopaque tablets.
``Treatment A. Emergency and Supportive Measures Treat hypotension aggressively with intravenous crystalloid solutions (0.9% saline or lactated Ringer solution). Fluid losses may be massive owing to vomiting and diarrhea as well as third-spacing into injured intestine. Perform whole bowel irrigation to remove unabsorbed pills from the intestinal tract (see p 1567). Activated charcoal is not effective but may be appropriate if other ingestants are suspected.
B. Specific Treatment Deferoxamine is a selective iron chelator. It is not useful as an oral binding agent. For patients with established manifestations of toxicity—and particularly those with markedly elevated serum iron levels (eg, > 800–1000 mcg/ dL)— administer 10–15 mg/kg/h by constant intravenous infusion; higher doses (up to 40–50 mg/kg/h) have been used in massive poisonings. Hypotension may occur. The presence of an iron-deferoxamine complex in the urine may give it a “vin rosé” appearance. Deferoxamine is safe for use in pregnant women with acute iron overdose. Caution: Prolonged infusion of deferoxamine (> 36–48 hours) has been associated with development of acute respiratory distress syndrome (ARDS)—the mechanism is not known. Chang TP et al. Iron poisoning: a literature-based review of epidemiology, diagnosis, and management. Pediatr Emerg Care. 2011 Oct;27(10):978–85. [PMID: 21975503] Ng HW et al. Endoscopic removal of iron bezoar following acute overdose. Clin Toxicol (Phila). 2008 Nov;46(9):913–5. [PMID: 18608283]
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``Clinical Findings Confusion, slurred speech, and seizures may occur abruptly after acute overdose. Severe lactic acidosis—out of proportion to the severity of seizures—is probably due to inhibited metabolism of lactate. Peripheral neuropathy and acute hepatitis may occur with long-term use. Diagnosis is based on a history of ingestion and the presence of severe acidosis associated with seizures. INH is not usually included in routine toxicologic screening, and serum levels are not readily available.
``Treatment A. Emergency and Supportive Measures Seizures may require higher than usual doses of benzodiazepines (eg, lorazepam, 3–5 mg intravenously) or administration of pyridoxine as an antidote (see below). Administer activated charcoal (see p 1567) after large recent ingestion, but with caution because of the risk of abrupt onset of seizures.
B. Specific Treatment Pyridoxine (vitamin B6) is a specific antagonist of the acute toxic effects of INH and is usually successful in controlling convulsions that do not respond to benzodiazepines. Give 5 g intravenously over 1–2 minutes or, if the amount ingested is known, give a gram-for-gram equivalent amount of pyridoxine. Patients taking INH are usually given 25–50 mg of pyridoxine orally daily to help prevent neuropathy. Gokhale YA et al. Isoniazid toxicity presenting as status epilepticus and severe metabolic acidosis. J Assoc Physicians India. 2009 Jan;57:70–1. [PMID: 19753763] Metushi IG et al. A fresh look at the mechanism of isoniazidinduced hepatotoxicity. Clin Pharmacol Ther. 2011 Jun;89(6):911–4. [PMID: 21412230]
LEAD Lead is used in a variety of industrial and commercial products, such as storage batteries, solders, paints, pottery, plumbing, and gasoline and is found in some traditional Hispanic and Ayurvedic ethnic medicines. Lead toxicity usually results from chronic repeated exposure and is rare after a single ingestion. Lead produces a variety of adverse effects on cellular function and primarily affects the nervous system, gastrointestinal tract, and hematopoietic system.
ISONIAZID
``Clinical Findings
INH is an antibacterial drug used mainly in the treatment and prevention of tuberculosis. It may cause hepatitis with long-term use, especially in alcoholic patients and elderly persons. It produces acute toxic effects by competing with pyridoxal 5-phosphate, resulting in lowered brain γ-aminobutyric acid (GABA) levels. Acute ingestion of as little as 1.5–2 g of INH can cause toxicity, and severe poisoning is likely to occur after ingestion of more than 80–100 mg/kg.
Lead poisoning often goes undiagnosed initially because presenting symptoms and signs are nonspecific and exposure is not suspected. Common symptoms include colicky abdominal pain, constipation, headache, and irritability. Severe poisoning may cause coma and convulsions. Chronic intoxication can cause learning disorders (in children) and motor neuropathy (eg, wrist drop). Lead-containing bullet fragments in or near joint spaces can result in chronic lead toxicity.
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Diagnosis is based on measurement of the blood lead level. Whole blood lead levels < 10 mcg/dL are usually considered nontoxic. Levels between 10 and 25 mcg/dL have been associated with impaired neurobehavioral development in children. Levels of 25–50 mcg/dL may be associated with headache, irritability, and subclinical neuropathy. Levels of 50–70 mcg/dL are associated with moderate toxicity, and levels > 70–100 mcg/dL are often associated with severe poisoning. Other laboratory findings of lead poisoning include microcytic anemia with basophilic stippling and elevated free erythrocyte protoporphyrin.
succimer (DMSA), is available for use in patients with mild to moderate intoxication. The usual dose is 10 mg/kg orally every 8 hours for 5 days, then every 12 hours for 2 weeks. Bradberry S et al. Dimercaptosuccinic acid (succimer; DMSA) in inorganic lead poisoning. Clin Toxicol (Phila). 2009 Aug; 47(7):617–31. [PMID: 19663612] Rehani B et al. Lead poisoning from a gunshot wound. South Med J. 2011 Jan;104(1):57–8. [PMID: 21079537] Saper RB et al. Lead, mercury, and arsenic in US- and Indianmanufactured Ayurvedic medicines sold via the Internet. JAMA. 2008 Aug 27;300(8):915–23. [PMID: 18728265]
``Treatment A. Emergency and Supportive Measures
LITHIUM
For patients with encephalopathy, maintain a patent airway and treat coma and convulsions as described at the beginning of this chapter. For recent acute ingestion, if a large lead-containing object (eg, fishing weight) is still visible in the stomach on abdominal radiograph, whole bowel irrigation (see p 1567), endoscopy, or even surgical removal may be necessary to prevent subacute lead poisoning. (The acidic gastric contents may corrode the metal surface, enhancing lead absorption. Once the object passes into the small intestine, the risk of toxicity declines.) Conduct an investigation into the source of the lead exposure. Workers with a single lead level > 60 mcg/dL (or three successive monthly levels > 50 mcg/dL) or construction workers with any single blood lead level > 50 mcg/dL must by federal law be removed from the site of exposure. Contact the regional office of the United States Occupational Safety and Health Administration (OSHA) for more information. Several states mandate reporting of cases of confirmed lead poisoning.
Lithium is widely used for the treatment of bipolar depression and other psychiatric disorders. The only normal route of lithium elimination is via the kidney, so patients with chronic kidney disease are at risk for accumulation of lithium resulting in gradual onset (chronic) toxicity. Intoxication resulting from chronic accidental overmedication or renal impairment is more common and usually more severe than that seen after acute oral overdose.
