Chapter 102. Toxicology in Adults

General Measures

• Supportive measures supercede other considerations in the management of the poisoned patient. After addressing the ABCDs of life support, the focus can switch to confirmation of intoxication and targeted therapy.
• Administer a “cocktail” of oxygen, dextrose, thiamine, and naloxone to patients with depressed mental status.
• An increase in anion gap, osmolal gap, or arterial saturation gap should raise the suspicion of intoxication.
• An osmolal gap of large magnitude (>25 mOsm) suggests methanol or ethylene glycol poisoning; however, serious intoxication with either agent can occur without increasing the osmolal gap. Serum levels of these alcohols should be measured when clinical features are suggestive.
• Carbon monoxide and methemoglobin elevate the arterial oxygen saturation gap. These toxins interfere with oxygen binding to hemoglobin and decrease oxygen content without lowering the PaO2. Oxygen saturation measured by pulse oximetry is falsely high in this setting.
• Toxicology screening can provide direct evidence of intoxication, but it rarely impacts initial management.
• Poison control center consultation is advised to determine appropriate laboratory testing and patient disposition and treatment. The emergency phone number is 1-800-222-1222.
• Gastric lavage only improves outcome in obtunded patients if performed within 1 hour of ingestion (this time may be extended in poisonings that delay gastric emptying). Risks of lavage preclude its use in nontoxic ingestions, subtoxic amounts of a toxic ingestion, ingestion of caustic liquids, and when the toxin is no longer expected to be in the stomach. The airway must be protected prior to lavage.
• Activated charcoal should be administered for most oral ingestions after the airway has been protected.
• Whole-bowel irrigation with a polyethylene glycol electrolyte solution is indicated for iron overdose, ingestion of sustained-release tablets, and “body packing" with illicit drugs.
• Urinary alkalinization enhances excretion of nonpolar weak acids. Urinary acidification augments excretion of nonpolar weak bases, but is generally not recommended.

Acetaminophen

• All overdose cases should be screened for acetaminophen poisoning.
• The antidote, n-acetylcysteine (NAC), should be started within 8 hours of ingestion to decrease the risk of hepatotoxicity. The Rumack-Matthew nomogram allows for stratification of selected patients into categories of probable, possible, and no hepatic toxicity.

Alcohols

• Metabolic acidosis with an elevated anion gap and/or the presence of an osmolal gap are classic in methanol and ethylene glycol poisoning.
• Features of methanol poisoning include inebriation, optic papillitis, and pancreatitis. Treatment with fomepizole or ethanol inhibits metabolism by alcohol dehydrogenase to the toxic metabolite formic acid. Dialysis is indicated in severe cases.
• Features of ethylene glycol poisoning include inebriation, acute renal failure, crystalluria, and myocardial dysfunction.
• Treatment with fomepizole or ethanol inhibits metabolism by alcohol dehydrogenase to toxic metabolites (oxalic and glycolic acids). Dialytic removal of ethylene glycol and its metabolites is indicated in severe poisonings.
• Isopropanol causes hemorrhagic gastritis, ketonemia, and ketonuria, but not acidosis. Fomepizole and ethanol are not indicated because metabolites are nontoxic. Dialysis is effective in severe cases.

Barbiturates

• Hypothermia, hypotension, bradycardia, flaccidity, hyporeflexia, coma, and apnea are features of barbiturate overdose. Severe overdose can mimic death.
• Supportive measures include gastric emptying and activated charcoal. Alkalinization of the urine increases elimination of phenobarbital, but not other barbiturates, and may aggravate pulmonary edema. Of disputed importance, hemoperfusion may be considered in severe cases.

Benzodiazepines

• Supportive measures, gastric emptying, activated charcoal, and flumazenil treat benzodiazepine overdose.
• Flumazenil reverses sedation but may increase the toxicity of coingested drugs. Flumazenil should be avoided in patients taking benzodiazepines therapeutically and in benzodiazepine-addicted patients.
• There is no role for forced diuresis, dialysis, or hemoperfusion in benzodiazepine overdose.

Beta-Blockers

• Cardiovascular manifestations of overdose are treated with fluids, vasopressors, atropine, electrical pacing, and glucagon.
• Glucagon effectively reverses myocardial depression and bradycardia.

Calcium Channel Blockers

• Hypotension is treated first with fluids and calcium chloride. Glucagon may decrease vasopressor requirements.

Carbon Monoxide

• Exposure to smoke, poorly ventilated charcoal or gas heaters, and automobile exhaust are responsible for most poisonings.
• Carbon monoxide poisoning can present with myocardial ischemia, arrhythmias, mental status changes, headache, and generalized weakness.
• Prompt oxygen therapy is crucial.
• Pulse oximetry is unreliable in detecting carboxyhemoglobin; pulse oximetry overestimates oxyhemoglobin by the amount of carboxyhemoglobin present; saturation by pulse oximetry may be normal despite elevated carboxyhemoglobin.
• The use of hyperbaric oxygen is controversial. Patients with potentially life-threatening exposures should receive hyperbaric therapy if it is readily available and other life-threatening conditions do not preclude its use.
• Delayed neurologic sequelae may occur in survivors.

Cocaine

• Cocaine is often mixed with other substances of abuse.
• Cocaine causes acute coronary syndromes, hypertensive crisis, seizures, rhabdomyolysis, intracranial hemorrhage, pneumomediastinum, and respiratory failure.
• Agitation and hyperthermia should be treated rapidly with benzodiazepines and cooling strategies. Paralysis is occasionally required.
• Benzodiazepines are first-line therapy for hypertensive crisis. Refractory patients should receive an α-adrenergic antagonist. Nonselective β-blockers (eg, propranolol) should not be used alone to treat hypertension because of the potential for unopposed α-adrenergic stimulation. Labetalol is controversial. Selective β-blockers do not aggravate hypertension but may cause hypotension.
• Acute coronary syndromes should be treated with nitrates and benzodiazepines. Refractory patients should receive α-adrenergic antagonists. Nonselective β-blockers are contraindicated; selective β-blockers do not aggravate hypertension, but may induce hypotension.

Cyanide

• Features of cyanide poisoning depend on the amount and rate of cyanide absorption. Patients who are asymptomatic after inhalation generally do not require treatment. Oral ingestion causes progressive symptoms over minutes to hours.
• Sodium nitroprusside infusions can cause cyanide and thiocyanate poisoning.
• Symptoms include anxiety, dyspnea, headache, confusion, tachycardia, and hypertension. High concentrations of cyanide cause stupor or coma, seizures, fixed and dilated pupils, hypoventilation, hypotension, arrhythmias, and cardiopulmonary collapse.
• In addition to supportive measures and oxygen, several antidotes are available: amyl and sodium nitrite, sodium thiosulfate, hydroxycobalamin, and dicobalt ethylenediamine tetraacetic acid (EDTA).

Cyclic Antidepressants

• Patients with anticholinergic, neurologic, or cardiac toxicity (including QRS prolongation ≥100 ms) require monitoring.
• Neurologic deterioration is often abrupt and unpredictable.
• Acidemia potentiates toxicity. Therapeutic alkalemia with sodium bicarbonate or hyperventilation is beneficial.
• Lidocaine should be used for ventricular arrhythmias resistant to sodium bicarbonate. Procainamide is contraindicated.

Digoxin

• Features of digitalis intoxication include fatigue, gastrointestinal symptoms, neurologic disturbances (blurred vision, visual color changes, headache, dizziness, and delirium), and cardiac arrhythmias (supraventricular tachycardia with AV block). Significant overdose may cause hyperkalemia.
• Supportive therapy includes rapid correction of arrhythmogenic metabolic disturbances, particularly hypokalemia if present. Hyperkalemia requires treatment unless Fab therapy is immediately available.
• Immunotherapy with digoxin-specific antibody Fab fragments is indicated for severe intoxications.
• Gastrointestinal decontamination measures include gastric lavage and activated charcoal. Hemodialysis removes only small amounts of total body digitalis, but may be indicated for correction of hyperkalemia or other acid-base derangements in renally impaired patients.
• Electrical cardioversion of a digitalis toxicity–induced arrhythmia should be reserved as a last resort, using the minimum effective energy level.

Gamma Hydroxybutyrate

• Depressed mental status, emesis, bradycardia, hypotension, and respiratory depression are features of GHB overdose.
• Treatment is mainly supportive.
• In cases of alleged sexual assault, GHB can be identified by analysis of hair, blood, and urine in selected laboratories.

Lithium

• Most cases of intoxication, associated with levels above 1.5 mEq/L, are caused by unintentional overdose during chronic therapy.
• High levels of lithium decrease the anion gap.
• Severe poisoning causes coma, seizures, and cardiovascular instability.
• Treatment includes seizure control and vasopressors for hypotension refractory to fluids. Gastric emptying should be performed initially. Oral charcoal is of little benefit. Whole-bowel irrigation is important with sustained-release preparations.
• Lithium is the prototypical dialyzable intoxicant.

Methemoglobinemia

• Hereditary methemoglobinemia (e.g., hemoglobin M or cytochrome b5 reductase deficiency) is generally insignificant and does not require treatment. Acquired and potentially life-threatening methemoglobinemia can occur after oxidant drug or toxin exposure.
• Methemoglobinemia decreases oxyhemoglobin saturation and blood oxygen carrying capacity by decreasing available hemoglobin and shifting the oxyhemoglobin dissociation curve to the left.
• Symptoms of moderate methemoglobinemia include dyspnea, headache, and weakness. Confusion, seizures, and death can occur with levels >60%.
• Co-oximetry measures methemoglobin saturation. Standard pulse oximetry registers falsely high in patients with methemoglobinemia. Arterial blood gases typically demonstrate a normal PaO2 and a normal calculated oxygen saturation.
• Treatment of methemoglobinemia consists of oxygen, methylene blue, and exchange transfusion.

Opioids

• The triad of miosis, respiratory depression, and coma suggests opioid intoxication.
• Naloxone reverses sedation, hypotension, and respiratory depression. The initial dose is 0.4 mg IV or 0.8 mg IM or SC. Lower doses should be given to opioid-dependent patients and when there is a concurrent stimulant overdose. Larger initial doses may be required when there is abuse of naloxone-resistant opioids. Lack of response to 6 to 10 mg of naloxone generally excludes opioid toxicity.

