Kent R. Olson, MD
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.
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 (opioids, anticholinergics, salicylate) 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.
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.
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.
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.
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 of hypothermia is discussed in Chapter 37. Gradual rewarming is preferred unless the patient is in cardiac arrest.
Assessment & Complications
Hypotension may be due to poisoning by many different drugs and poisons, including antihypertensive drugs, beta-blockers, calcium channel blockers, disulfiram (ethanol interaction), iron, trazodone, quetiapine, and other antipsychotic agents and antidepressants. Poisons causing hypotension include cyanide, carbon monoxide, hydrogen sulfide, aluminum or zinc 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.
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 beta-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 Beta-Adrenergic Blockers and Calcium Channel Blockers, below). Intralipid 20% lipid emulsion 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.
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]
Waring WS. Intravenous lipid administration for drug-induced toxicity: a critical review of the existing data. Expert Rev Clin Pharmacol. 2012 Jul;5(4):437–44. [PMID: 22943123]
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.
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 beta-blockers alone, since doing so may paradoxically worsen hypertension as a result of unopposed alpha-adrenergic stimulation.
Grossman E et al. Drug-induced hypertension: an unappreciated cause of secondary hypertension. Am J Med. 2012 Jan;125(1):14–22. [PMID: 22195528]
Perruchoud C et al. Severe hypertension following accidental clonidine overdose during the refilling of an implanted intrathecal drug delivery system. Neuromodulation. 2012 Jan–Feb;15(1):31–4. [PMID: 21943355]
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.
Table 38–1. Common toxins or drugs causing arrhythmias.1
Arrhythmias may be caused by hypoxia or electrolyte imbalance, and these conditions should be sought and treated. If 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 infusion. (See discussion of tricyclic antidepressant poisoning.) Caution: Avoid class Ia antiarrhythmic agents (eg, procainamide, disopyramide), which may aggravate arrhythmias caused by tricyclic antidepressants. 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).
Behr ER et al. Drug-induced arrhythmia: pharmacogenomic prescribing? Eur Heart J. 2013 Jan;34(2):89–95. [PMID: 23091201]
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, tramadol, and theophylline. The onset of seizures may be delayed for up to 24 hours after extended-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.
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
Bekjarovski N et al. Seizures after use and abuse of tramadol. Prilozi. 2012 Jul;33(1):313–8. [PMID: 22983066]
Thundiyil JG et al. Risk factors for complications of drug-induced seizures. J Med Toxicol. 2011 Mar;7(1):16–23. [PMID: 20661684]
Assessment & Complications
Hyperthermia may be associated with poisoning by amphetamines (especially methylenedioxymethamphetamine [MDMA; “Ecstasy”]), atropine and other anticholinergic 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 kidney injury, and coagulopathy (see Chapter 37).
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.
Menaker J et al. Cocaine-induced agitated delirium with associated hyperthermia: a case report. J Emerg Med. 2011 Sep;41(3):e49–53. [PMID: 18823733]
Perry PJ et al. Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Ann Clin Psychiatry. 2012 May;24(2):155–62. [PMID: 22563571]
ANTIDOTES & OTHER TREATMENT
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.
Table 38–3. Some toxic agents for which there are specific antidotes.1
Marraffa JM et al. Antidotes for toxicological emergencies: a practical review. Am J Health Syst Pharm. 2012 Feb 1;69(3):199–212. [PMID: 22261941]
Thanacoody RH et al. National audit of antidote stocking in acute hospitals in the UK. Emerg Med J. 2013 May;30(5):393–6. [PMID: 22875840]
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 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 serious conjunctival or corneal injury should be immediately referred to an ophthalmologist.
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. In these cases, aggressive gut decontamination may be indicated.
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.
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.
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.
Activated charcoal effectively adsorbs almost all drugs and poisons. Poorly adsorbed substances include iron, lithium, potassium, sodium, mineral acids, and alcohols.