B. Specific Treatment The indications for chelation depend on the blood lead level and the patient’s clinical state. A medical toxicologist or regional poison control center (1-800-222-1222) should be consulted for advice about selection and use of these antidotes. Note: It is impermissible under the law to treat asymptomatic workers with elevated blood lead levels in order to keep their levels < 50 mcg/dL rather than remove them from the exposure. 1. Severe toxicity—Patients with severe intoxication (encephalopathy or levels > 70–100 mcg/dL) should receive edetate calcium disodium (ethylenediaminetetraacetic acid, EDTA), 1500 mg/m2/kg/d (approximately 50 mg/ kg/d) in four to six divided doses or as a continuous intravenous infusion. Most clinicians also add dimercaprol (BAL), 4–5 mg/kg intramuscularly every 4 hours for 5 days, for patients with encephalopathy. 2. Less severe toxicity—Patients with less severe symptoms and asymptomatic patients with blood lead levels between 55 and 69 mcg/dL may be treated with edetate calcium disodium alone in dosages as above. An oral chelator,
``Clinical Findings Mild to moderate toxicity causes lethargy, confusion, tremor, ataxia, and slurred speech. This may progress to myoclonic jerking, delirium, coma, and convulsions. Recovery may be slow and incomplete following severe intoxication. Laboratory studies in patients with chronic intoxication often reveal an elevated serum creatinine and an elevated BUN/creatinine ratio due to underlying volume contraction. The white blood cell count is often elevated. ECG findings include T-wave flattening or inversion, and sometimes bradycardia or sinus node arrest. Nephrogenic diabetes insipidus can occur with overdose or with therapeutic doses. Lithium levels may be difficult to interpret. Lithium has a low toxic:therapeutic ratio and chronic intoxication can be seen with levels only slightly above the therapeutic range (0.8–1.2 mEq/L). In contrast, patients with acute ingestion may have transiently very high levels (up to 10 mEq/L reported) without any symptoms before the lithium fully distributes into tissues. Note: Falsely high lithium levels (as high as 6–8 mEq/L) can be measured if a green-top blood specimen tube (containing lithium heparin) is used instead of a red- or marbled-top tube.
``Treatment fter acute oral overdose, consider gastric lavage (see p A 1567) or whole bowel irrigation (see p 1567) to prevent systemic absorption (lithium is not adsorbed by activated charcoal). In all patients, evaluate renal function and volume status, and give intravenous saline-containing fluids as needed. Monitor serum lithium levels, and seek assistance with their interpretation and the need for dialysis from a medical toxicologist or regional poison control center (1-800-222-1222). Consider hemodialysis if the patient is markedly symptomatic or if the serum level
Poisoning exceeds 10 mEq/L after an acute overdose. Continuous renal replacement hemofiltration may be an effective alternative to hemodialysis. Bailey AR et al. Comparison of intermittent haemodialysis, prolonged intermittent renal replacement therapy and continuous renal replacement haemofiltration for lithium toxicity: a case report. Crit Care Resusc. 2011 Jun;13(2):120–2. [PMID: 21627581]
LSD & OTHER HALLUCINOGENS A variety of substances—ranging from naturally occurring plants and mushrooms to synthetic substances such as phencyclidine (PCP), toluene and other solvents, dextromethorphan, and lysergic acid diethylamide (LSD)—are abused for their hallucinogenic properties. The mechanism of toxicity and the clinical effects vary for each substance. Many hallucinogenic plants and mushrooms produce anticholinergic delirium, characterized by flushed skin, dry mucous membranes, dilated pupils, tachycardia, and urinary retention. Other plants and mushrooms may contain hallucinogenic indoles such as mescaline and LSD, which typically cause marked visual hallucinations and perceptual distortion, widely dilated pupils, and mild tachycardia. PCP, a dissociative anesthetic agent similar to ketamine, can produce fluctuating delirium and coma, often associated with vertical and horizontal nystagmus. Toluene and other hydrocarbon solvents (butane, trichloroethylene, “chemo,” etc) cause euphoria and delirium and may sensitize the myocardium to the effects of catecholamines, leading to fatal dysrhythmias. Newer drugs used for their psychostimulant effects include synthetic cannabinoid receptor agonists (street names include “spice” and “K2”), Salvia divinorum, and mephedrone. See www.erowid.org for very thorough descriptions of a variety of hallucinogenic substances.
``Treatment A. Emergency and Supportive Measures Maintain a patent airway and assist respirations if necessary. Treat coma, hyperthermia, hypertension, and seizures as outlined at the beginning of this chapter. For recent large ingestions, consider giving activated charcoal orally or by gastric tube (see p 1567).
B. Specific Treatment Patients with anticholinergic delirium may benefit from a dose of physostigmine, 0.5–1 mg intravenously, not to exceed 1 mg/min. Dysphoria, agitation, and psychosis associated with LSD or mescaline intoxication may respond to benzodiazepines (eg, lorazepam, 1–2 mg orally or intravenously) or haloperidol (2–5 mg intramuscularly or intravenously) or another antipsychotic drug (eg, olanzapine or ziprasidone). Monitor patients who have sniffed solvents for cardiac dysrhythmias (most commonly premature ventricular contractions, ventricular tachycardia, ventricular fibrillation); treatment with β-blockers such as propranolol (1–5 mg intravenously) or esmolol (250–500 mcg/kg intravenously,
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then 50 mcg/kg/min by infusion) may be more effective than lidocaine or amiodarone. Atwood BK et al. JWH018, a common constituent of ‘Spice’ herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. Br J Pharmacol. 2010 Jun;160(3):585–93. [PMID: 20100276] Björnstad K et al. Bioanalytical and clinical evaluation of 103 suspected cases of intoxications with psychoactive plant materials. Clin Toxicol (Phila). 2009 Jul;47(6):566–72. [PMID: 19586355] Jamison SC et al. A 60-year-old woman with agitation and psychosis following ingestion of dextromethorphan and opioid analgesics. J Psychopharmacol. 2009 Nov;23(8):989–91. [PMID: 18583439]
MERCURY Acute mercury poisoning usually occurs by ingestion of inorganic mercuric salts or inhalation of metallic mercury vapor. Ingestion of the mercuric salts causes a burning sensation in the throat, discoloration and edema of oral mucous membranes, abdominal pain, vomiting, bloody diarrhea, and shock. Direct nephrotoxicity causes acute kidney injury. Inhalation of high concentrations of metallic mercury vapor may cause acute fulminant chemical pneumonia. Chronic mercury poisoning causes weakness, ataxia, intention tremors, irritability, and depression. Exposure to alkyl (organic) mercury derivatives from highly contaminated fish or fungicides used on seeds has caused ataxia, tremors, convulsions, and catastrophic birth defects. Nearly all fish have some traces of mercury contamination; the US Environmental Protection Agency (EPA) advises consumers to avoid swordfish, shark, king mackerel, and tilefish because they contain higher levels. Fish that are generally low in mercury content include shrimp, canned light tuna (not albacore “white” tuna), salmon, pollock, and catfish. Dental fillings composed of mercury amalgam pose a very small risk of chronic mercury poisoning and their removal is rarely justified.
``Treatment A. Acute Poisoning There is no effective specific treatment for mercury vapor pneumonitis. Remove ingested mercuric salts by lavage, and administer activated charcoal (see p 1567). For acute ingestion of mercuric salts, give dimercaprol (BAL) at once, as for arsenic poisoning. Unless the patient has severe gastroenteritis, consider succimer (DMSA), 10 mg/kg orally every 8 hours for 5 days and then every 12 hours for 2 weeks. Unithiol (DMPS) is a chelator that can be given orally or parenterally, but is not commonly available in the United States. Maintain urinary output. Treat oliguria and anuria if they occur.