Organophosphate and Carbamate Insecticides

• Organophosphates are irreversible inhibitors of acetylcholinesterase (AChE); carbamates reversibly inhibit AChE.
• Signs of cholinergic poisoning include salivation, lacrimation, urination, diarrhea, gastrointestinal cramping and emesis (SLUDGE). Muscle fasciculations, coma, and seizures also occur.
• Respiratory failure results from muscle weakness, bronchorrhea, depressed respiratory drive, and bronchoconstriction.
• The level of red blood cell cholinesterase helps diagnose organophosphate poisoning.
• Treatment includes supportive measures, atropine, and oximes.

Phencyclidine

• PCP intoxication incites bizarre behavior, violence, agitation, euphoria, and lethargy, as well as stupor and coma that may last for days. Additional features include fever, tachycardia, hypertension, leukocytosis, renal failure, intracranial hemorrhage, and rhabdomyolysis.
• Pinpoint pupils in an agitated patient suggests PCP intoxication.
• Haloperidol is the drug of choice to treat PCP psychosis. Benzodiazepines expedite control of the difficult patient.

Salicylates

• The Done nomogram for predicting salicylate toxicity is of limited use in current practice.
• Salicylate poisoning causes respiratory alkalosis and metabolic acidosis; the latter is more prominent in children.
• Manifestations of chronic ingestion may be subtle and occur at relatively low serum salicylate levels.
• Acidemia favors tissue penetration of salicylates; urinary alkalinization enhances renal clearance; hypokalemia must be corrected to succeed in urinary alkalinization; carbonic anhydrase inhibitors should not be used to alkalinize urine.
• Seizures, coma, refractory acidosis, and high serum salicylate levels are indications for hemodialysis.

Selective Serotonin Reuptake Inhibitors

• In combination with a number of drugs, SSRIs may cause serotonin syndrome. Toxic combinations may not be evident for days to weeks.
• Features of serotonin syndrome include confusion, agitation, shivering, flushing, hyperthermia, tachycardia, disseminated intravascular coagulation, convulsions, coma, muscle rigidity, myoclonus, hyperreflexia, involuntary movements, autonomic instability, nausea, diarrhea, orthostatic hypotension, rhabdomyolysis, hyponatremia, and SIADH. Trazodone, which is also an α-adrenergic blocker, causes hypotension.
• Treatment is supportive. Gastric emptying and activated charcoal are effective. Serotonin antagonists have not been studied adequately in controlled trials.

Theophylline

• Clinical features of theophylline toxicity are cardiovascular, metabolic, and neurologic.
• Tachyarrhythmias are common at plasma levels >20 mg/L.
• Metabolic abnormalities include hypokalemia, hypomagnesemia, hyperglycemia, hypophosphatemia, hypercalcemia, and respiratory alkalosis.
• Uncontrolled seizures cause hyperthermia and rhabdomyolysis.
• For any plasma level, chronic intoxication causes more severe clinical sequelae.
• Extracorporeal removal by “in-series" hemodialysis and hemoperfusion is indicated for severe intoxications.

Envenomations

• The majority of poisonous snake bites in the United States involve the Crotalidae or pit viper family of snakes (e.g., rattlesnakes, copperheads, and water moccasins).
• Treatment of rattlesnake bite consists of immobilizing the bitten extremity and placing a loose-fitting tourniquet proximal to the bite to impede venom spread. Surgical consultation may be required for local wound management.
• Unstable patients should be treated with equine Crotalidae antivenin.
• In North America, only the widow spiders (Latrodectus species) and the recluse spiders (Loxosceles species) are medically important.
• Features of black widow spider bite include local pain and erythema followed by muscle cramps and fasciculations that may generalize to the abdomen, back, and chest. Hypertension, tachycardia, tremor, fever, agitation, diaphoresis, and nausea are common.
• Treatment of black widow spider bite consists of supportive measures, analgesia, calcium, methocarbamol, and in severe cases, equine-derived antivenin.
• Recluse spider bite (loxoscelism) is characterized by localized swelling, erythema, and formation of bullae, often forming a “bull's eye" lesion with central necrosis. Some patients develop fever, myalgias, headache, and nausea. Rare patients develop intravascular hemolysis, disseminated intravascular coagulopathy, acute renal failure, and the acute respiratory distress syndrome. Treatment is supportive; antivenin is not available.

In their 2001 annual report, the American Association of Poison Control Centers reported 2,267,979 human toxic exposure cases. Three percent of these cases, or more than 69,000 patients, required critical care. There were 1074 fatalities, occurring most commonly after intentional overdose.1

Intentional overdose or accidental exposure may be the chief complaint at the time of emergency department evaluation, but not all patients provide this information, particularly when toxin or trauma clouds mental status. In these cases signs and symptoms may be attributed to another disorder and poisoning remains obscure. In hospital, inappropriate drug dosing or unforeseen drug interactions may lead to toxic side effects.

Classic features of overdose, referred to as a toxidrome, help establish a diagnosis, but signs and symptoms may be nonspecific or lacking altogether, as in the early stages of acetaminophen overdose. The protean manifestations of intoxication mandate a high index of suspicion in critically ill patients.

Treatment of the poisoned patient often occurs before a diagnosis has been established. Most important in this regard are standard supportive measures. The ABCDs (airway, breathing, circulation, and differential diagnosis) come first while efforts ensue to confirm intoxication and initiate targeted therapy.

In this chapter we will review (1) initial supportive efforts, (2) diagnosis of poisoning and drug overdose, (3) techniques to limit drug absorption and enhance drug elimination, and (4) specific treatments of the most commonly encountered drugs, toxins, and envenomations seen in the intensive care unit.

Primary physician responsibilities are to identify and treat life-threatening problems. The ABCDs of life support should be addressed as in any medically unstable patient, but for the first time, the 2000 version of the American Heart Association guidelines included a separate section on resuscitating the poisoned patient.2 Recommendations provided in these guidelines are discussed in this chapter.

With cervical spine precautions in place (unless trauma has been reasonably excluded) airway patency must be established. In obtunded patients, obstruction by the tongue is treated initially with a jaw-thrust maneuver, followed by either placement of an oral airway, nasal trumpet, or endotracheal tube. The choice of airway depends on the level of obtundation, the vigor of protective reflexes, the degree of respiratory depression, and initial response to pharmacologic therapy (Table 102-1). In nonintubated patients, the left side down, head-down position allows the tongue to drop forward and decreases risk of aspiration of oral secretions and stomach contents.

Patients with an adequate airway and intact protective reflexes may not require intubation (even if they are lethargic), particularly if treatment improves mental status. Intubation is indicated when a patient is unable to protect the airway or maintain respirations. Intubation protects the airway and decreases but does not eliminate the risk of aspiration, which occurs in approximately 11% of comatose patients with drug overdose.3–5 Intubation further allows for administration of high concentrations of oxygen and assisted ventilation.

Selected causes of hypoxemia in drug overdose and toxic ingestion are listed in Table 102-2. Hypoxemia must be corrected quickly to avoid anoxic brain injury, myocardial ischemia, and arrhythmias. In some poisonings (eg, carbon monoxide, cyanide, and methemoglobinemia), a fraction of inspired oxygen (FiO2) of 1.0 is therapeutic, whereas in paraquat poisoning and bleomycin toxicity oxygen potentiates lung injury.

The clinician should choose a ventilator mode with which she or he is familiar and which achieves the greatest degree of synchrony between patient and machine. The initial ventilator mode should provide adequate back-up minute ventilation (which can be achieved with either assist control or synchronized intermittent mandatory ventilation). If intubation is performed solely to protect the airway or to provide supplemental oxygen, the endotracheal tube may be connected to a T-tube. Positive end-expiratory pressure (PEEP) recruits atelectatic and fluid-filled alveoli and may decrease ventilator-induced lung injury in selected patients. PEEP should be used cautiously in hypotensive patients to avoid decreasing cardiac preload. Low levels of pressure support ventilation (5 to 8 cm H2O) help overcome endotracheal tube resistance and may decrease inspiratory work of breathing.

Circulatory manifestations of drug overdose are common and varied. Bradycardia and/or atrioventricular (AV) block can result from cholinergic excess (e.g., with organophosphate, carbamate, physostigmine, and digoxin toxicity), sympatholytic drugs (e.g., β-blockers, clonidine, and opioids), membrane-depressant agents (e.g., type 1a and 1c antiarrhythmic drugs, quinidine, and cyclic antidepressants), calcium channel blockers, and lithium overdose (Table 102-3). Bradycardia can also occur from a reflex response to α-adrenergic-induced hypertension (e.g., phenylpropanola mine).

The differential diagnosis of bradycardia includes hypoxemia, myocardial infarction, hyperkalemia, hypothermia, hypothyroidism, and intracranial hypertension. If bradycardia persists despite correction of hypoxemia or hypothermia and is hemodynamically significant, atropine 0.5 to 1.0 mg IV should be given and repeated every 5 to 10 minutes until a therapeutic response has been achieved or adverse drug effects appear. Three milligrams of atropine is fully vagolytic, so further administration of atropine beyond this dose is unlikely to be beneficial. An exception to this tenet is cholinergic poisoning, in which extremely high doses of atropine may be required to increase heart rate and dry secretions. In selected overdoses, antidotes are available for treatment of bradycardia: calcium chloride for calcium channel blocker toxicity; glucagon in β-blocker overdose; sodium bicarbonate in cyclic antidepressant overdose; naloxone in opioid overdose; and digoxin-specific antibodies in digoxin toxicity. Refractory and symptomatic bradycardia or heart block is an indication for transcutaneous or transvenous pacing or infusion with dopamine or epinephrine. If transcutaneous pacing is used successfully, a prophylactic transvenous pacemaker is not recommended because the wire may trigger ventricular arrhythmias.2

Table 102-3 includes selected drugs and toxins causing tachycardia. Sinus tachycardia and supraventricular arrhythmias commonly result from sympathetic overstimulation (e.g., with cocaine, theophylline, amphetamines, or phencyclidine) or inhibition of parasympathetic tone (e.g., with cyclic antidepressants, phenothiazines, or antihistamines). Anxiety, hypovolemia, hypoxemia, myocardial infarction, hyperthermia, infection, and pregnancy are in the differential diagnosis. Treatment of sinus tachycardia should be aimed at correcting the underlying cause. In the setting of stimulant intoxication, sedation with benzodiazepines is usually sufficient. β-Blockade can be helpful in the setting of excessive sympathetic stimulation and myocardial ischemia; however, nonselective β-blockers should not be used alone to treat cocaine toxicity because of the potential for unopposed α-adrenergic stimulation. In anticholinergic intoxication, physostigmine decreases heart rate by increasing acetylcholine concentration at myoneural junctions; however, the potential for physostigmine to worsen cardiac conduction disturbances precludes its use in most cases of cyclic antidepressant overdose.