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.
Table 38–4. Recommended use of hemodialysis in poisoning.
Continuous renal replacement therapy (including continuous venovenous hemodiafiltration and similar techniques) is of uncertain benefit for elimination of most poisons but has the advantage of gradual removal of the toxin and correction of any accompanying acidosis, and its use has been reported in the management of lithium intoxication.
Benson BE et al; American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Position paper update: gastric lavage for gastrointestinal decontamination. Clin Toxicol (Phila). 2013 Mar;51(3):140–6. [PMID: 23418938]
Dohlman CH et al. Chemical burns to the eye: paradigm shifts in treatment. Cornea. 2011 Jun;30(6):613–4. [PMID: 21242777]
Ghannoum M et al. Enhanced poison elimination in critical care. Adv Chronic Kidney Dis. 2013 Jan;20(1):94–101. [PMID: 23265601]
Isbister GK et al. Indications for single-dose activated charcoal administration in acute overdose. Curr Opin Crit Care. 2011 Aug;17(4):351–7. [PMID: 21716104]
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 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.
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.
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.
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, gamma-hydroxybutyrate (GHB), clonidine and related antihypertensives, ethanol, opioids.
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.
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.
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), creatine kinase, urinalysis (eg, oxalate crystals with ethylene glycol poisoning, myoglobinuria with rhabdomyolysis), and electrocardiography. Serum acetaminophen and ethanol quantitative levels should be determined in all patients with drug overdoses.
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.
Table 38–5. Use of the osmol gap in toxicology.
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.
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 comprehensive toxicology screen is of little value in the initial care of the poisoned patient because results usually 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.
Table 38–6. Specific quantitative levels and potential therapeutic interventions.1
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 only opiates, amphetamines, and cocaine, and some add benzodiazepines, barbiturates, methadone, and tetrahydrocannabinol [marijuana]). There are numerous false-positive and false-negative results. For example, synthetic opioids, such as fentanyl, oxycodone, and methadone are often 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.
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 (1-800-222-1222) 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.
When to Admit
Goldfrank LR (editor). Goldfrank’s Toxicologic Emergencies, 9th ed. McGraw-Hill, 2010.
Holstege CP et al. Toxidromes. Crit Care Clin. 2012 Oct;28(4):479–98. [PMID: 22998986]
Olson KR (editor). Poisoning & Drug Overdose, 6th ed. McGraw-Hill, 2011.
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 mixed-function 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 intermediate attacks other cell proteins, causing necrosis. Patients with enhanced P450 2E1 activity, such as those who chronically abuse alcohol and patients taking INH, are at increased risk for developing hepatotoxicity. Hepatic toxicity may also occur after 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.
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 sustained-release products or coingestion of an anticholinergic agent, salicylate, or opioid drug may cause delayed elevation of serum levels which can make it difficult to interpret the nomogram. The nomogram is also not useful after repeated overdose.
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.)
Administer activated charcoal (see p. 1554) 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.
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 hepatotoxicity (eg, alcoholic, liver disease, long-term use of P450-inducing 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.
Hodgman MJ et al. A review of acetaminophen poisoning. Crit Care Clin. 2012 Oct;28(4):499–516. [PMID: 22998987]
Rumack BH et al. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin Toxicol (Phila). 2012 Feb;50(2):91–8. [PMID: 22320209]
Wolf MS et al. Risk of unintentional overdose with non-prescription acetaminophen products. J Gen Intern Med. 2012 Dec;27(12):1587–93. [PMID: 22638604]
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 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.
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.
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).
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.
Remove from further exposure to fumes or gas. Check skin and clothing. Treat pulmonary edema.
Singh P et al. Ocular chemical injuries and their management. Oman J Ophthalmol. 2013 May;6(2):83–86. [PMID: 24082664]
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.
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.
Wash with running water until the skin no longer feels soapy. Relieve pain and treat shock.
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.