B. Chronic Poisoning Remove from exposure. Neurologic toxicity is not considered reversible with chelation, although some authors recommend a trial of succimer or unithiol (contact a regional poison center or medical toxicologist for advice).
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Alhamad T et al. Lessons learned from a fatal case of mercury intoxication. Int Urol Nephrol. 2012 Apr; 44(2):647-51 [PMID: 21234679] Vearrier D et al. Care of patients who are worried about mercury poisoning from dental fillings. J Am Board Fam Med. 2010 Nov–Dec;23(6):797–8. [PMID: 21057078]
METHANOL & ETHYLENE GLYCOL Methanol (wood alcohol) is commonly found in a variety of products, including solvents, duplicating fluids, record cleaning solutions, and paint removers. It is sometimes ingested intentionally by alcoholic patients as a substitute for ethanol and may also be found as a contaminant in bootleg whiskey. Ethylene glycol is the major constituent in most antifreeze compounds. The toxicity of both agents is caused by metabolism to highly toxic organic acids—methanol to formic acid; ethylene glycol to glycolic and oxalic acids. Diethylene glycol is a nephrotoxic solvent that has been improperly substituted for glycerine in various liquid medications (cough syrup, teething medicine, acetaminophen) causing numerous deaths in Haiti, Panama, and Nigeria.
``Clinical Findings Shortly after ingestion of methanol or ethylene glycol, patients usually appear “drunk.” The serum osmolality (measured with the freezing point device) is usually increased, but acidosis is often absent early. After several hours, metabolism to toxic organic acids leads to a severe anion gap metabolic acidosis, tachypnea, confusion, convulsions, and coma. Methanol intoxication frequently causes visual disturbances, while ethylene glycol often produces oxalate crystalluria and acute renal failure.
``Treatment A. Emergency and Supportive Measures For patients presenting within 30–60 minutes after ingestion, empty the stomach by aspiration through a naso gastric tube (see p 1567). Charcoal is not very effective but should be administered if other poisons or drugs have also been ingested.
B. Specific Treatment Patients with significant toxicity (manifested by severe metabolic acidosis, altered mental status, and markedly elevated osmol gap) should undergo hemodialysis as soon as possible to remove the parent compound and the toxic metabolites. Treatment with folic acid, thiamine, and pyridoxine may enhance the breakdown of toxic metabolites. Ethanol blocks metabolism of the parent compounds by competing for the enzyme alcohol dehydrogenase. Fomepizole (4-methylpyrazole; Antizol) blocks alcohol dehydrogenase and is much easier to use than ethanol. If started before onset of acidosis, fomepizole may be used as the sole treatment for ethylene glycol ingestion in some cases. A regional poison control center (1-800-222-1222) should be contacted for indications and dosing.
Brent J. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009 May 21;360(21):2216–23. [PMID: 19458366] Buller GK et al. When is it appropriate to treat ethylene glycol intoxication with fomepizole alone without hemodialysis? Semin Dial. 2011 Jul–Aug;24(4):441–2. [PMID: 21801226] Caravati EM et al. Breath alcohol analyzer mistakes methanol poisoning for alcohol intoxication. Ann Emerg Med. 2010 Feb;55(2):198–200. [PMID: 19833410] Sanaei-Zadeh H et al. Hyperglycemia is a strong prognostic factor of lethality in methanol poisoning. J Med Toxicol. 2011 Sep;7(3):189–94. [PMID: 21336799]
METHEMOGLOBINEMIA-INDUCING AGENTS A large number of chemical agents are capable of oxidizing ferrous hemoglobin to its ferric state (methemoglobin), a form that cannot carry oxygen. Drugs and chemicals known to cause methemoglobinemia include benzocaine (a local anesthetic found in some topical anesthetic sprays and a variety of nonprescription products), aniline, propanil (an herbicide), nitrites, nitrogen oxide gases, nitrobenzene, dapsone, phenazopyridine (Pyridium), and many others. Dapsone has a long elimination half-life and may produce prolonged or recurrent methemoglobinemia.
``Clinical Findings Methemoglobinemia reduces oxygen-carrying capacity and may cause dizziness, nausea, headache, dyspnea, confusion, seizures, and coma. The severity of symptoms depends on the percentage of hemoglobin oxidized to methemoglobin; severe poisoning is usually present when methemoglobin fractions are > 40–50%. Even at low levels (15–20%), victims appear cyanotic because of the “chocolate brown” color of methemoglobin, but they have normal Po2 results on arterial blood gas determinations. Conventional pulse oximetry gives inaccurate oxygen saturation measurements; the reading is often between 85% and 90%. (A newer pulse oximetry device [Masimo Pulse CO-oximeter] is capable of estimating the methemoglobin level.) Severe metabolic acidosis may be present. Hemolysis may occur, especially in patients susceptible to oxidant stress (ie, those with glucose-6-phosphate dehydrogenase deficiency).
``Treatment A. Emergency and Supportive Measures Administer high-flow oxygen. If the causative agent was recently ingested, administer activated charcoal (see p 1567). Repeat-dose activated charcoal may enhance dapsone elimination (see p 1568).
B. Specific Treatment Methylene blue enhances the conversion of methemoglobin to hemoglobin by increasing the activity of the enzyme methemoglobin reductase. For symptomatic patients, administer 1–2 mg/kg (0.1–0.2 mL/kg of 1% solution)
Poisoning intravenously. The dose may be repeated once in 15–20 minutes if necessary. Patients with hereditary methemoglobin reductase deficiency or glucose-6-phosphate dehydrogenase deficiency may not respond to methylene blue treatment. In severe cases where methylene blue is not available or is not effective, exchange blood transfusion may be necessary. Barclay J et al. Dapsone-induced methemoglobinemia: a primer for clinicians. Ann Pharmacother. 2011 Sep;45(9):1103–15. [PMID: 21852596] Harvey M et al. Fatal methaemoglobinaemia induced by selfpoisoning with sodium nitrite. Emerg Med Australas. 2010 Oct;22(5):463–5. [PMID: 21040485]
MONOAMINE OXIDASE INHIBITORS Overdoses of MAO inhibitors (isocarboxazid, phenelzine, selegiline, moclobemide) cause ataxia, excitement, hypertension, and tachycardia, followed several hours later by hypotension, convulsions, and hyperthermia. Ingestion of tyramine-containing foods may cause a severe hypertensive reaction in patients taking MAO inhibitors. Foods containing tyramine include aged cheese and red wines. Hypertensive reactions may also occur with any sympathomimetic drug. Severe or fatal hyperthermia (serotonin syndrome) may occur if patients receiving MAO inhibitors are given meperidine, fluoxetine, paroxetine, fluvoxamine, venlafaxine, tryptophan, dextromethorphan, tramadol, or other serotonin-enhancing drugs. This reaction can also occur with the newer selective MAO inhibitor moclobemide, and the antibiotic linezolid, which has MAO-inhibiting properties. The serotonin syndrome has also been reported in patients taking selective serotonin reuptake inhibitors (SSRIs) in large doses or in combination with other SSRIs, even in the absence of an MAO inhibitor or meperidine. It is characterized by fever, agitation, delirium, diaphoresis, hyperreflexia, and clonus (spontaneous, inducible, or ocular). Hyperthermia can be life-threatening.