Drugs such as cocaine, caffeine, and amphetamines cause ventricular arrhythmias through sympathomimetic effects. Membrane depressants such as cyclic antidepressants are arrhythmogenic by prolonging depolarization and negative inotropy. Drugs which prolong the QT interval (e.g., amiodarone, astemizole, terfenadine, cyclic antidepressants, quinidine, procainamide, and disopyramide) may induce polymorphic ventricular tachycardia or torsades de pointes. Drug-induced torsades de pointes is treated by correction of risk factors (hypokalemia, hypomagnesemia, and hypoxemia), magnesium supplementation (even when serum concentrations are normal), and overdrive pacing by electrical stimulation or isoproterenol.2

Treatment of ventricular tachycardia and ventricular fibrillation is similar to that recommended in advanced cardiac life support. However, important exceptions pertain to cyclic antidepressant overdose.6 These patients should immediately receive hypertonic sodium bicarbonate (1 to 2 mEq/kg IV bolus) aiming for a serum pH of 7.5 to 7.55. In intubated patients, hyperventilation achieves alkalemia without the need to deliver a large sodium load, but hypertonic sodium usually provides greater benefit. Lidocaine is the drug of choice when ventricular arrhythmias are refractory to sodium bicarbonate.6 Class 1a antiarrhythmics (e.g., procainamide) are contraindicated in cyclic antidepressant overdose because of added cardiac toxicity. Anecdotal reports have also suggested a primary role for phenytoin; however, convincing data are not available to support the use of phenytoin in the setting of cyclic antidepressant overdose as either a prophylactic or therapeutic drug.7,8 Physostigmine should not be used in cyclic antidepressant overdose because of possible worsening of cardiac conduction disturbances.

Based on limited data in humans and animals and extensive unpublished experience, the expert panel on toxicologic-oriented advanced life support suggests a primary role for sodium bicarbonate and lidocaine in cocaine-associated ventricular tachycardia and ventricular fibrillation.6,9–12 In making these recommendations the panel did take into account studies in animals showing that lidocaine worsened seizures and widened the QRS complex in the setting of cocaine toxicity.6

Cardioversion or defibrillation is appropriate for pulseless patients with drug-induced ventricular tachycardia (VT) or ventricular fibrillation (VF). Whether epinephrine should be used in this setting is unknown; if used, the working group of the AHA recommends increasing the interval between doses and avoidance of high-dose epinephrine.2 This group also recommends more prolonged cardiopulmonary resuscitation (CPR) in poisoning cases because of anecdotal reports of good neurologic recovery after 3 to 5 hours of CPR.2,13,14

A variety of mechanisms are responsible for hypotension in drug overdose: hypovolemia, cardiac arrhythmias, systemic vasodilation and myocardial depression. An initial strategy of rapid fluid administration (e.g., 1 L normal saline over 30 minutes) is appropriate in most cases, although caution is warranted in the setting of pulmonary edema or poor cardiac contractility (e.g., in verapamil overdose). Cardiac arrhythmias and hypothermia should be corrected and antidotes administered if appropriate. Hypotension refractory to the above measures should be treated with vasopressors. Dopamine (5 to 20 μg/kg per minute IV) stimulates α, β, and dopaminergic receptors to increase heart rate, blood pressure, and cardiac output in most patients. In patients with tachyarrhythmias or ventricular fibrillation, agents with weak β1-activity (norepinephrine) or no β-receptor activity (phenylephrine) are preferred. Norepinephrine and phenylephrine are preferred in cyclic antidepressant overdose because cyclic antidepressants deplete presynaptic catecholamine stores, limiting the effectiveness of dopamine.15–17 In contrast, in the presence of cocaine, dopamine and other vasopressors may trigger an exaggerated response caused by inhibition of catecholamine reuptake; in the presence of monoamine oxidase inhibitors an exaggerated response occurs because of inhibition of catecholamine degradation. An enhanced hypertensive response to phenylephrine can occur in anticholinergic overdose because anticholinergics interfere with phenylephrine-induced reflex bradycardia. Vasopressor agents should not be used in the setting of ergot derivative toxicity because of the potential for severe and sustained vasoconstriction.

Hypertension with tachycardia occurs in the setting of (1) sympathomimetic drugs (amphetamines, cocaine, lysergic acid diethylamide [LSD], marijuana, monoamine oxidase inhibitors, and phencyclidine [PCP]); (2) anticholinergics (antihistamines, atropine, cyclic antidepressants, and phenothiazines); and (3) withdrawal from nicotine, alcohol, and sedative-hypnotics. Hypertension with reflex bradycardia occurs in ergot derivative, methoxamine, phenylephrine, and phenylpropanolamine toxicity.

Treatment of hypertension depends on the chronicity and severity of hypertension and on the response to initial supportive efforts (e.g., agitated patients often respond well to benzodiazepines alone). When hypertension is severe in the setting of chronic hypertension, lowering diastolic blood pressure by 20% or to approximately 100 to 110 mm Hg is recommended. In the absence of prior hypertension, diastolic blood pressure may be lowered safely into the normal range. Drug-induced hypertension refractory to benzodiazepines should be treated with a short-acting agent such as nitroprusside. Phentolamine is effective in the setting of α-adrenergic stimulation from phenylephrine, phenylpropanolamine, or cocaine. Labetalol in carefully titrated doses is a third-line agent. Nonselective β-blockers are contraindicated because they may worsen α-adrenergic-induced hypertension.2,18

“Coma Cocktail"

A “cocktail" of oxygen, dextrose, thiamine, and naloxone should be administered to patients with depressed mental status (see Table 102-1). These relatively innocuous drugs are helpful diagnostically and therapeutically. Although not well supported in the literature,19 thiamine is administered to prevent Wernicke-Korsakoff syndrome. This disorder is characterized by ocular disturbances (nystagmus and weak external rectus muscles), ataxia, and deranged mental status (confusion, apathy, drowsiness, and confabulation). Tachycardia, hypotension, electrocardiographic abnormalities, and cardiovascular collapse also occur. Thiamine is particularly important in the nutritionally depleted alcoholic receiving intravenous glucose. Glucose further depletes thiamine and may precipitate or worsen Wernicke-Korsakoff syndrome. There are no compelling data to support the practice of withholding dextrose until thiamine has been administered.19

A blood dipstick test can be used to detect severe hypoglycemia. However, a normal value for glucose by dipstick does not exclude a low serum level, thereby warranting treatment in all patients with normal or low values. If the dipstick reading is high, it is reasonable to wait for serum confirmation of hyperglycemia. There is concern that overadministration of dextrose may cause harm by increasing serum osmolality or extending ischemic stroke, but this has not been well supported in the literature.19

Naloxone is an opioid antagonist with no opioid agonist properties. It can rapidly reverse opioid-induced coma, hypotension, respiratory depression, and analgesia.20 Naloxone is administered intravenously, intramuscularly, or subcutaneously. The initial dose is 0.4 mg IV or 0.8 mg IM or SC. Lower doses (0.1 to 0.2 mg) are preferred in opioid-dependent patients to avoid severe withdrawal.6 A low dose is also appropriate when concurrent stimulant use is suspected.6,19

The goal is to restore airway reflexes and adequate ventilation, not complete arousal. Abrupt withdrawal may increase the risk of arrhythmias, agitation, and acute pulmonary edema.2,21 If naloxone does not produce a clinical response after 2 to 3 minutes, an additional 1 to 2 mg IV may be administered to a total dose of 6 to 10 mg. In general, a lack of response to 6 to 10 mg of naloxone is required to exclude opioid toxicity.6 Even higher doses may be required to antagonize the effects of meperidine, propoxyphene, diphenoxylate, methadone, and pentazocine.22 Continuing naloxone beyond a total dose of 10 mg is reasonable if there is a suspicion of opioid overdose and a partial response has been achieved.

In general, opioid antagonism occurs within minutes of naloxone administration and lasts for 1 to 2 hours. The effects of naloxone do not last as long as those of heroin or methadone, so repeat boluses may be required every 20 to 60 minutes to maintain an adequate clinical response. Alternatively, a continuous naloxone infusion may be started (0.4 to 0.8 mg/h, or two thirds of the initial dose needed to achieve a response per hour IV).

Consider flumazenil if benzodiazepine overdose is highly suspected or confirmed and benzodiazepines have not been prescribed for a potentially life-threatening condition (such as status epilepticus or raised intracranial pressure). In the setting of long-term benzodiazepine use, flumazenil may result in severe withdrawal or seizures.23,24 In a rat model of combined cocaine-diazepam poisoning, flumazenil precipitated seizures and increased mortality.25

Seizures may occur in the setting of cyclic antidepressant coingestion; however, prospective data demonstrate that cautious administration of flumazenil is safe in this setting.26 Flumazenil is effective in improving mental status in patients with suspected drug overdose and depressed mental status; however, it does not decrease the cost or number of major diagnostic and therapeutic interventions.27

Flumazenil is generally not recommended as a routine diagnostic or therapeutic agent in patients with depressed mental status.2 Still, flumazenil can be useful to distinguish benzodiazepine overdose from mixed-drug intoxication or non–drug-induced coma, and it may improve clinical status. The recommended initial dose of flumazenil is 0.2 mg (2 mL) IV over 30 seconds. A further 0.3-mg (3-mL) dose can be given over 30 seconds if the desired clinical effect is not seen within 30 seconds. Additional 0.5-mg doses can be administered over 30 seconds at 1-minute intervals as needed to a total dose of 3 mg. Flumazenil dosed beyond 3 mg generally does not provide additional benefit. Patients should be monitored for resedation, particularly in cases involving high-dose or long-acting preparations or when there has been long-term use of benzodiazepines.