Pavelites JJ et al. Deaths related to chemical burns. Am J Forensic Med Pathol. 2011 Dec;32(4):387–92. [PMID: 21860322]
AMPHETAMINES & COCAINE
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).
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.
Maintain a patent airway and assist ventilation, if necessary. Treat seizures as described at the beginning of this chapter (see p. 1552). Rapidly lower the body temperature (see hyperthermia, p. 1552) in patients who are hyperthermic (temperature > 39–40°C). Give intravenous fluids to prevent myoglobinuric renal injury in patients who have rhabdomyolysis.
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 vasodilator drug such as phentolamine (1–5 mg intravenously) or a combined alpha- and beta-adrenergic blocker such as labetalol (10–20 mg intravenously). Do not administer a pure beta-blocker such as propranolol alone, as this may result in paradoxic worsening of the hypertension as a result of unopposed alpha-adrenergic effects.
Treat tachycardia or tachyarrhythmias with a short-acting beta-blocker such as esmolol (25–100 mcg/kg/min by intravenous infusion). Treat hyperthermia as described above (see p. 1552). Treat hyponatremia as outlined in Chapter 21.
Gibbons S. ‘Legal highs’—novel and emerging psychoactive drugs: a chemical overview for the toxicologist. Clin Toxicol (Phila). 2012 Jan;50(1):15–24. [PMID: 22248120]
Prosser JM et al. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol. 2012 Mar;8(1):33–42. [PMID: 22108839]
Warfarin and related compounds (including ingredients of many commercial rodenticides, the so-called “superwarfarins” such as brodifacoum, difenacoum, and related compounds) inhibit the clotting mechanism by blocking hepatic synthesis of vitamin K–dependent clotting factors. After ingestion of “superwarfarins,” inhibition of clotting factor synthesis may persist for several weeks or even months after a single dose. Newer oral anticoagulants include the direct thrombin inhibitors dabigatran and rivaroxaban.
Excessive anticoagulation 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 overdose of warfarin or “superwarfarins” but is not as predictably abnormal after overdose of dabigatran or rivaroxiban.
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. 1554).
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 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.
Vitamin K does not reverse the anticoagulant effects of the direct thrombin inhibitors dabigatran and rivaroxaban. The efficacy of fresh frozen plasma and clotting factor concentrates is uncertain.
Godier A et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012 Jan;116(1):94–102. [PMID: 22042412]
Siegal DM et al. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J. 2013 Feb;34(7):489–498b. [PMID: 23220847]
Watson KS et al. Superwarfarin intoxication: two case reports and review of pathophysiology and patient management. J La State Med Soc. 2012 Mar–Apr;164(2):70–2. [PMID: 22685854]
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 zero-order 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 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 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.
For recent ingestions, give activated charcoal orally or by gastric tube (see p. 1554). For large ingestions of carbamazepine or valproic acid—especially of sustained-release formulations—consider whole bowel irrigation (see p. 1554). Combined multiple-dose activated charcoal and whole-bowel irrigation may be beneficial in ensuring gut decontamination for selected large ingestions.
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]).
Larkin TM et al. Overdose with levetiracetam: a case report and review of the literature. J Clin Pharm Ther. 2013 Feb;38(1):68–70. [PMID: 22725831]
Ozhasenekler A et al. Benefit of hemodialysis in carbamazepine intoxications with neurological complications. Eur Rev Med Pharmacol Sci. 2012 Mar;16(Suppl 1):43–7. [PMID: 22582484]
Pons S et al. Acute overdose of enteric-coated valproic acid and olanzapine: unusual presentation and delayed toxicity. Clin Toxicol (Phila). 2012 Apr;50(4):268. [PMID: 22385067]
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 life-threatening (see Chapter 25).
Administer activated charcoal (see p. 1554) for large or recent ingestions. For severe hypotension, treatment with intravenous fluids and vasopressor agents may be necessary. Treat hyperthermia as outlined on p. 1552. Maintain cardiac monitoring.