``Treatment Administer activated charcoal (see p 1567). Treat severe hypertension with nitroprusside, phentolamine, or other rapid-acting vasodilators (see p 1564). Treat hypotension with fluids and positioning, but avoid use of pressor agents if possible. Observe patients for at least 24 hours, since hyperthermic reactions may be delayed. Treat hyperthermia with aggressive cooling; neuromuscular paralysis may be required (see p 1565). Cyproheptadine, 4 mg orally (or by gastric tube) every hour for three or four doses, or chlorpromazine, 25 mg intravenously, has been reported to be effective against serotonin syndrome. Sun-Edelstein C et al. Drug-induced serotonin syndrome. Expert Opin Drug Saf. 2008 Sep;7(5):587–96. [PMID: 18759711] Wu ML et al. Serotonin toxicity caused by moclobemide too soon after paroxetine-selegiline. J Chin Med Assoc. 2009 Aug;72(8): 446–9. [PMID: 19687003]
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MUSHROOMS There are thousands of mushroom species that cause a variety of toxic effects. The most dangerous species of mushrooms are A phalloides, Amanita ocreata, Amanita verna, Amanita virosa, Gyromitra esculenta, and the Galerina species, all of which contain potent cytotoxins (amatoxins). Ingestion of even a portion of one mushroom of a dangerous species may be sufficient to cause death. The characteristic pathologic finding in fatalities from amatoxin-containing mushroom poisoning is acute massive necrosis of the liver.
``Clinical Findings (Table 38–9) A. Symptoms and Signs Amatoxin-containing mushrooms typically cause a delayed onset (8–12 hours after ingestion) of severe abdominal cramps, vomiting and profuse diarrhea, followed by hepatic necrosis, hepatic encephalopathy, and frequently acute kidney injury in 1–2 days. Cooking the mushrooms does not prevent poisoning. Monomethylhydrazine poisoning (Gyromitra and Helvella species) is more common following ingestion of uncooked mushrooms, as the toxin is water-soluble. Vomiting, diarrhea, hepatic necrosis, convulsions, coma, and hemolysis may occur after a latent period of 8–12 hours. The clinical effects of these and other mushrooms are described in Table 38–9.
``Treatment A. Emergency Measures After the onset of symptoms, efforts to remove the toxic agent are probably useless, especially in cases of amatoxin or gyromitrin poisoning, where there is usually a delay of 12 hours or more before symptoms occur and patients seek medical attention. However, induction of vomiting or administration of activated charcoal is recommended for any recent ingestion of an unidentified or potentially toxic mushroom (see p 1567).
B. Specific Treatment A variety of purported antidotes (eg, thioctic acid, penicillin, corticosteroids) have been suggested for amatoxin-type mushroom poisoning, but controlled studies are lacking and experimental data in animals are equivocal. Aggressive fluid replacement for diarrhea and intensive supportive care for hepatic failure are the mainstays of treatment. Silymarin (silibinin), a derivative of milk thistle, is commonly used in Europe but is currently only commercially available in the United States as a nutritional supplement given orally. The European intravenous product (Legalon-SIL) can be obtained in the United States under an emergency IND provided by the FDA. Contact the regional poison control center (1-800-222-1222) for more information. Interruption of enterohepatic circulation of the amatoxin by the administration of activated charcoal or by cannulation and drainage of the bile duct may be of value
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Table 38–9. Poisonous mushrooms. Toxin
Genus
Symptoms and Signs
Amanitin
Amanita (A phalloides, A verna, A virosa)
Severe gastroenteritis followed by delayed hepatic failure and acute kidney injury after 48–72 hours
6–24 hours
Supportive. Correct dehydration. Give repeated doses of activated charcoal orally. Consider intravenous silibinin (Legalon-SIL) (see text).
Muscarine
Inocybe, Clitocybe
Muscarinic (salivation, miosis, bradycardia, diarrhea)
30–60 minutes
Supportive. Give atropine, 0.5–2 mg intravenously, for severe cholinergic symptoms and signs.
Ibotenic acid, muscimol
Amanita muscaria (“fly agaric”)
Anticholinergic (mydriasis, tachycardia, hyperpyrexia, delirium)
30–60 minutes
Supportive. Give physostigmine, 0.5–2 mg intravenously, for severe anticholinergic symptoms and signs.
Coprine
Coprinus
Disulfiram-like effect occurs with ingestion of ethanol
30–60 minutes
Supportive. Abstain from ethanol for 3–4 days.
Monomethylhydrazine
Gyromitra
Gastroenteritis; occasionally seizures, hemolysis, hepatic failure, and acute kidney injury
6–12 hours
Supportive. Correct dehydration. Pyridoxine, 2.5 mg/kg intravenously, may be helpful for seizures.
Orellanine
Cortinarius
Nausea, vomiting; acute kidney injury after 1–3 weeks
2–14 days
Supportive.
Psilocybin
Psilocybe
Hallucinations
15–30 minutes
Supportive.
Gastrointestinal irritants
Many species
Nausea and vomiting, diarrhea
1/2–2 hours
Supportive. Correct dehydration.
in removing some of the toxin, based on animal studies and isolated case reports. Liver transplant may be the only hope for survival in gravely ill patients—contact a liver transplant center early. Garrouste C et al. Amanita phalloides poisoning-induced endstage renal failure. Clin Nephrol. 2009 May;71(5):571–4. [PMID: 19473620] Trabulus S et al. Clinical features and outcome of patients with amatoxin-containing mushroom poisoning. Clin Toxicol (Phila). 2011 Apr;49(4):303–10. [PMID: 21563906] West PL et al. Amanita smithiana mushroom ingestion: a case of delayed renal failure and literature review. J Med Toxicol. 2009 Mar;5(1):32–8. [PMID: 19191214]
OPIATES & OPIOIDS Prescription and illicit opiates and opioids (morphine, heroin, codeine, oxycodone, fentanyl, hydromorphone, etc) are popular drugs of misuse and abuse and the cause of frequent hospitalizations for overdose. These drugs have widely varying potencies and durations of action; for example, some of the illicit fentanyl derivatives are up to 2000 times more potent than morphine. All of these agents decrease central nervous system activity and sympathetic outflow by acting on opiate receptors in the brain. Tramadol is an analgesic that is unrelated chemically to the opioids but acts on opioid receptors. Buprenorphine is a partial agonist-antagonist opioid used for the outpatient treatment of opioid addiction.
``Clinical Findings Mild intoxication is characterized by euphoria, drowsiness, and constricted pupils. More severe intoxication may cause
Onset
Treatment
hypotension, bradycardia, hypothermia, coma, and respiratory arrest. Pulmonary edema may occur. Death is usually due to apnea or pulmonary aspiration of gastric contents. Methadone has been associated with QT interval prolongation and torsades de pointes. Tramadol, dextromethorphan, and meperidine also occasionally cause seizures. With meperidine, the metabolite normeperidine is probably the cause of seizures and is most likely to accumulate with repeated dosing in patients with chronic kidney disease. While the duration of effect for heroin is usually 3–5 hours, methadone intoxication may last for 48–72 hours or longer. Propoxyphene may cause seizures and prolongs the QRS interval; it has now been removed from the US market by the FDA. Many opioids, including fentanyl, tramadol, oxycodone, and methadone, are not detected on routine urine toxicology “opiate” screening. Wound botulism has been associated with skin-popping, especially involving “black tar” heroin. Buprenorphine added to an opioid regimen may produce acute narcotic withdrawal symptoms.