When mental status changes persist, other conditions should be considered. These include subdural or epidural hematoma, intracerebral hemorrhage, embolic stroke, abnormalities of sodium and other electrolytes, hypoxemia, hypothyroidism, liver or renal failure, central nervous system infection, seizures, and significant alterations in temperature. A head CT scan should be performed early in the course of an obtunded patient, and there should be a low threshold to perform lumbar puncture.

The Agitated or Seizing Patient

Agitated, violent, or acutely psychotic patients unresponsive to verbal counseling and a calm environment require pharmacologic treatment and/or physical restraints to establish adequate control and enhance patient and staff safety. A common error in the management of the agitated patient is to delay treatment, allowing patients to harm themselves and others. Causes of agitation other than drug overdose should be considered: drug withdrawal, head trauma with subdural hematoma, intracerebral hemorrhage, meningitis, hypoglycemia, thyrotoxicosis, pheochromocytoma, malignant hypertension, hyperthermia, and acute psychiatric illnesses.

Haloperidol (1 to 5 mg IM or IV) may be repeated every 30 to 60 minutes to a total dose not exceeding 100 mg/d. Debilitated and elderly patients should receive lower doses, and care must be taken in patients with cardiovascular disease to avoid hypotension and arrhythmias. Haloperidol prolongs the QT interval and therefore must be used cautiously (and with continuous monitoring) in the presence of other QT-prolonging drugs. Haloperidol lowers the seizure threshold and can cause neuroleptic malignant syndrome, tardive dyskinesia, and extrapyramidal symptoms (which may be treated with benztropine 1 to 4 mg PO). Haloperidol also has anticholinergic effects that are undesirable in anticholinergic overdose. Adding a benzodiazepine (e.g., lorazepam 1 mg) to each dose of haloperidol may accelerate control of the difficult patient.

Seizures are a common cause of drug-related morbidity and mortality. Multiple drugs and toxins (Table 102-4) cause them, but other etiologies such as CNS infection, stroke, head trauma, and severe metabolic disturbance must be considered in the differential diagnosis. A brief seizure that is temporally related to drug ingestion (e.g., cocaine) may be observed without further evaluation, provided the patient is alert and has a normal neurologic exam. Recurrent seizures should raise suspicion of body packing (which may be evaluated by abdominal imaging and digital and visual search of body cavities). Status epilepticus should be treated with a benzodiazepine IV followed by a barbiturate (amobarbital or phenobarbital) if necessary. Phenytoin is less likely to be of benefit in cocaine or caffeine/theophylline overdose. Patients who continue to seize despite adequate treatment with a benzodiazepine and barbiturate should be considered for paralysis to prevent hyperthermia and rhabdomyolysis. Paralysis requires continuous electroencephalographic (EEG) monitoring to follow seizure activity.

Alterations in Temperature

Drugs and toxins have the potential to alter body temperature through a number of mechanisms (Table 102-5). Hypothermia is caused by peripheral vasodilation, inhibition of shivering, depression of metabolic activity, and exposure to a cold environment. Hyperthermia occurs when there is excessive heat generation from seizures, muscle rigidity, increased metabolic rate, or decreased sweating. Hyperthermia also occurs when drugs alter hypothalamic activity or a patient loses consciousness in a hot environment.

The differential diagnosis for hypothermia includes infection, hypoglycemia, CNS injury, and hypothyroidism. For hyperthermic patients consider infection, thyrotoxicosis, environmental heat stroke, and drug withdrawal.

Extreme temperatures must be treated aggressively to minimize life-threatening complications.28 Specifics regarding complications and treatment of hypo- and hyperthermia are included in Chaps. 110 and 111. Two of the more notable life-threatening hyperthermic disorders are neuroleptic malignant syndrome and malignant hyperthermia. Neuroleptic malignant syndrome occurs in patients taking antipsychotic medications or withdrawing from levodopa. Clinical features include hyperthermia, muscle rigidity, mental status changes, rhabdomyolysis, and metabolic acidosis. Treatment consists of immediate administration of bromocriptine. Malignant hyperthermia is an inherited disorder characterized by hyperthermia, rigidity, and metabolic acidosis. It occurs in response to certain anesthetic agents and is treated with dantrolene.

History and Physical Examination

Clinical features mandating consideration of drug overdose or poisoning are listed in Table 102-6. Whenever possible, a careful history should be elicited from the patient to identify potential drugs or toxins, the timing and amount of drugs taken, and the clinical course. Information should be sought regarding prescription medications, over-the-counter drugs, and illicit substances. Friends, relatives, and other involved health care providers (including paramedics) should be questioned, and medications available to or in the vicinity of the patient should be identified. The pharmacy on the medication label should be called to determine the status of all prescription medications. Information gathered might prove unreliable or incomplete, particularly in cases of attempted suicide or illicit drug abuse, but it may also favorably impact care.29

Physical examination is directed toward evaluation and support of airway patency, respiration, and circulation (see above), followed by rapid assessment of mental status, temperature, pupil size, muscle tone, reflexes, skin, and peristaltic activity. In cases of a single or dominant exposure, the examination may reveal signs of a toxic syndrome (or toxidrome). A toxidrome is a pattern of signs and symptoms that suggests a specific class of poisoning. Common toxidromes are listed in Table 102-7.

When initial signs and symptoms are less specific, we find it is useful to categorize patients as physiologically depressed (Table 102-8) or agitated and hyperadrenergic (Table 102-9). This categorization narrows the list of possible ingestions and impacts initial treatment strategies (see below). When confusion or delirium are primary, drugs listed in Table 102-10 deserve consideration.30 Note that certain drugs, such as anticholinergics, present variably with stupor, coma, agitation, confusion, or delirium, depending on the timing, dose, and host factors.

Drugs affecting the autonomic nervous system (Table 102-11) alter pupil size. Combining the patient's physiologic state (i.e., agitated or depressed) with pupil size provides for rapid assessment of the dominant ingestion. For example, the constellation of agitation, tachycardia, and pinpoint pupils is suspicious for phencyclidine intoxication; lethargy and pinpoint pupils is characteristic of narcotic overdose.

Pupil reactivity and nystagmus are additional useful signs. In anticholinergic intoxication, pupils dilate and generally do not react to light, whereas in cocaine intoxication, dilated pupils usually respond to light. Alcohols, cholinergics, lithium, carbamazepine, phenytoin, and barbiturates cause horizontal gaze nystagmus. Phencyclidine, phenytoin, and barbiturates cause horizontal, vertical, or rotatory nystagmus.

Selected drugs and toxins affecting muscle tone and movement are listed in Table 102-12.28,30 Dystonic reactions characterized by torticollis, tongue movements, and trismus are classic in haloperidol, phenothiazine, or metoclopramide overdose. Dyskinesias (e.g., myoclonus, hyperkinetic activity, and repetitive activity) are seen with anticholinergics, PCP, and cocaine. Muscle rigidity with hyperthermia is characteristic of neuroleptic malignant syndrome, malignant hyperthermia, PCP intoxication, and black widow spider bite.

Laboratory Evaluation

Clinical laboratory data include assessment of the “three gaps of toxicology": the anion gap, the osmolal gap, and the arterial oxygen saturation gap. Unexplained widening of these gaps should raise the possibility of drug overdose or toxic ingestion.

Anion Gap

The anion gap (AG) refers to the difference between one measured cation (Na+) and two measured anions (mainly Cl– and HCO3−):

with a normal value of approximately 12 ± 4 mEq/L.31–34

The presence of an anion gap indicates that there are more unmeasured anions than cations, since total serum cations equals total serum anions. Unmeasured cations include potassium, magnesium, and calcium, totaling about 11 mEq/L under normal conditions. The concentration of unmeasured anions, including mainly albumin, sulfates, phosphates, and organic acids, is about 23 mEq/L (and thus the difference of approximately 12 mEq/L).35 It follows that the presence of hypoalbuminemia requires a downward adjustment of the expected normal anion gap: the anion gap falls 2.5 mEq/L for every 1 g/L decrease in plasma albumin concentration.36

The anion gap increases through three possible mechanisms: a decrease in unmeasured cations, an increase in unmeasured anions, or a laboratory error in measurement of Na+, Cl− or HCO3−. An increase in anion gap resulting from decreased unmeasured cations is rare but may occur in severe potassium, calcium, or magnesium depletion. The most common cause of an elevated anion gap is an increase in unmeasured anions. This includes accumulation of organic acids, as in lactic acidosis or ketoacidosis, or accumulation of the anions of organic acids such as sulfate and phosphate in uremia. Common causes of an elevated anion gap are listed in Table 102-13.

Toxic ingestions may increase unmeasured anions and elevate the anion gap (e.g., ethylene glycol elevates the anions glycolate and lactate). An elevated anion gap mandates consideration of toxic ingestion, even in the presence of ketones or lactate, which can occur with toxic ingestion.37,38 Drugs associated with an elevated anion gap are included in Table 102-14.

Rarely, toxic ingestion decreases the anion gap (<6 mEq/L). Causes of decreased anion gap are listed in Table 102-15. Note the presence of lithium on this list.

Osmolal Gap

Certain drugs and toxins of low molecular weight (Table 102-16) produce a discrepancy between measured and calculated plasma osmolality, commonly referred to as the osmolal gap (osmolal gap equals measured minus calculated osmolality). The plasma osmolal gap can thus be used to detect the presence of these toxins in the blood. Normal plasma osmolality, determined by the millimolar concentrations of major solutes in plasma, is approximately 285 to 295 mOsm and is calculated as:

where Na+ (in mmol/L) is multiplied by two to account for accompanying anions (chloride and bicarbonate), and the concentrations of BUN (blood urea nitrogen) and glucose are divided by 2.8 and 18, respectively, to convert mg/dL to mmol/L. Dividing ethanol concentration by 4.6 accounts for the effect of a measured plasma ethanol concentration (in mg/dL) on calculated plasma osmolality. Of note, spuriously low serum sodium values (pseudohyponatremia) due to hyperlipidemia or hyperproteinemia may indicate the presence of a factitious osmolal gap.

Methanol and ethylene glycol are unique in producing both severe metabolic acidosis with elevated anion gap and an elevated osmolal gap. Isopropanol intoxication can elevate the osmolal gap and cause ketonemia and ketonuria (owing to its metabolism to acetone) without elevation of the anion gap or acidosis. Through CNS and cardiac effects, isopropanol may cause respiratory acidosis and lactic acidosis, respectively.