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. 1552) is preferred.
Levine M et al. Overdose of atypical antipsychotics: clinical presentation, mechanisms of toxicity and management. CNS Drugs. 2012 Jul 1;26(7):601–11. Erratum in: CNS Drugs. 2012 Sep 1;26(9):812. [PMID: 22668123]
Minns AB et al. Toxicology and overdose of atypical antipsychotics. J Emerg Med. 2012 Nov;43(5):906–13. [PMID: 22555052]
Arsenic is found in some pesticides and industrial chemicals and is used 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.
After recent ingestion (within 1–2 hours), perform gastric lavage (see p. 1554). Activated charcoal is of uncertain benefit because it binds arsenic poorly. Administer intravenous fluids to replace losses due to vomiting and diarrhea.
For patients with severe acute intoxication, administer a chelating agent. The preferred drug is 2,3-dimercaptopropanesulfonic acid (DMPS, Unithiol) (3–5 mg/kg intravenously every 4 hours); although there is no FDA-approved commercial formulation of DMPS in the United States, it can be obtained from some compounding pharmacies. An alternative parenteral chelator is dimercaprol (British anti-Lewisite, BAL), which comes as a 10% solution in peanut oil, and is given 3–5 mg/kg intramuscularly every 4–6 hours for 2 days. The side effects include nausea, vomiting, headache, and hypertension. When gastrointestinal symptoms allow, switch to the oral chelator 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.
Hughes MF et al. Arsenic exposure and toxicology: a historical perspective. Toxicol Sci. 2011 Oct;123(2):305–32. [PMID: 21750349]
Yunus M et al. Arsenic exposure and adverse health effects: a review of recent findings from arsenic and health studies in Matlab, Bangladesh. Kaohsiung J Med Sci. 2011 Sep;27(9):371–6. [PMID: 21914523]
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. Symptoms of toxicity include dryness of the mouth, thirst, difficulty in swallowing, and blurring of vision. 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 diphenhydramine overdose may mimic tricyclic antidepressant cardiotoxic poisoning.
Administer activated charcoal (see p. 1554). External cooling and sedation, or neuromuscular paralysis in rare cases, are indicated to control high temperatures (see p. 1552).
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.
Cole JB et al. Wide complex tachycardia in a pediatric diphenhydramine overdose treated with sodium bicarbonate. Pediatr Emerg Care. 2011 Dec;27(12):1175–7. [PMID: 22158278]
Rosenbaum C et al. Timing and frequency of physostigmine redosing for antimuscarinic toxicity. J Med Toxicol. 2010 Dec;6(4):386–92. [PMID: 20405266]
There are a wide variety of beta-adrenergic blocking drugs, with varying pharmacologic and pharmacokinetic properties (see Table 11–6). The most toxic beta-blocker is propranolol, which not only blocks beta-1 and beta-2 adrenoceptors but also has direct membrane-depressant and central nervous system effects.
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 beta-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 beta-blockers.
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. 1554).
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 beta-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 antidepressant poisoning. Intravenous lipid emulsion (Intralipid 20%, 1.5 mL/kg) has been used successfully in severe propranolol overdose.
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]
CALCIUM CHANNEL BLOCKERS
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.
For ingested drugs, administer activated charcoal (see p. 1554). In addition, whole bowel irrigation (see p. 1554) should be initiated as soon as possible if the patient has ingested a sustained-release product.
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. 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.
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 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).
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.)
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.
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 consciousness, CoHb > 25%, metabolic acidosis, age over 50 years, and cerebellar findings on neurologic examination.
Buckley NA et al. Hyperbaric oxygen for carbon monoxide poisoning. Cochrane Database Syst Rev. 2011 Apr 13;(4):CD002041. [PMID: 21491385]
Guzman JA. Carbon monoxide poisoning. Crit Care Clin. 2012 Oct;28(4):537–48. [PMID: 22998990]
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 alpha-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.