``Treatment A. Emergency and Supportive Measures Protect the airway and assist ventilation. Administer activated charcoal (see p 1567) for recent large ingestions.
B. Specific Treatment Naloxone is a specific opioid antagonist that can rapidly reverse signs of narcotic intoxication. Although it is structurally related to the opioids, it has no agonist effects of its own. Administer 0.2–2 mg intravenously, and repeat as needed to awaken the patient and maintain airway protective
Poisoning reflexes and spontaneous breathing. Very large doses (10–20 mg) may be required for patients intoxicated by some opioids (eg, codeine, fentanyl derivatives). Caution: The duration of effect of naloxone is only about 2–3 hours; repeated doses may be necessary for patients intoxicated by longacting drugs such as methadone. Continuous observation for at least 3 hours after the last naloxone dose is mandatory. Bohnert AS et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011 Apr 6; 305(13):1315–21. [PMID: 21467284] Okie S. A flood of opioids, a rising tide of deaths. N Engl J Med. 2010 Nov 18;363(21):1981–5. [PMID: 21083382] Taghaddosinejad F et al. Factors related to seizure in tramadol poisoning and its blood concentration. J Med Toxicol. 2011 Sep;7(3):183–8. [PMID: 21735309]
PESTICIDES: CHOLINESTERASE INHIBITORS Organophosphorus and carbamate insecticides (organophosphates: parathion, malathion, etc; carbamates: carbaryl, aldicarb, etc) are widely used in commercial agriculture and home gardening and have largely replaced older, more environmentally persistent organochlorine compounds such as DDT and chlordane. The organophosphates and carbamates—also called anticholinesterases because they inhibit the enzyme acetylcholinesterase— cause an increase in acetylcholine activity at nicotinic and muscarinic receptors and in the central nervous system. There are a variety of chemical agents in this group, with widely varying potencies. Most of them are poorly watersoluble, are often formulated with an aromatic hydrocarbon solvent such as xylene, and are well absorbed through intact skin. Most chemical warfare “nerve agents” (such as GA [tabun], GB [sarin], GD [soman] and VX) are organophosphates.
``Clinical Findings Inhibition of cholinesterase results in abdominal cramps, diarrhea, vomiting, excessive salivation, sweating, lacrimation, miosis (constricted pupils), wheezing and bronchorrhea, seizures, and skeletal muscle weakness. Initial tachycardia is usually followed by bradycardia. Profound skeletal muscle weakness, aggravated by excessive bronchial secretions and wheezing, may result in respiratory arrest and death. Symptoms and signs of poisoning may persist or recur over several days, especially with highly lipidsoluble agents such as fenthion or dimethoate. The diagnosis should be suspected in patients who present with miosis, sweating, and hyperperistalsis. Serum and red blood cell cholinesterase activity is usually depressed at least 50% below baseline in those victims who have severe intoxication.
``Treatment A. Emergency and Supportive Measures If the agent was recently ingested, consider gut decontamination by aspiration of the liquid using a nasogastric tube
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followed by administration of activated charcoal (see p 1567). If the agent is on the victim’s skin or hair, wash repeatedly with soap or shampoo and water. Providers should take care to avoid skin exposure by wearing gloves and waterproof aprons. Dilute hypochlorite solution (eg, household bleach diluted 1:10) is reported to help break down organophosphate pesticides and nerve agents on equipment or clothing.
B. Specific Treatment Atropine reverses excessive muscarinic stimulation and is effective for treatment of salivation, bronchial hypersecretion, wheezing, abdominal cramping, and sweating. However, it does not interact with nicotinic receptors at autonomic ganglia and at the neuromuscular junction and has no direct effect on muscle weakness. Administer 2 mg intravenously, and if there is no response after 5 minutes, give repeated boluses in rapidly escalating doses (eg, doubling the dose each time) as needed to dry bronchial secretions and decrease wheezing; as much as several hundred milligrams of atropine has been given to treat severe poisoning. Pralidoxime (2-PAM, Protopam) is a specific antidote that reverses organophosphate binding to the cholinesterase enzyme; therefore, it should be effective at the neuromuscular junction as well as other nicotinic and muscarinic sites. It is most likely to be clinically effective if started very soon after poisoning, to prevent permanent binding of the organophosphate to cholinesterase. However, clinical studies have yielded conflicting results regarding the effectiveness of pralidoxime in reducing mortality. Administer 1–2 g intravenously as a loading dose, and begin a continuous infusion (200–500 mg/h, titrated to clinical response). Continue to give pralidoxime as long as there is any evidence of acetylcholine excess. Pralidoxime is of questionable benefit for carbamate poisoning, because carbamates have only a transitory effect on the cholinesterase enzyme. Other, unproven therapies for organophosphate poisoning include magnesium, sodium bicarbonate, clonidine, and extracorporeal removal. Blain PG. Organophosphorus poisoning (acute). Clin Evid (Online). 2011 May 17;2011. pii2102. [PMID: 21575287] Peter JV et al. Clinical profile and outcome of patients hospitalized with dimethyl and diethyl organophosphate poisoning. Clin Toxicol (Phila). 2010 Nov;48(9):916–23. [PMID: 21171848] Thiermann H et al. Atropine maintenance dosage in patients with severe organophosphate pesticide poisoning. Toxicol Lett. 2011 Sep 25;206(1):77–83. [PMID: 21771644]
PETROLEUM DISTILLATES & SOLVENTS Petroleum distillate toxicity may occur from inhalation of the vapor or as a result of pulmonary aspiration of the liquid during or after ingestion. Acute manifestations of aspiration pneumonitis are vomiting, coughing, and bronchopneumonia. Some hydrocarbons—ie, those with aromatic or halogenated subunits—can also cause severe systemic poisoning after oral ingestion. Hydrocarbons can also cause systemic intoxication by inhalation. Vertigo,
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muscular incoordination, irregular pulse, myoclonus, and seizures occur with serious poisoning and may be due to hypoxemia or the systemic effects of the agents. Chlorinated and fluorinated hydrocarbons (trichloroethylene, Freons, etc) and many other hydrocarbons can cause ventricular arrhythmias due to increased sensitivity of the myocardium to the effects of endogenous catecholamines.