Caution must be used when interpreting the osmolal gap. First, measurement of osmolality by vapor pressure osmometry does not detect volatile alcohols such as ethanol and methanol (but does detect ethylene glycol); freezing point depression osmometry does measure these solutes.39,40 Although 10 mOsm is often used as the upper limit of normal, osmolal gaps may range from −9 mOsm to +5 mOsm in normal individuals (using the standard formula for calculations).41 Thus, an osmolal gap of 10 mOsm in a patient whose baseline value is −2 mOsm could represent the presence of significant amounts of low-molecular-weight substances (e.g., ethylene glycol level over 70 mg/dL).42,43 In one study the range of osmolal gaps measured in 300 consecutive patients presenting to Bellevue Hospital in New York (with indications for measurement of electrolytes and ethanol) was −2 ± 6 mOsm using the standard formula, including the contribution of measured ethanol concentrations.44 Large variations existed in the range of osmolal gap that was very dependent on the equation used. Because of the large range of values, the authors noted that small osmolal gaps in no way exclude the possibility of toxic alcohol ingestion. Furthermore, as ethylene glycol/glycoaldehyde and methanol/formaldehyde are metabolized, the osmolal gap may decrease into the normal range in the continued presence of toxic metabolites. By contrast, concurrent ethanol ingestion may prevent early development of metabolic acidosis, so that the presence of an osmolal gap greater than expected from the measured ethanol level may be the only clue to the presence of a non-ethanol alcohol.45 Lactic acidosis and ketoacidosis have also been reported to cause elevation of the osmolal gap.46 Finally, chronic (but not acute) renal failure is a cause of increased osmolal gap, a phenomenon corrected by dialysis.47

In summary, the presence of an elevated anion gap metabolic acidosis, even in the presence of an apparent clinical explanation, warrants consideration of intoxication. The additional presence of an elevated osmolal gap, particularly of large magnitude (>25 mOsm), is indicative of methanol or ethylene glycol intoxication (see below). The converse is not true, in that serious intoxications with either agent can occur in the absence of a documented increased osmolal gap. Thus measuring serum levels of these alcohols is important in any patient in whom inebriation, acidosis, or other clinical features suggest intoxication with these agents.

Oxygen Saturation Gap

An elevated arterial oxygen saturation gap is defined by a >5% difference between saturation calculated from an arterial blood gas and saturation measured by co-oximetry. Elevated oxygen saturation gap is seen in carbon monoxide poisoning and with methemoglobinemia. These toxins interfere with oxygen binding to hemoglobin and thereby significantly decrease oxygen content without lowering arterial oxygen pressure (PaO2). It is important to note that oxygen saturation measured by pulse oximetry is falsely high in these settings. Hydrogen sulfide and cyanide interfere with cellular utilization of oxygen, leading to an abnormally high venous oxygen saturation and “arteriolization" of venous blood.

Additional Laboratory Tests

Additional useful laboratory data include: urine ferric chloride analysis, which provides rapid evidence of salicylate or phenothiazine intake; a pregnancy test in women of childbearing age; and abdominal radiography, which may detect retained pills (such as iron pills). Sustained-release preparations may be detected more easily through digital enhancement of the radiograph.48

Toxicology Screening

Toxicology screening provides direct evidence of ingestion, but it rarely impacts initial management; supportive measures should never await results of such analysis. In Brett's review of 209 cases of intentional drug overdose,49 toxicology analysis supported the clinical suspicion in 47% of cases. Clinically unsuspected drugs were detected in 27% of cases, but unexpected findings altered management in only three cases. Kellerman and coworkers reviewed urine toxicology screens in 361 of 405 consecutive ED patients with suspected drug overdose.50 Management changes followed drug screening in only 16 (4.4%) of cases.

Toxicology screening confirms the presence of a drug and provides grounds for treatment with a specific antidote or method for enhancing elimination. Toxicology screening also identifies drugs that should be quantitated to guide subsequent management.51 If at all possible, samples should be collected before administration of medications that might confuse toxicologic analysis.

Understanding the limitations of toxicology screening is important, including which drugs are (and which drugs are not) included in routine screening panels. These panels are institutionally variable. Most institutions offer urine screening for commonly abused drugs only, preferring to send more extensive screening panels to outside laboratories. Other institutions routinely perform extensive urine and blood analysis on all patients in selected categories (e.g., trauma patients). Urine screens used in the ED are aimed at detecting six or seven of the most commonly abused drugs (Table 102-17). Results are generally available in 30 minutes. Approximately 60 drugs are included in the expanded screening panel (Table 102-18), the results of which should be available in 2 to 3 hours. Table 102-19 lists some drugs not included in routine drug screening.

Toxicologic screening of blood is generally not additive to comprehensive urine testing,52 although rarely blood analysis is useful in acute cases when the drug or toxin is not yet detectable in urine (particularly in anuric or oliguric patients). Quantitative blood analysis of suspected drugs can be useful for diagnostic and therapeutic reasons, particularly in overdoses involving alcohols, acetaminophen, salicylates, and cyclic antidepressants. A strong argument can be made for checking acetaminophen levels in all cases of suspected intoxication given the subtle manifestations of early poisoning and the importance of targeted therapy.

Poison control centers provide 24-hour emergency and technical information by telephone to anyone concerned with drug overdose or toxic ingestion. These centers are staffed variably by nurses, pharmacists, pharmacologists, and physicians trained in clinical toxicology. The staff provides information regarding substance identification, drug interactions, adverse drug reactions, and management of poisoned patients. These centers maintain current references and information about toxins or drugs specific to certain areas, including information about street drug activity.

Poison control center consultation is strongly advised to help determine appropriate laboratory testing, patient disposition, and treatment, including the need for a specific antidote or method to enhance drug elimination. Information provided by regional poison control centers may be more accurate than advice provided by local EDs.53 The national toll-free emergency phone number is 1-800-222-1222.

Gastric Emptying

Gastric emptying is achieved by gastric lavage (GL) or syrup of ipecac. Ipecac is useful for certain ingestions in pediatric patients, but it is contraindicated in poisoning with corrosives, petroleum products, antiemetics, and strychnine. There is little role for ipecac in hospital because delayed use is of questionable efficacy and it is contraindicated in obtunded patients.54,55

GL is advocated in the initial management of many orally ingested agents. However, risk-benefit analysis casts doubt as to the appropriateness of GL in many situations. The risks associated with GL (including aspiration, arrhythmias, and stomach perforation) preclude its use in patients who have ingested a nontoxic substance or a nontoxic amount of a toxic substance. Additionally, GL should not be performed when the toxin is no longer expected to be present in the stomach. Examples include patients who have vomited extensively prior to admission, patients who present several hours after ingesting an agent that does not decrease gut motility, and patients who have taken agents that are readily absorbed from the gastrointestinal tract.

To minimize risk, experienced personnel should perform GL lavage in a facility where resources are available to manage complications. Nonintubated patients must be alert and have adequate pharyngeal and laryngeal protective reflexes. In semicomatose patients, GL should be performed after intubation. Intubation for the sole purpose of GL is reasonable only if there is a high likelihood that a highly lethal agent remains in the stomach.

The usual teaching is to empty the stomach of alert patients (who are expected to remain alert), with GL within 1 hour of ingestion of potentially dangerous amounts of a toxic substance.56 In obtunded patients, GL results in a more satisfactory clinical outcome only if performed within 1 hour of ingestion.57 Although controversial, this time limit may be extended to 12 hours in cases of poisoning with agents that delay gastric emptying such as cyclic antidepressants, opioids, or salicylates. In cases of ingestion of a caustic liquid like kerosene or its derivatives, GL should be avoided because of the risk of aspiration-induced lung injury.

Prior to inserting a large-bore gastric tube (Ewald tube), the mouth should be inspected for foreign material and equipment should be readied for suctioning. Large gastric tubes (37F to 40F) are less likely to enter the trachea than smaller nasogastric tubes, and are necessary to facilitate removal of gastric debris. Once the tube has been passed with the help of patient swallowing, proper position is confirmed by aspirating acidic stomach contents and auscultating the left upper abdominal quadrant during insufflation of air. Stomach contents should be retained for analysis. Lavage is performed by instilling 200-mL aliquots of warmed tap water until there is clearing of aspirated fluid. Tap water is preferred over normal saline because it avoids unnecessary salt loading, and neither irrigant significantly alters blood cell concentrations or electrolyte concentrations.58 After clearing, the Ewald tube may be replaced by a nasogastric tube for intermittent suctioning and/or administration of activated charcoal.

Activated Charcoal

Charcoal is a by-product of the combustion of various organic compounds such as wood, coconut parts, bone, sucrose, rice, and starch. It is activated by removing materials previously absorbed by a process that involves steam heating and chemical treatment, thereby increasing the surface area available for absorption. The result is a powerful nonspecific adsorbent that irreversibly binds intraluminal drugs and interferes with their absorption. Activated charcoal (AC) also decreases serum drug levels in some cases by creating a favorable diffusion gradient between blood and gut, referred to as gastrointestinal dialysis.59

Activated charcoal should be administered in a timely fashion after gastric emptying (if performed) because efficacy decreases with time.60 It should not be given to stuporous, comatose, or convulsing patients unless an endotracheal tube protects the airway and a gastric tube is in place to administer the charcoal. Gastric stapling is a risk factor for emesis and aspiration in patients treated with single or repeated doses of AC.61 Aspiration of this particulate has been associated with pneumonia62 (including fungal pneumonia),63 bronchiolitis obliterans,64 acute respiratory distress syndrome,65 and death.66

Activated charcoal is generally given as a single dose. The dose is based on patient weight (1 g/kg added to 4 parts water to form an aqueous slurry). Mixing AC with juice may improve patient acceptance of this black and gritty adsorbent.

Multiple-dose AC can enhance the elimination of selected toxins that have been absorbed.67 This may occur through interruption of the enterohepatic/enterogastric circulation of drugs or through the binding of drugs that diffuse from the circulation into the gut lumen (so called gastrointestinal dialysis). However, multiple-dose AC is of limited use because the toxin must have a low volume of distribution, low protein binding, prolonged elimination half-life, and low pKa (negative logarithm of the acid ionization constant), which maximizes transport across mucosal membranes into the gastrointestinal tract.68 Based on experimental and clinical studies, it should be considered only in life-threatening ingestions of selected drugs: carbamazepine, dapsone, phenobarbital, quinine, or theophylline.69

In a recent review, the American Academy of Clinical Toxicologists reported that multidose AC increases drug elimination, but has not been shown to reduce morbidity and mortality in controlled trials.69 The optimal dose and frequency of administration of AC following the initial dose has not been established. Most experts recommend a dose not less than 12.5 g/h.70 After the initial dose of 1 g/kg, AC may be administered at 0.5 g/kg every 2 to 4 hours for at least 3 doses. Multiple doses should be used with caution in patients with decreased bowel sounds, abdominal distension, and emesis.