Give activated charcoal (see p. 1554). 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.
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.
Perruchoud C et al. Severe hypertension following accidental clonidine overdose during the refilling of an implanted intrathecal drug delivery system. Neuromodulation. 2012 Jan–Feb;15(1):31–4. [PMID: 21943355]
See Amphetamines & Cocaine.
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. 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.
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.
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. 1554). 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).
In the United States, there are two available cyanide antidote regimens. The conventional cyanide antidote package (Taylor Pharmaceuticals) 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).
Anseeuw K et al. Cyanide poisoning by fire smoke inhalation: a European expert consensus. Eur J Emerg Med. 2013 Feb;20(1):2–9. [PMID: 22828651]
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]
Thompson JP et al. Hydroxocobalamin in cyanide poisoning. Clin Toxicol (Phila). 2012 Dec;50(10):875–85. [PMID: 23163594]
DIETARY SUPPLEMENTS & HERBAL PRODUCTS
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 38–7 lists selected examples of clinical toxicity from some of these products.
Table 38–7. Examples of potential toxicity associated with some dietary supplements and herbal medicines.
Pendleton M et al. Potential toxicity of caffeine when used as a dietary supplement for weight loss. J Diet Suppl. 2012 Dec;9(4):293–8. [PMID: 23157583]
Posadzki P et al. Contamination and adulteration of herbal medicinal products (HMPs): an overview of systematic reviews. Eur J Clin Pharmacol. 2013 Mar;69(3):295–307. [PMID: 22843016]
Teschke R et al. Herbal hepatotoxicity: a critical review. Br J Clin Pharmacol. 2013 Mar;75(3):630–6. [PMID: 22831551]
DIGITALIS & OTHER CARDIAC GLYCOSIDES
Cardiac glycosides 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) 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.
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 cross-reactivity of immunologic tests.
After acute ingestion, administer activated charcoal (see p. 1554). Monitor potassium levels and cardiac rhythm closely. Treat bradycardia initially with atropine (0.5–2 mg intravenously) or a transcutaneous external cardiac pacemaker.
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.
Note: After administration of digoxin-specific Fab antibody fragments, serum digoxin levels may be falsely elevated depending on the assay technique.
Kanji S et al. Cardiac glycoside toxicity: more than 200 years and counting. Crit Care Clin. 2012 Oct;28(4):527–35. [PMID: 22998989]
Manini AF et al. Prognostic utility of serum potassium in chronic digoxin toxicity: a case-control study. Am J Cardiovasc Drugs. 2011 Jun 1;11(3):173–8. [PMID: 21619380]
Yang EH et al. Digitalis toxicity: a fading but crucial complication to recognize. Am J Med. 2012 Apr;125(4):337–43. [PMID: 22444097]
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 benzodiazepine-like 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.
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.
Administer activated charcoal if the patient has ingested a massive dose and the airway is protected (see p. 1554). 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.
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 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.
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]
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 gamma-butyrolactone (GBL). A prolonged withdrawal syndrome has been described in some heavy users.
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.
Schep LJ et al. The clinical toxicology of gamma-hydroxybutyrate, gamma-butyrolactone and 1,4-butanediol. Clin Toxicol (Phila). 2012 Jul;50(6):458–70. [PMID: 22746383]
Medications used for diabetes mellitus include insulin, sulfonylureas and other insulin secretagogues, alpha-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.
Hypoglycemia may occur quickly after injection of short-acting insulins or may be delayed and prolonged, especially if a large amount has been injected into a single area, creating a “depot” effect (Figure 27–3). Hypoglycemia after sulfonylurea ingestion is usually apparent within a few hours but may be delayed several hours, especially if food or glucose-containing fluids have been given (see Table 27–8).
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.