``Treatment Remove the patient to fresh air. For simple aliphatic hydrocarbon ingestion, gastric emptying and activated charcoal are not recommended, but these procedures may be indicated if the preparation contains toxic solutes (eg, an insecticide) or is an aromatic or halogenated product. Observe the victim for 6–8 hours for signs of aspiration pneumonitis (cough, localized crackles or rhonchi, tachypnea, and infiltrates on chest radiograph). Corticosteroids are not recommended. If fever occurs, give a specific antibiotic only after identification of bacterial pathogens by laboratory studies. Because of the risk of arrhythmias, use bronchodilators with caution in patients with chlorinated or fluorinated solvent intoxication. If tachyarrhythmias occur, use esmolol intravenously 25–100 mcg/kg/min. Amiri AH et al. Clinical finding and outcome in suicidal attempt due to intravenous injection of kerosene. Pak J Biol Sci. 2009 Mar 1;12(5):439–42. [PMID: 19579984] Argo A et al. A fatal case of a paint thinner ingestion: comparison between toxicological and histological findings. Am J Forensic Med Pathol. 2010 June;31(2):186–91. [PMID: 20010286]
QUINIDINE & RELATED ANTIARRHYTHMICS Quinidine, procainamide, and disopyramide are class Ia antiarrhythmic agents, and flecainide and propafenone are class Ic agents. These drugs have membrane-depressant effects on the sodium-dependent channel responsible for cardiac cell depolarization. Manifestations of cardiotoxicity include arrhythmias, syncope, hypotension, and widening of the QRS complex on the ECG (> 100–120 ms). With type Ia drugs, a lengthened QT interval and atypical or polymorphous ventricular tachycardia (torsades de pointes) may occur. The antimalarials chloroquine and hydroxychloroquine, and the tricyclic antidepressants, have similar cardiotoxic effects in overdose.
``Treatment A. Emergency and Supportive Measures Administer activated charcoal (see p 1567); consider gastric lavage (see p 1567) after large recent overdose. Assist ventilation if needed. Perform continuous cardiac monitoring.
B. Specific Treatment Treat cardiotoxicity (hypotension, QRS interval widening) with intravenous boluses of sodium bicarbonate, 50–100 mEq. Torsades de pointes may be treated with intravenous magnesium or overdrive pacing.
Gunja N et al. Survival after massive hydroxychloroquine overdose. Anaesth Intensive Care. 2009 Jan;37(1):130–3. [PMID: 19157361]
SALICYLATES Salicylates (aspirin, methyl salicylate, etc) are found in a variety of over-the-counter and prescription medications. Salicylates uncouple cellular oxidative phosphorylation, resulting in anaerobic metabolism and excessive production of lactic acid and heat, and they also interfere with several Krebs cycle enzymes. A single ingestion of more than 200 mg/kg of salicylate is likely to produce significant acute intoxication. Poisoning may also occur as a result of chronic excessive dosing over several days. Although the half-life of salicylate is 2–3 hours after small doses, it may increase to 20 hours or more in patients with intoxication.
``Clinical Findings Acute ingestion often causes nausea and vomiting, occasionally with gastritis. Moderate intoxication is characterized by hyperpnea (deep and rapid breathing), tachycardia, tinnitus, and elevated anion gap metabolic acidosis. Serious intoxication may result in agitation, confusion, coma, seizures, cardiovascular collapse, pulmonary edema, hyperthermia, and death. The prothrombin time is often elevated owing to salicylate-induced hypoprothrombinemia. Central nervous system intracellular glucose depletion can occur despite normal measured serum glucose levels. Diagnosis of salicylate poisoning is suspected in any patient with metabolic acidosis and is confirmed by measuring the serum salicylate level. Patients with levels > 100 mg/dL (1000 mg/L or 7.2 mcmol/L) after an acute overdose are more likely to have severe poisoning. On the other hand, patients with subacute or chronic intoxication may suffer severe symptoms with levels of only 60–70 mg/dL (4.3–5 mcmol/L). The arterial blood gas typically reveals a respiratory alkalosis with an underlying metabolic acidosis.
``Treatment A. Emergency and Supportive Measures Administer activated charcoal orally (see p 1567). Gastric lavage followed by administration of extra doses of activated charcoal may be needed in patients who ingest more than 10 g of aspirin (see p 1567). The desired ratio of charcoal to aspirin is about 10:1 by weight; while this cannot always be given as a single dose, it may be administered over the first 24 hours in divided doses every 2–4 hours along with whole bowel irrigation (see p 1567). Give glucose-containing fluids to reduce the risk of cerebral hypoglycemia. Treat metabolic acidosis with intravenous sodium bicarbonate. This is critical because acidosis (especially acidemia, pH < 7.40) promotes greater entry of salicylate into cells, worsening toxicity. Warning: Sudden and severe deterioration can occur after rapid sequence intubation and controlled ventilation if the pH is allowed to fall during the apneic period.
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B. Specific Treatment
``Treatment
Alkalinization of the urine enhances renal salicylate excretion by trapping the salicylate anion in the urine. Add 100 mEq (two ampules) of sodium bicarbonate to 1 L of 5% dextrose in 0.2% saline, and infuse this solution intravenously at a rate of about 150–200 mL/h. Unless the patient is oliguric or hyperkalemic, add 20–30 mEq of potassium chloride to each liter of intravenous fluid. Patients who are volume-depleted often fail to produce an alkaline urine (paradoxical aciduria) unless potassium is given. Hemodialysis may be lifesaving and is indicated for patients with severe metabolic acidosis, markedly altered mental status, or significantly elevated salicylate levels (eg, > 100–120 mg/dL [1000–1200 mg/L or 7.2–8.6 mcmol/L] after acute overdose or > 60–70 mg/dL [600–700 mg/L or 4.3–5 mcmol/L] with subacute or chronic intoxication).
A. Emergency and Supportive Measures
Herres J et al. Delayed salicylate toxicity with undetectable initial levels after large-dose aspirin ingestion. Am J Emerg Med. 2009 Nov;27(9):1173.e1–3. [PMID: 19931787] Jacob J et al. Falsely normal anion gap in severe salicylate poisoning caused by laboratory interference. Ann Emerg Med. 2011 Sep;58(3):280–1. [PMID: 21492961] Minns AB et al. Death due to acute salicylate intoxication despite dialysis. J Emerg Med. 2011 May;40(5):515–7. [PMID: 20347249]
SEAFOOD POISONINGS A variety of intoxications may occur after eating certain types of fish or other seafood. These include scombroid, ciguatera, paralytic shellfish, and puffer fish poisoning. The mechanisms of toxicity and clinical presentations are described in Table 38–10. In the majority of cases, the seafood has a normal appearance and taste (scombroid may have a peppery taste).
Caution: Abrupt respiratory arrest may occur in patients with acute paralytic shellfish and puffer fish poisoning. Observe patients for at least 4–6 hours. Replace fluid and electrolyte losses from gastroenteritis with intravenous saline or other crystalloid solution. For recent ingestions, it may be possible to adsorb residual toxin in the gut with activated charcoal, 50–60 g orally (see p 1567).
B. Specific Treatment There is no specific antidote for paralytic shellfish or puffer fish poisoning. 1. Ciguatera—There are anecdotal reports of successful treatment of acute neurologic symptoms with mannitol, 1 g/kg intravenously, but this approach is not widely accepted. 2. Scombroid—Antihistamines such as diphenhydramine, 25–50 mg intravenously, and the H2-blocker cimetidine, 300 mg intravenously, are usually effective. For severe reactions, give also epinephrine, 0.3–0.5 mL of a 1:1000 solution subcutaneously. Hungerford JM. Scombroid poisoning: a review. Toxicon. 2010 Aug 15;56(2):231–43. [PMID: 20152850] Stewart I et al. Emerging tropical diseases in Australia. Part 2. Ciguatera fish poisoning. Ann Trop Med Parasitol. 2010 Oct;104(7):557–71. [PMID: 21092393]
SNAKE BITES The venom of poisonous snakes and lizards may be predominantly neurotoxic (coral snake) or predominantly cytolytic (rattlesnakes, other pit vipers). Neurotoxins
Table 38–10. Common seafood poisonings. Type of Poisoning
Mechanism
Clinical Presentation
Ciguatera
Reef fish ingest toxic dinoflagellates, whose toxins accumulate in fish meat. Commonly implicated fish in the United States are barracuda, jack, snapper, and grouper.