Combining AC with a cathartic may facilitate evacuation of the toxin and avoids constipation. Preparations for coadministration with AC include 1 to 2 mL/kg of a 70% solution of sorbitol titrated to several loose stools over the first day of treatment. An alternative is to use 2 to 3 mL/kg of a 10% solution of magnesium sulfate PO, but magnesium-based cathartics may lead to magnesium accumulation in the setting of renal failure, and sodium-based products carry the risk of exacerbating hypertension or congestive heart failure. If aspirated, oil-based cathartics may produce lipoid pneumonia.

The efficacy of adding a cathartic to AC is unclear. Keller and colleagues demonstrated that AC with sorbitol decreased absorption of salicylates compared to AC alone.71 McNamara and colleagues found no benefit to adding sorbitol to a simulated acetaminophen overdose.72 Catharsis has not been shown to decrease morbidity, mortality, or hospital length of stay, and it is not recommended for routine use in combination with AC by the American Academy of Clinical Toxicology.73,74

Whole-Bowel Irrigation

Whole-bowel irrigation (WBI) with a polyethylene glycol electrolyte solution (e.g., GoLYTELY) 1 to 2 L/h by mouth or nasogastric tube may clear tablets or packages from the gastrointestinal tract. Irrigation is generally continued until the rectal effluent is clear or there is radiographic evidence of clearance. The efficacy of WBI has not been established in controlled trials, but it is reasonable to consider its use in iron and lithium overdose (situations in which AC is ineffective), ingestion of sustained-release tablets, and in cases of “body packing" with packages of illicit drugs. Contraindications to WBI include ileus, gastrointestinal hemorrhage, and bowel perforation.

Forced Diuresis and Urinary pH Manipulations

We do not recommend forced diuresis by volume loading and diuretic administration, which is intended to augment elimination of renally excreted toxins through inhibition of tubular reabsorption. This regimen is of unproven benefit and has the potential to compromise fluid and electrolyte homeostasis.75–78 The minimum criteria for augmented clearance of a drug by forced diuresis are that the substance normally undergoes extensive tubular reabsorption and that renal excretion becomes the major route of elimination under conditions of forced diuresis. It is notable that if tubular reabsorption is pH sensitive, then increased urine flow does not significantly increase urinary drug elimination when added to alkaline or acid diuresis (see below).79

Therapeutic manipulation of urinary pH can enhance elimination of some intoxicants. Most drugs are weak acids or bases and are present in both ionized and nonionized fractions in serum and glomerular filtrate. Normally, passive renal tubular reabsorption of the nonionized lipid-soluble fraction of such drugs occurs by nonionic diffusion; this process is accentuated by the progressive tubular reabsorption of water and solutes as the glomerular filtrate traverses the nephron, resulting in an increasing filtrate/serum concentration gradient which favors drug reabsorption. Back-diffusion of some acidic and basic drugs from renal tubular lumen to the peritubular fluid and capillaries can be decreased by manipulation of urinary pH to create more of the ionized (less lipid-soluble) salt of the drug. Urinary alkalinization is expected to augment excretion of nonpolar weak acids with pKa values between 3 and 7.5 (Table 102-20), because these drugs become more dissociated as urinary pH rises, resulting in ion trapping of the drug in the tubular lumen.79 (The dissociation constant, pKa, of a drug refers to the pH at which the compound is equally ionized and unionized.) Because the limits of urinary pH are 4.5 to 7.5 under conditions of enhanced alkalinization and acidification, elimination of very strong (pKa <3) or very weak (pKa >8) acids is unaltered by urinary pH manipulation. Other acidic or basic drugs do not undergo renal tubular absorption regardless of urinary pH since they are polar in their nonionized form (e.g., gentamicin). Urinary alkalinization (pH >7) is usually achieved by administration of intravenous sodium bicarbonate (1 to 2 mEq/kg every 3 to 4 hours); this may be administered as two 50-mL ampules of 8.4% sodium bicarbonate (each containing 50 mEq of NaHCO3 ) per liter of 5% dextrose in water infused at 250 mL/h.80 Complications of this therapy include alkalemia (particularly in the presence of concurrent respiratory alkalosis), volume overload, hypernatremia, and hypokalemia. It is particularly important to avoid hypokalemia, which prevents excretion of alkaline urine by promoting distal tubular potassium reabsorption in exchange for hydrogen ion. Accordingly, bicarbonate administration in the presence of significant hypokalemia will not achieve an alkaline urine, yet increases the risk of alkalemia. Since urinary alkalinization can cause hypokalemia (caused by alkalemia-induced intracellular potassium shift and by increased urinary potassium losses with alkaline diuresis), addition of potassium chloride to the bicarbonate infusion is commonly required and may be considered prophylactically.78 We do not recommend the use of acetazolamide to induce alkaline diuresis. This therapy causes metabolic acidosis, which can further complicate management, particularly in the case of salicylate intoxication (where acidemia increases CNS entry of the drug).

Urinary acidification (pH <5.5) likewise increases renal clearance of some nonpolar weak bases (see Table 102-20), with pKa values between 6 and 12. These drugs include PCP (pKa 8.5) and amphetamines (pKa 9.9).79 Again, elimination of very weak (pKa <6) or very strong (pKa >12) nonpolar bases is less affected by urinary pH changes. Arginine or lysine hydrochloride or ammonium chloride is most commonly used for urinary acidification. However, this therapy is generally not recommended because of the potential for urinary acidification to exacerbate myoglobinuric renal tubular injury. Also, systemic acidosis must be carefully controlled to avoid potential additive effects with toxin-induced metabolic or respiratory acidosis.

Extracorporeal Removal of Toxins

In some instances, treatment of an intoxicated patient with supportive measures, decontamination, and acceleration of renal drug elimination does not alter the course of events to optimize outcome. Application of extracorporeal drug removal (ECR) techniques may be life-saving for such patients, although clear proof that ECR favorably alters the course of any intoxication is generally lacking.81 Application of ECR for any intoxication is based on critical appraisal of both the clinical status of the patient and of current available data on the prognosis and treatment of the intoxication. In general, ECR should be considered when (1) supportive care fails to stabilize the patient's clinical status; (2) the intoxication is projected to undergo delayed or insufficient clearance because of renal, hepatic, or cardiac dysfunction; (3) the intoxicating agent produces toxic metabolites; or (4) delayed toxicity is characteristic of the intoxication.76–78,81–83 In addition to these general considerations, specific clinical features or serum drug levels may indicate the necessity for ECR. Finally, physicochemical properties of the intoxicant, and its pharmacokinetic behavior in overdose (which may differ from the agent's pharmacokinetic properties in the therapeutic range), also dictate the feasibility of ECR and the choice of method. Three methods for ECR are generally available: (1) dialysis (usually hemodialysis rather than peritoneal dialysis); (2) hemoperfusion; and (3) hemofiltration. Rarely, other techniques such as plasmapheresis and exchange transfusion are considered for specific intoxications; these will not be further discussed here.

Hemodialysis

Hemodialysis (HD) is the treatment of choice for ECR of very few intoxicants, because hemoperfusion (HP) provides superior drug extraction in most cases in which ECR is considered. Hemodialysis is still preferred to HP for removal of substances that are particularly dialyzable (see below), especially in the presence of metabolic acidosis, renal failure, dialyzable toxic metabolites, or other HD indications. Hemodialysis removes water-soluble unbound (free) solutes that are small enough to pass through the pores of the semipermeable dialysis membrane, which separates the patient's blood from the countercurrent flow of the dialysis bath fluid (which is discarded as effluent dialysate following passage through the dialyzer). Solute transport, including transfer of drugs, toxins, or metabolites, occurs by diffusion down the blood-to-dialysis bath concentration gradient, which is maintained by countercurrent flow of dialysate. In addition to low molecular weight and water solubility, both low protein binding and a small volume of distribution are necessary characteristics of a substance that is readily cleared by HD.84–88

Criteria for potential dialyzability include:

1. Water solubility: Water-soluble substances cross dialysis membranes more readily than lipid-soluble agents (drugs or metabolites).

2. Low molecular weight: Traditionally, a substance is described as small enough to be significantly removed by hemodialysis when it has a molecular weight of <500 daltons (Da). More recently, high-flux dialysis membranes with increased porosity and surface area have been introduced. Such membranes are capable of removing drugs with weights in the middle-molecule range, up to 5000 Da. For example, vancomycin has a molecular weight of 1500 Da, but is significantly cleared by HD with a high-flux membrane.87,89,90

3. Protein binding: Low protein binding (<90%) facilitates drug removal by hemodialysis, since only unbound drug is free to cross the hemodialysis membrane; for example, for a drug which is 90% protein-bound, hemodialytic removal of 50% of free drug only reduces its concentration in blood passing through the dialyzer by 5%.

4. Volume of distribution (Vd): This is the theoretical volume into which the intoxicant is distributed. As a general rule, substances with a Vd of <250 L (approximately 3 to 4 L/kg) are potentially significantly cleared by hemodialysis. Conversely, hemodialytic removal of substances with a larger Vd is generally insignificant in comparison to the total body load of the substance, which often equilibrates too slowly with the vascular space to allow significant removal. In fact, most substances substantially removed by HD have a smaller Vd of 1 L/kg (Table 102-21).

5. Intrinsic clearance of the substance: Most drugs have a hemodialysis clearance of 5 to 100 mL/min; if a patient's clearance of a substance exceeds 500 to 700 mL/70 kg per minute, hemodialysis is unlikely to significantly augment the substance's clearance.89 It is important to note that the clearance of a drug at toxic levels may be significantly less than that reported within the therapeutic range, because of saturable hepatic metabolism at high drug concentrations (concentration-dependent kinetics) or intoxication-induced renal, hepatic, or cardiac dysfunction. Furthermore, there is usually a paucity of information regarding the production and relative clearance (intrinsic versus extracorporeal) of toxic metabolites.