Furukawa S et al. Suicide attempt by an overdose of sitagliptin, an oral hypoglycemic agent: a case report and a review of the literature. Endocr J. 2012;59(4):329–33. [PMID: 22277726]
Glatstein M et al. Octreotide for the treatment of sulfonylurea poisoning. Clin Toxicol (Phila). 2012 Nov;50(9):795–804. [PMID: 23046209]
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.
Ingestion of < 30 mg/kg of elemental iron usually produces only mild gastrointestinal upset. Ingestion of > 40–60 mg/kg 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.
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. 1554). Activated charcoal is not effective but may be appropriate if other ingestants are suspected.
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.
Audimoolam VK et al. Iron and acetaminophen a fatal combination? Transpl Int. 2011 Oct;24(10):e85–8. [PMID: 21883506]
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]
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 gamma-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.
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.
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. 1554) after large recent ingestion, but with caution because of the risk of abrupt onset of seizures.
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.
Eyüboğlu T et al. Rhabdomyolysis due to isoniazid poisoning resulting from the use of intramuscular pyridoxine. Turk J Pediatr. 2013 May–Jun;55(3):328–30. [PMID: 24217082]
Minns AB et al. Isoniazid-induced status epilepticus in a pediatric patient after inadequate pyridoxine therapy. Pediatr Emerg Care. 2010 May;26(5):380–1. [PMID: 20453796]
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.
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.
Diagnosis is based on measurement of the blood lead level. Whole blood lead levels < 10 mcg/dL are usually considered nontoxic, although that limit has been lowered to 5 mcg/dL in children. 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.
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. 1554), 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.
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.
Centers for Disease Control and Prevention (CDC). Lead poisoning in pregnant women who used Ayurvedic medications from India—New York City, 2011–2012. MMWR Morb Mortal Wkly Rep. 2012 Aug 24;61(33):641–6. [PMID: 22914225]
Rehani B et al. Lead poisoning from a gunshot wound. South Med J. 2011 Jan;104(1):57–8. [PMID: 21079537]
Thihalolipavan S et al. Examining pica in NYC pregnant women with elevated blood lead levels. Matern Child Health J. 2013 Jan;17(1):49–55. [PMID: 22302239]
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.
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.
After acute oral overdose, consider gastric lavage (see p. 1554) or whole bowel irrigation (see p. 1554) 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 exceeds 10 mEq/L after an acute overdose. Continuous renal replacement hemofiltration may be an effective alternative to hemodialysis.
Chen WY et al. Reversible oro-lingual dyskinesia related to lithium intoxication. Acta Neurol Taiwan. 2013 Mar;22(1):32–5. [PMID: 23479244]
McKnight RF et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012 Feb 25;379(9817):721–8. [PMID: 22265699]
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 and related cathinone derivatives. See www.erowid.org for very thorough descriptions of a variety of hallucinogenic substances.
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. 1554).
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 beta-blockers such as propranolol (1–5 mg intravenously) or esmolol (250–500 mcg/kg intravenously, then 50 mcg/kg/min by infusion) may be more effective than lidocaine or amiodarone.
Cámara-Lemarroy CR et al. Clinical presentation and management in acute toluene intoxication: a case series. Inhal Toxicol. 2012 Jun;24(7):434–8. [PMID: 22642292]
Gunderson EW et al. “Spice” and “K2” herbal highs: a case series and systematic review of the clinical effects and biopsychosocial implications of synthetic cannabinoid use in humans. Am J Addict. 2012 Jul–Aug;21(4):320–6. [PMID: 22691010]
Harris CR et al. Synthetic cannabinoid intoxication: a case series and review. J Emerg Med. 2013 Feb;44(2):360–6. [PMID: 22989695]
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.
There is no effective specific treatment for mercury vapor pneumonitis. Remove ingested mercuric salts by lavage, and administer activated charcoal (see p. 1554). 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; it can be obtained from some compounding pharmacies. Maintain urinary output. Treat oliguria and anuria if they occur.