1–6 hours after ingestion, victims develop abdominal pain, vomiting, and diarrhea accompanied by a variety of neurologic symptoms, including paresthesias, reversal of hot and cold sensation, vertigo, headache, and intense itching. Autonomic disturbances, including hypotension and bradycardia, may occur.
Scombroid
Improper preservation of large fish results in bacterial degradation of histidine to histamine. Commonly implicated fish include tuna, mahimahi, bonita, mackerel, and kingfish.
Allergic-like (anaphylactoid) symptoms are due to histamine, usually begin within 15–90 minutes, and include skin flushing, itching, urticaria, angioedema, bronchospasm, and hypotension as well as abdominal pain, vomiting, and diarrhea.
Paralytic shellfish poisoning
Dinoflagellates produce saxitoxin, which is concentrated by filter-feeding mussels and clams. Saxitoxin blocks sodium conductance and neuronal transmission in skeletal muscles.
Onset is usually within 30–60 minutes. Initial symptoms include perioral and intraoral paresthesias. Other symptoms include nausea and vomiting, headache, dizziness, dysphagia, dysarthria, ataxia, and rapidly progressive muscle weakness that may result in respiratory arrest.
Puffer fish poisoning
Tetrodotoxin is concentrated in liver, gonads, intestine, and skin. Toxic effects are similar to those of saxitoxin. Tetrodotoxin is also found in some North American newts and Central American frogs.
Onset is usually within 30–40 minutes but may be as short as 10 minutes. Initial perioral paresthesias are followed by headache, diaphoresis, nausea, vomiting, ataxia, and rapidly progressive muscle weakness that may result in respiratory arrest.
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cause respiratory paralysis; cytolytic venoms cause tissue destruction by digestion and hemorrhage due to hemolysis and destruction of the endothelial lining of the blood vessels. The manifestations of rattlesnake envenomation are mostly local pain, redness, swelling, and extravasation of blood. Perioral tingling, metallic taste, nausea and vomiting, hypotension, and coagulopathy may also occur. Thrombocytopenia can persist for several days after a rattlesnake bite. Neurotoxic envenomation may cause ptosis, dysphagia, diplopia, and respiratory arrest.
causes generalized muscular pains, muscle spasms, and rigidity. The brown recluse spider (Loxosceles reclusa) causes progressive local necrosis as well as hemolytic reactions (rare). Stings by most scorpions in the United States cause only local pain. Stings by the more toxic Centruroides species (found in the southwestern United States) may cause muscle cramps, twitching and jerking, and occasionally hypertension, convulsions, and pulmonary edema. Stings by scorpions from other parts of the world are not discussed here.
``Treatment
``Treatment
A. Emergency Measures
A. Black Widow Spider Bites
Immobilize the patient and the bitten part in a neutral position. Avoid manipulation of the bitten area. Transport the patient to a medical facility for definitive treatment. Do not give alcoholic beverages or stimulants; do not apply ice; do not apply a tourniquet. The potential trauma to underlying tissues resulting from incision and suction performed by unskilled people is probably not justified in view of the small amount of venom that can be recovered.
Pain may be relieved with parenteral opioids or muscle relaxants (eg, methocarbamol, 15 mg/kg). Calcium gluconate 10%, 0.1–0.2 mL/kg intravenously, may transiently relieve muscle rigidity, though its effectiveness is unproven. Latrodectus antivenom is very effective, but because of concerns about acute hypersensitivity reactions (horse serumderived), it is often reserved for very young or elderly patients or those who do not respond promptly to the above measures. Horse serum sensitivity testing is required. (Instruction and testing materials are included in the antivenin kit.)
B. Specific Antidote and General Measures 1. Pit viper (eg, rattlesnake) envenomation—For local signs such as swelling, pain, and ecchymosis but no systemic symptoms, give 4–6 vials of crotalid antivenin (CroFab) by slow intravenous drip in 250–500 mL saline. Repeated doses of 2 vials every 6 hours for up to 18 hours has been recommended. For more serious envenomation with marked local effects and systemic toxicity (eg, hypotension, coagulopathy), higher doses and additional vials may be required. Monitor vital signs and the blood coagulation profile. Type and crossmatch blood. The adequacy of venom neutralization is indicated by improvement in symptoms and signs, and the rate that swelling slows. Prophylactic antibiotics are not indicated after a rattlesnake bite. 2. Elapid (coral snake) envenomation—Give 1–2 vials of specific antivenom as soon as possible. To locate antisera for exotic snakes, call a regional poison control center (1-800-222-1222). Cruz LS et al. Snakebite envenomation and death in the developing world. Ethn Dis. 2009 Spring;19(1 Suppl 1):S1–42–6. [PMID: 19484874] Lavonas EJ et al. Crotaline Fab antivenom appears to be effective in cases of severe North American pit viper envenomation: an integrative review. BMC Emerg Med. 2009 Jun 22;9:13. [PMID: 19545426] Lavonas EJ et al; Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority. Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop. BMC Emerg Med. 2011 Feb 3;11:2. [PMID: 21291549]
SPIDER BITES & SCORPION STINGS The toxin of most species of spiders in the United States causes only local pain, redness, and swelling. That of the more venomous black widow spiders (Latrodectus mactans)
B. Brown Recluse Spider Bites Because bites occasionally progress to extensive local necrosis, some authorities recommend early excision of the bite site, whereas others use oral corticosteroids. Anecdotal reports have claimed success with dapsone and colchicine. All of these treatments remain of unproved value.
C. Scorpion Stings No specific treatment other than analgesics is required for envenomations by most scorpions found in the United States. For Centruroides stings, a specific antivenom developed in Arizona was proved effective and was granted FDA approval in 2011. Bawaskar HS et al. Efficacy and safety of scorpion antivenom plus prazosin compared with prazosin alone for venomous scorpion (Mesobuthus tamulus) sting: randomised open label clinical trial. BMJ. 2011 Jan 5;342:c7136. [PMID: 21209062] Boyer LV et al. Antivenom for critically ill children with neurotoxicity from scorpion stings. N Engl J Med. 2009 May 14; 360(20):2090–8. [PMID: 19439743] Khattabi A et al; Scorpion Consensus Expert Group. Classification of clinical consequences of scorpion stings: consensus development. Trans R Soc Trop Med Hyg. 2011 Jul;105(7):364–9. [PMID: 21601228] Isbister GK et al. Spider bite. Lancet. 2011 Dec 10;378(9808): 2039–s47. [PMID: 21762981] Tuuri RE et al. Scorpion envenomation and antivenom therapy. Pediatr Emerg Care. 2011 Jul;27(7):667–72. [PMID: 21730810]
THEOPHYLLINE & CAFFEINE Theophylline may cause intoxication after an acute single overdose, or intoxication may occur as a result of chronic
Poisoning accidental repeated overmedication or reduced elimination resulting from hepatic dysfunction or interacting drug (eg, cimetidine, erythromycin). The usual serum half-life of theophylline is 4–6 hours, but this may increase to more than 20 hours after overdose. Caffeine and caffeinecontaining herbal products can produce similar toxicity.