Complications of HD include:

1. Intravenous access complications: If possible, temporary vascular access should be placed in the femoral vein to minimize the potential for serious complications (pneumothorax, central vessel or nerve injury, or catheter-induced arrhythmia). Vascular access should also be removed as soon as possible (but not before the period for potential development of rebound intoxication has passed) to minimize the potential for access infection or thrombosis.

2. Hypophosphatemia: In patients without concomitant renal failure and hyperphosphatemia, the dialysis bath should be supplemented with phosphorus to prevent severe dialysis-induced hypophosphatemia. Addition of 1.3 mmol/L of phosphorus to the dialysis bath should prevent hypophosphatemia.

3. Alkalemia: Since the usual dialysis bath bicarbonate (buffer) concentration is 35 to 38 mEq/L, severe alkalemia can result from hemodialysis against a standard bath in the absence of associated acidosis (particularly in the presence of hyperventilation or emesis-induced metabolic alkalosis). If the predialysis plasma bicarbonate concentration is 28 mEq/L or higher, then the bath bicarbonate concentration must be lowered to 15 to 28 mEq/L.

4. Disequilibrium syndrome: Acute neurologic deterioration caused by large, rapid changes in cerebral tissue osmolality may occur in an acutely uremic patient who receives a prolonged initial session of intensive hemodialysis for drug removal. High-sodium dialysis bath and intravenous mannitol may be useful prophylactically in blunting large acute transcellular water shifts caused by HD removal of uremic toxins.

5. System saturation: This is not possible using standard hemodialysis, because of maintenance of the concentration gradient for diffusion by countercurrent flow (blood versus dialysate), except when a sorbent dialysis system is used. This system is inappropriate for extracorporeal removal of an intoxicant, since the sorbent cartridge used to regenerate new dialysis solution from dialysate may become saturated and cease to function. If such a system is the only available option, frequent cartridge changes will be required.

6. Other: Hypotension is a potential adverse effect of HD (or HP), particularly if this therapy is instituted in an already unstable patient, though hemodynamic compromise is less likely if not actively removing plasma volume (by ultrafiltration). Finally, air embolism is an extremely rare consequence of HD.

Peritoneal Dialysis

Intoxicant removal across the peritoneal membrane is generally only one-eighth to one-fourth as efficient as hemodialysis, even when maximizing solute exchange volume and frequency. This technique is therefore never the preferred method for extracorporeal drug removal, unless other considerations supervene (e.g., use as an adjunctive measure or in the absence of available HD or HP).

Hemoperfusion

Hemoperfusion (HP) is defined as direct contact of blood with a sorbent system.82,91 Currently available systems perfuse a cartridge packed with coated AC (carbon). Blood perfusing such a cartridge is exposed (via a highly porous coating) to a large sorbent surface area, thus maximizing drug adsorption. Activated charcoal adsorbs both water-soluble and lipid-soluble substances and can remove essentially all of an adsorbing substance from blood perfusing the cartridge. Thus it is not unusual to achieve drug clearances of 200 to 400 mL/min, particularly early in the treatment period, before cartridge saturation begins. Polymer coating reduces adsorption of larger compounds (>3500 Da). The drug adsorption process competes with plasma proteins and tissue stores to greatly augment removal of bound drug beyond the level achievable by HD.

Complications of HP include:

1. Cartridge saturation: The extraction ratio (EX) of a substance by HP (or HD) is the amount of the solute removed as a fraction of the maximum it is theoretically possible to remove: EX = (A − V)/A, where A and V are the cartridge inlet and outlet blood concentrations, respectively. This ratio declines during an HP treatment session as the cartridge becomes saturated; as noted above, this occurs during HD only if a sorbent-based dialysis system is used.

2. Hematologic: Thrombocytopenia commonly occurs due to platelet adsorption, inducing up to a 30% decrement in platelet count, which usually recovers within 24 to 48 hours. Leukopenia and coagulation factor depletion also occur, to a lesser extent.

3. Metabolic: Cartridge adsorption can cause hypoglycemia and hypocalcemia.

4. Technical: Access complications can occur as for HD. Hypothermia is an additional risk, because HP pumps do not warm blood as the HD apparatus does. Particle embolization (prevented by a filter in the line returning effluent blood to the patient) and development of pyrogenic reactions are of largely historic interest at this point.

Most drugs are extractable by HP, which is particularly suitable for extracorporeal removal of toxins that are of high molecular weight, highly protein-bound, or lipid-soluble. Drugs poorly extracted by HP include heavy metals (lithium and bromide), some alcohols (ethanol and methanol), carbon monoxide, and some illicit drugs (cocaine, phencyclidine, and others). Efficacy of intoxicant removal is diminished for substances with a large Vd (i.e., highly lipid-soluble and/or extensively tissue-bound), which may be more effectively removed by hemofiltration.

Hemofiltration

Hemofiltration (HF) achieves drug removal by convection, transporting drugs and other solutes through a highly porous membrane by bulk flow with filtered plasma water. Such membranes are generally permeable to substances with weights of up to 6000 Da, including virtually all drugs, and in some cases HF membranes are permeable to substances weighing up to 20,000 Da.92–94 There are increasing numbers of case reports of extracorporeal intoxicant removal using hemofiltration, by either the arteriovenous (continuous arteriovenous hemofiltration; CAVH) or venovenous (continuous venovenous hemofiltration; CVVH) method.95,96 Hemofiltration is potentially useful for removal of substances with a large Vd, slow intercompartmental transfer, or avid tissue binding. Specific highly porous HF cartridges are also particularly useful for removal of large-molecular-weight solutes or complexes, such as combined digoxin-Fab fragment complexes or deferoxamine complexes with iron or with aluminum. CAVH also has the advantage that trained personnel can perform this technique without the assistance of a pump.

Antidotes

An antidote is any substance that increases the mean lethal dose of a toxin, or that can favorably affect the toxic effects of a poison.97 Table 102-22 lists antidotes for specific drugs/poisons.

In the current healthcare environment, the practice of routinely admitting poisoned patients to the medical intensive care unit or a cardiac monitored bed is being questioned. In one retrospective study, Brett and colleagues identified several factors that predicted the need for ICU admission: partial pressure of arterial carbon dioxide (PaCO2) ≥45 mm Hg, the need for intubation, seizures, QRS duration ≥0.12 seconds, second- or third-degree atrioventricular block, cardiac arrhythmias, systolic blood pressure <80 mm Hg, and unresponsiveness to verbal stimuli.98 If none of these factors was present, no ICU interventions (intubation, vasopressors, antiarrhythmics, dialysis, or hemoperfusion) were required. Other considerations include a Glasgow Coma Scale score <12, progressive metabolic acidosis, and a cyclic antidepressant or phenothiazine overdose with signs of anticholinergic cardiac toxicity.99,100 Cyclic antidepressants in particular may cause delayed cardiac toxicity.101 Severe hyperkalemia, extreme body temperatures, and need for continuous infusion of naloxone are also reasons to admit to an ICU. Often, staffing issues including the availability of a “sitter" in cases of attempted suicide, have an important impact on the disposition of the patient.

Acetaminophen

In 2001, alone or in combination with other drugs, acetaminophen accounted for over 112,000 exposures, making it the most common pharmaceutical overdose reported to poison control centers. Approximately 60,000 of these cases were treated in health care facilities; 12,744 patients received n-acetylcysteine (NAC); 2257 had major complications; 238 died.1

The evolution of acetaminophen toxicity is often divided into four phases.102,103 Phase I refers to the first 24 hours after ingestion. During this period, acetaminophen is absorbed and metabolized, glutathione stores are depleted, and hepatotoxicity begins. Patients are alert but may experience nausea, vomiting, anorexia, malaise, pallor, or diaphoresis. These nonspecific signs and symptoms create the potential for a missed diagnosis. Furthermore, when acetaminophen is combined with another drug such as codeine or oxycodone, the effects of the other drug may further mask the initial subtle manifestations of acetaminophen poisoning.

Phase II occurs 24 to 72 hours after untreated ingestion. During this period, patients may develop right upper quadrant pain and minor abnormalities of liver function consisting of elevation of hepatic enzymes, prothrombin time, and bilirubin. Phase III (72 to 96 hours after untreated ingestion) is characterized by continued hepatic necrosis, hepatic encephalopathy, disseminated intravascular coagulation, and jaundice. Liver function abnormalities typically peak during phase III. It is not unusual for serum aspartate aminotransferase levels to rise to 10,000 IU/L or higher. Extreme elevation of alanine aminotransferase may also be seen. Rare phase III sequelae include hemorrhagic pancreatitis, myocardial necrosis, and acute renal failure.103 Phase IV takes place 4 days to 2 weeks after ingestion. During this period, the patient may die, fully recover without chronic liver disease, or undergo emergent liver transplantation. Some patients with untreated acetaminophen poisoning exhibit a pattern of rising prothrombin time, ammonia, and bilirubin, as levels of hepatic enzymes decline, indicating fulminant hepatic necrosis.

A product of normal acetaminophen metabolism is responsible for hepatotoxicity. As acetaminophen is metabolized by the cytochrome P-450 mixed oxidase system, a toxic product (possibly N-acetyl-p-benzoquinone imine or NAPQI)104 is rapidly detoxified by hepatic intracellular glutathione. In overdose cases, glutathione is depleted, allowing the toxic metabolite to combine with hepatic cell proteins and cause centrilobular necrosis with periportal sparing. Local production of NAPQI makes the liver the primary target, but other organs can be affected as indicated above.

It follows that a relationship exists between plasma levels of acetaminophen and the potential for toxicity. The Rumack-Matthew nomogram (Fig. 102-1) for acetaminophen poisoning allows stratification of patients into categories of probable hepatic toxicity, possible hepatic toxicity, and no hepatic toxicity, based on the relationship between acetaminophen level and time after ingestion.105 The lower line of this nomogram, which defines serum levels 25% below those expected to cause hepatotoxicity, is generally used to guide treatment.