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).
Mercer JJ et al. Acrodynia and hypertension in a young girl secondary to elemental mercury toxicity acquired in the home. Pediatr Dermatol. 2012 Mar–Apr;29(2):199–201. [PMID: 22409470]
Oz SG et al. Mercury vapor inhalation and poisoning of a family. Inhal Toxicol. 2012 Aug;24(10):652–8. [PMID: 22906171]
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.
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 kidney injury.
For patients presenting within 30–60 minutes after ingestion, empty the stomach by aspiration through a nasogastric tube (see p. 1554). Charcoal is not very effective but should be administered if other poisons or drugs have also been ingested.
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.
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]
Coulter CV et al. Methanol and ethylene glycol acute poisonings—predictors of mortality. Clin Toxicol (Phila). 2011 Dec;49 (10):900–6. [PMID: 22091788]
Kruse JA. Methanol and ethylene glycol intoxication. Crit Care Clin. 2012 Oct;28(4):661–711. [PMID: 22998995]
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.
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).
Administer high-flow oxygen. If the causative agent was recently ingested, administer activated charcoal (see p. 1554). Repeat-dose activated charcoal may enhance dapsone elimination (see p. 1554).
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) 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]
Gupta A et al. A fatal case of severe methaemoglobinemia due to nitrobenzene poisoning. Emerg Med J. 2012 Jan;29(1):70–1. [PMID: 22186264]
Shahani L et al. Acquired methaemoglobinaemia related to phenazopyridine ingestion. BMJ Case Rep. 2012 Sep 17;2012. [PMID: 22987905]
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.
Administer activated charcoal (see p. 1554). Treat severe hypertension with nitroprusside, phentolamine, or other rapid-acting vasodilators (see p. 1552). 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. 1552 and Chapter 37). 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.
Flockhart DA. Dietary restrictions and drug interactions with monoamine oxidase inhibitors: an update. J Clin Psychiatry. 2012;73(Suppl 1):17–24. [PMID: 22951238]
Iqbal MM et al. Overview of serotonin syndrome. Ann Clin Psychiatry. 2012 Nov;24(4):310–8. [PMID: 23145389]
Wu ML et al. Fatal serotonin toxicity caused by moclobemide and fluoxetine overdose. Chang Gung Med J. 2011 Nov–Dec;34(6):644–9. [PMID: 22196068]
There are thousands of mushroom species that cause a variety of toxic effects. The most dangerous species of mushrooms are Amanita phalloides and related species, which contain potent cytotoxins (amatoxins). Ingestion of even a portion of one amatoxin-containing mushroom may be sufficient to cause death.
The characteristic pathologic finding in fatalities from amatoxin-containing mushroom poisoning is acute massive necrosis of the liver.
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 38–8.
Table 38–8. Poisonous mushrooms.
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. 1554).
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 in removing some of the toxin, based on animal studies and isolated case reports, but proof of efficacy and safety is lacking.
Liver transplant may be the only hope for survival in gravely ill patients—contact a liver transplant center early.
Santi L et al. Acute liver failure caused by Amanita phalloides poisoning. Int J Hepatol. 2012;2012:487–90. [PMID: 22811920]
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]
Ward J et al. Amatoxin poisoning: case reports and review of current therapies. J Emerg Med. 2013 Jan;44(1):116–21. [PMID: 22555054]
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.
Mild intoxication is characterized by euphoria, drowsiness, and constricted pupils. More severe intoxication may cause 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.
Protect the airway and assist ventilation. Administer activated charcoal (see p. 1554) for recent large ingestions.
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 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 long-acting drugs such as methadone. Continuous observation for at least 3 hours after the last naloxone dose is mandatory.
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Bohnert AS et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011 Apr 6;305(13):1315–21. [PMID: 21467284]
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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 water-soluble, 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.
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 lipid-soluble 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.