``Clinical Findings Mild intoxication causes nausea, vomiting, tachycardia, and tremulousness. Severe intoxication is characterized by ventricular and supraventricular tachyarrhythmias, hypotension, and seizures. Status epilepticus is common and often intractable to the usual anticonvulsants. After acute overdose (but not chronic intoxication), hypokalemia, hyperglycemia, and metabolic acidosis are common. Seizures and other manifestations of toxicity may be delayed for several hours after acute ingestion, especially if a sustained-release preparation such as Theo-Dur was taken. Diagnosis is based on measurement of the serum theophylline concentration. Seizures and hypotension are likely to develop in acute overdose patients with serum levels > 100 mg/L (555 mcmol/L). Serious toxicity may develop at lower levels (ie, 40–60 mg/L [222–333 mcmol/L]) in patients with chronic intoxication.
``Treatment A. Emergency and Supportive Measures After acute ingestion, administer activated charcoal (see p 1567). Repeated doses of activated charcoal may enhance theophylline elimination by “gut dialysis.” Addition of whole bowel irrigation should be considered for large ingestions involving sustained-release preparations (see p 1567). Hemodialysis is effective in removing theophylline and is indicated for patients with status epilepticus or markedly elevated serum theophylline levels (eg, > 100 mg/L [555 mcmol/L] after acute overdose or > 60 mg/L [333 mcmol/L] with chronic intoxication).
B. Specific Treatment Treat seizures with benzodiazepines (lorazepam, 2–3 mg intravenously, or diazepam, 5–10 mg intravenously) or phenobarbital (10–15 mg/kg intravenously). Phenytoin is not effective. Hypotension and tachycardia—which are mediated through excessive β-adrenergic stimulation— may respond to β-blocker therapy even in low doses. Administer esmolol, 25–50 mcg/kg/min by intravenous infusion, or propranolol, 0.5–1 mg intravenously. Rudolph T et al. A case of fatal caffeine poisoning. Acta Anaesthesiol Scand. 2010 Apr;54(4):521–3. [PMID: 20096021] Trabulo D et al. Caffeinated energy drink intoxication. Emerg Med J. 2011 Aug;28(8):712–4. [PMID: 21788240]
TRICYCLIC & OTHER ANTIDEPRESSANTS Tricyclic and related cyclic antidepressants are among the most dangerous drugs involved in suicidal overdose. These
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drugs have anticholinergic and cardiac depressant properties (“quinidine-like” sodium channel blockade). Tricyclic antidepressants produce more marked membranedepressant cardiotoxic effects than the phenothiazines. Newer antidepressants such as trazodone, fluoxetine, citalopram, paroxetine, sertraline, bupropion, venlafaxine, and fluvoxamine are not chemically related to the tricyclic antidepressant agents and do not generally produce quinidine-like cardiotoxic effects. However, they may cause seizures in overdoses and they may cause serotonin syndrome (see Monoamine Oxidase Inhibitors section).
``Clinical Findings Signs of severe intoxication may occur abruptly and without warning within 30–60 minutes after acute tricyclic overdose. Anticholinergic effects include dilated pupils, tachycardia, dry mouth, flushed skin, muscle twitching, and decreased peristalsis. Quinidine-like cardiotoxic effects include QRS interval widening (> 0.12 s; Figure 38–2), ventricular arrhythmias, AV block, and hypotension. Rightward-axis deviation of the terminal 40 ms of the QRS has also been described. Prolongation of the QT interval and torsades de pointes have been reported with several of the newer antidepressants. Seizures and coma are common with severe intoxication. Life-threatening hyperthermia may result from status epilepticus and anticholinergic- induced impairment of sweating. Among newer agents, bupropion and venlafaxine have been associated with a greater risk of seizures. The diagnosis should be suspected in any overdose patient with anticholinergic side effects, especially if there is widening of the QRS interval or seizures. For
A
B
C
s Figure 38–2. Cardiac arrhythmias resulting from tricyclic antidepressant overdose. A: Delayed intraventricular conduction results in prolonged QRS interval (0.18 s). B and C: Supraventricular tachycardia with progressive widening of QRS complexes mimics ventricular tachycardia. (Reproduced, with permission, from Benowitz NL, Goldschlager N. Cardiac disturbances in the toxicologic patient. In: Haddad LM, Winchester JF [editors], Clinical Management of Poisoning and Drug Overdose, 3rd edition. Saunders/Elsevier, 1998.)
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intoxication by most tricyclic antidepressants, the QRS interval correlates with the severity of intoxication more reliably than the serum drug level. Serotonin syndrome should be suspected if agitation, delirium, diaphoresis, tremor, hyperreflexia, clonus (spontaneous, inducible, or ocular), and fever develop in a patient taking serotonin reuptake inhibitors.
``Treatment A. Emergency and Supportive Measures Observe patients for at least 6 hours, and admit all patients with evidence of anticholinergic effects (eg, delirium, dilated pupils, tachycardia) or signs of cardiotoxicity (see above). Administer activated charcoal (see p 1567) and consider gastric lavage (see p 1567) after recent large ingestions. All of these drugs are highly tissue-bound and are not effectively removed by hemodialysis procedures.
B. Specific Treatment Cardiotoxic sodium channel-depressant effects of tricyclic antidepressants may respond to boluses of sodium bicarbonate (50–100 mEq intravenously). Sodium bicarbonate provides a large sodium load that alleviates depression of the sodium-dependent channel. Reversal of acidosis may
also have beneficial effects at this site. Maintain the pH between 7.45 and 7.50. Alkalinization does not promote excretion of tricyclic antidepressants. Prolongation of the QT interval or torsades de pointes is usually treated with intravenous magnesium or overdrive pacing. Severe cardiotoxicity in patients with overdoses of lipid-soluble drugs (eg, amitriptyline, bupropion) has responded to intravenous lipid emulsion (Intralipid). Mild serotonin syndrome may be treated with benzodiazepines and withdrawal of the antidepressant. Moderate cases may respond to cyproheptadine (4 mg orally or via gastric tube hourly for three or four doses) or chlorpromazine (25 mg intravenously). Severe hyperthermia should be treated with neuromuscular paralysis and endotracheal intubation in addition to external cooling measures. Body R et al. Guidelines in Emergency Medicine Network (GEMNet): guideline for the management of tricyclic antidepressant overdose. Emerg Med J. 2011 Apr;28(4):347–68. [PMID: 21436332] Boegevig S et al. Successful reversal of life threatening cardiac effect following dosulepin overdose using intravenous lipid emulsion. Clin Toxicol (Phila). 2011 Apr;49(4):337–9. [PMID: 21563912] Engels PT et al. Intravenous fat emulsion to reverse haemodynamic instability from intentional amitriptyline overdose. Resuscitation. 2010 Aug;81(8):1037–9. [PMID: 20605670]