If the agent was recently ingested, consider gut decontamination by aspiration of the liquid using a nasogastric tube followed by administration of activated charcoal (see p. 1554). 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.
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.
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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, 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.
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.
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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.
Administer activated charcoal (see p. 1554); consider gastric lavage (see p. 1554) after large recent overdose. Assist ventilation if needed. Perform continuous cardiac monitoring.
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.
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Salicylates (aspirin, methyl salicylate, bismuth subsalicylate, 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.
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.
Administer activated charcoal orally (see p. 1554). 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. 1554). 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. 1554). 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.
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).
Glisson JK et al. Current management of salicylate-induced pulmonary edema. South Med J. 2011 Mar;104(3):225–32. [PMID: 21297545]
Minns AB et al. Death due to acute salicylate intoxication despite dialysis. J Emerg Med. 2011 May;40(5):515–7. [PMID: 20347249]
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 38–9. In the majority of cases, the seafood has a normal appearance and taste (scombroid may have a peppery taste).
Table 38–9. Common seafood poisonings.
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. 1554).
There is no specific antidote for paralytic shellfish or puffer fish poisoning.
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Schlaich C et al. Outbreak of ciguatera fish poisoning on a cargo ship in the port of hamburg. J Travel Med. 2012 Jul;19(4):238–42. [PMID: 22776385]
The venom of poisonous snakes and lizards may be predominantly neurotoxic (coral snake) or predominantly cytolytic (rattlesnakes, other pit vipers). Neurotoxins 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.
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.
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]
Punguyire D et al. Bedside whole-blood clotting times: validity after snakebites. J Emerg Med. 2013 Mar;44(3):663–7. [PMID: 23047197]
Spano S et al. Snakebite Survivors Club: retrospective review of rattlesnake bites in Central California. Toxicon. 2013 Jul;69:38–41. [PMID: 23200707]
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) 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.
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 serum-derived), 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.)
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.
No specific treatment other than analgesics is required for envenomations by most scorpions found in the United States. An FDA-approved specific antivenom is now available for Centruroides stings.
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THEOPHYLLINE & CAFFEINE
Theophylline may cause intoxication after an acute single overdose, or intoxication may occur as a result of chronic 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 in herbal or dietary supplement products can produce similar toxicity.
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.
After acute ingestion, administer activated charcoal (see p. 1514). 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. 1514).
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).
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 beta-adrenergic stimulation—may respond to beta-blocker therapy even in low doses. Administer esmolol, 25–50 mcg/kg/min by intravenous infusion, or propranolol, 0.5–1 mg intravenously.
Kneser J et al. Successful treatment of life threatening theophylline intoxication in a pregnant patient by hemodialysis. Clin Nephrol. 2013 Jul;80(1):72–4. [PMID: 22541679]
Trabulo D et al. Caffeinated energy drink intoxication. Emerg Med J. 2011 Aug;28(8):712–4. [PMID: 21788240]
Vaglio JC et al. Arrhythmogenic Munchausen syndrome culminating in caffeine-induced ventricular tachycardia. J Electrocardiol. 2011 Mar–Apr;44(2):229–31. [PMID: 20888004]
Wolk BJ et al. Toxicity of energy drinks. Curr Opin Pediatr. 2012 Apr;24(2):243–51. [PMID: 22426157]
TRICYCLIC & OTHER ANTIDEPRESSANTS
Tricyclic and related cyclic antidepressants are among the most dangerous drugs involved in suicidal overdose. These drugs have anticholinergic and cardiac depressant properties (“quinidine-like” sodium channel blockade). Tricyclic antidepressants produce more marked membrane-depressant 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).
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.
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.)
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 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.
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. 1554) and consider gastric lavage (see p. 1554) after recent large ingestions. All of these drugs are highly tissue-bound and are not effectively removed by hemodialysis procedures.
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), 1.5 mL/kg repeated one or two times if needed. Plasma exchange using albumin has been reported successful in a few cases.
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.
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