There are several limitations to the use of the Rumack-Matthew nomogram. First, note that a serum level obtained prior to 4 hours postingestion is not interpretable because of ongoing absorption and distribution of the drug, and patients in phases II to IV may have trivial or undetectable serum concentrations despite a potentially lethal dose. Second, the nomogram is less predictive in chronic ingestion or use of an extended-release preparation. For extended-release preparations serial acetaminophen levels should be drawn every 4 to 6 hours after ingestion and plotted on the Rumack-Matthew nomogram. If any point is above the lower line, an entire course of the antidote NAC is indicated. Third, the nomogram does not take into account at-risk populations. Acute ingestion of 7.5 to 10 g is potentially hepatotoxic in normal adults; however, the risk of toxicity increases in alcoholics, individuals who are malnourished, patients with induced cytochrome P-450 enzymes, and patients with low glutathione stores at baseline (as may be seen with recent subtoxic acetaminophen use).106 In such cases doses as low as 4 to 6 g may be toxic. In this situation, NAC should be considered even if the serum level falls below the lower line. Fourth, accurate risk assessment requires an accurate time of ingestion, which is not always attainable. A 1- to 2-hour difference easily moves the borderline patient above or below the treatment line. Based on these limitations, Bond and Lite reported that the Rumack-Matthew nomogram could not be used for risk assessment in 44% of hospitalized patients and 83% of patients who suffered severe hepatic injury.107

Treatment of acetaminophen overdose should be initiated during phase I. Gastric lavage is indicated in patients seen within 1 hour of ingestion. Children at home may be given ipecac. Activated charcoal may be administered even though it has the potential to partially adsorb orally administered NAC. Activated charcoal reduces the number of patients reaching toxic serum levels after ingesting more than 10 g of acetaminophen and presenting within 24 hours of ingestion, and may reduce the need for a full treatment course of NAC and hospital length of stay.108 When AC and NAC are used simultaneously, they should be administered 2 hours apart to minimize interaction. Hemoperfusion effectively accelerates removal of acetaminophen from the blood; however, benefit has not been demonstrated in controlled trials. This technique may prove helpful in patients with high acetaminophen levels presenting late in the course of intoxication.103

All patients with probable or possible hepatic toxicity based on the Rumack-Matthew nomogram (i.e., all patients with serum acetaminophen levels above the lower line) should receive NAC to replete glutathione stores. NAC should also be given if there is >5 μg/mL acetaminophen and an unknown time of ingestion (but <24 hours), evidence of hepatotoxicity, or if a serum acetaminophen level is not immediately available. In this latter situation, the antidote may be discontinued if the acetaminophen level is found to be at a nontoxic level according to the nomogram. Importantly, NAC should be considered in at-risk patients even if levels are nontoxic.

The effectiveness of NAC depends on the time of administration. It is almost 100% effective when administered within the first 8 to 10 hours. Efficacy decreases over time, but there is still benefit for up to 24 hours.109 NAC may even improve outcome when it is administered after the onset of fulminant hepatic failure.110 In the setting of liver failure, NAC lowers the incidence of hepatic encephalopathy and improves oxygen transport and consumption.111,112

The oral loading dose of NAC is 140 mg/kg. This is followed by a dose of 70 mg/kg every 4 hours for 17 doses. There are limited data supporting shorter treatment courses in selected patients. Woo and colleagues conducted a retrospective, observational case study of short-course treatment in acute overdose with acetaminophen levels in the toxic range.113 Patients received an oral loading dose of 140 mg/kg NAC followed by 70 mg/kg every 4 hours until the serum acetaminophen level was undetectable. Of the 75 patients, 25 (33.3%) were treated for less than 24 hours. The mean duration of therapy was 31 ± 16 hours. The incidence of hepatotoxicity was low and comparable to patients treated in the standard way. Protocols using a 20-hour IV course and a 48-hour IV course have also been shown to be safe and effective.114,115 NAC is prepared using the standard 10% (100 mg/mL) or 20% (200 mg/mL) formulations diluted to a 5% solution in juice. If vomiting interferes with oral NAC use, the dose should be repeated along with an antiemetic such as metoclopramide or ondansetron. Occasionally, a nasogastric tube is necessary. Intravenous administration of NAC using the same dose and dosing schedule may be beneficial in patients unable to tolerate the oral preparation. When administered intravenously, a micropore filter should be used to decrease the risk of adverse reactions.

Fatal outcomes in acetaminophen overdose are associated with late presentation, high coma grade, prothrombin time >100 seconds, pH <7.30, creatinine >300 μmol/L, cerebral edema, and sepsis.116,117 When poor prognostic features are present, liver transplantation is often considered, but whether to perform liver transplantation is a difficult decision. An accurate assessment of prognosis at the time of admission to the ICU would help to apply this therapy to the appropriate patient population. To this end, investigators from King's College Hospital Liver Unit demonstrated that an Acute Physiology and Chronic Health Evaluation (APACHE) II score >15 provided an accurate assessment of hospital mortality and identified patients in need of transplantation in the setting of acetaminophen-induced liver failure.118

Alcohols

Clinical features of ethylene glycol, methanol, and isopropanol poisoning are listed in Table 102-23. Ethylene glycol is an odorless and sweet tasting fluid that is found in antifreeze, de-icers and industrial solvents. Blue or green fluorescent dye is added to some (e.g., antifreeze) but not all products to identify leaks, allowing for evidence of poisoning by urinary fluorescence under a Wood lamp. Methanol is colorless and odorless but has a bitter taste. It is present in many paint removers, gas-line antifreeze, windshield washing fluid, and solid canned fuel. Isopropanol is a colorless and bitter tasting alcohol. It has the smell of acetone or alcohol and is found in rubbing alcohol, skin lotions, hair tonics, aftershave, de-icers, and glass cleaners.

A history of ingestion or inebriation that is not explained by a blood ethanol level suggests toxic alcohol poisoning. Metabolic acidosis with an elevated anion gap and an elevated osmolal gap are cardinal features of methanol and ethylene glycol poisoning, but poisoning can occur without either.119,120 Isopropanol elevates the osmolal gap but does not cause metabolic acidosis.121

Ethylene glycol is metabolized by alcohol dehydrogenase to glycoaldehyde and glycolic acid, and then to glyoxylic acid and oxalic acid. Accumulation and precipitation of oxalic acid and calcium oxalate in renal tubules produces calcium oxalate crystals that are present in the urine in 50% of cases.122 Ingestion of as little as 100 mL can be lethal in an adult patient.

Ethylene glycol poisoning has a triphasic clinical course: stage 1 (30 minutes to 12 hours postingestion) consists of inebriation, ataxia, seizures, variable levels of elevated anion gap metabolic acidosis with Kussmaul breathing, elevated osmolal gap, crystalluria, and hypocalcemia. Cerebral edema causes coma or death. Symptoms may be delayed if there is concurrent ethanol consumption, which competes for alcohol dehydrogenase and limits conversion of ethylene glycol to its toxic metabolites.

Stage 2 (12 to 24 hours) is dominated by myocardial dysfunction with high- or low-pressure pulmonary edema. Myocardial dysfunction or respiratory failure causes death in this stage. Stage 3 (2 to 3 days) is dominated by acute renal failure due to acute tubular necrosis with an element of tubular obstruction from calcium oxalate precipitation.68,123,124 Late (6 to 18 days) neurologic sequelae have also been described in survivors.125–128

Methanol is metabolized by alcohol dehydrogenase to formaldehyde, which is metabolized to formic acid by aldehyde dehydrogenase. Formic acid is the primary toxin responsible for metabolic derangements and ocular disturbances. Intoxication can occur orally, by inhalation, or by absorption through skin. As little as 30 mL causes significant morbidity; 150 to 240 mL of 40% solution can be lethal. Methanol causes an initial period of headache, inebriation, dizziness, ataxia, and confusion. As formic acid accumulates (6 to 72 hours), the anion gap elevates and the optic nerve swells. Decreased visual acuity and blindness are classic features of this poisoning. Pancreatitis also occurs.129,130 As in ethylene glycol poisoning, symptoms of methanol poisoning may be delayed by concurrent ethanol use.

Treatment of ethylene glycol and methanol poisoning is similar.131 Inhibiting the formation of toxic metabolites by alcohol dehydrogenase and/or urgent dialytic removal of these alcohols and their metabolites are the cornerstones of therapy. Supportive measures include gastric lavage in the first hour postingestion. Bicarbonate infusion may be necessary to improve metabolic acidosis, but has not been shown to improve outcome. Hypocalcemia and hypoglycemia should be corrected. In methanol intoxication, folate is important in the metabolism of formic acid to CO2 and water; in ethylene glycol poisoning, pyridoxine and thiamine are important in the metabolism of glycolic acid.

Fomepizole (4-methylpyrazole) inhibits alcohol dehydrogenase; ethanol prolongs the half-life of methanol and ethylene glycol by competing for alcohol dehydrogenase. Of the two, fomepizole is preferred because it does not exacerbate the inebriated state or require blood monitoring.132,133 The protocol consists of a 15 mg/kg IV loading dose followed by a 10 mg/kg IV bolus every 12 hours. After 48 hours, the bolus dose should be increased to 15 mg/kg every 12 hours to account for enhanced fomepizole metabolism. For both ethylene glycol and methanol, patients are treated until serum levels fall below 20 mg/dL. Hemodialysis can be performed concurrently with fomepizole if clinically indicated. In ethylene glycol poisoning, hemodialysis is indicated when serum levels are greater than 50 mg/dL, when there is significant and refractory metabolic acidosis, or when there is evidence of end-organ damage. In methanol poisoning, hemodialysis is indicated if serum methanol levels are above 50 mg/dL, a lethal dose of methanol has been ingested, or there is significant and refractory metabolic acidosis or evidence of end-organ damage.

Ethanol can be administered orally or intravenously aiming for a level of 100 to 200 mg/dL. One protocol for therapeutic ethanol administration to such patients is as follows:134

Loading dose: 0.6 g/kg ethanol IV

Maintenance dose: Nonalcoholic patient: 66 mg/kg per hour ethanol by continuous IV infusion

Alcoholic patient: 154 mg/kg per hour ethanol by continuous IV infusion

Patients receiving HD: double continuous infusion rate

Intravenous ethanol is supplied as a 10% solution in 5% dextrose, containing 10 g of ethanol per 100 mL of solution. Blood ethanol levels should be maintained in the target range during hemodialysis by either dialysis bath supplementation with 200 mg/dL ethanol, or doubling the dose of intravenous ethanol infusion.134–140

A high index of clinical suspicion is necessary to identify methanol- or ethylene glycol–intoxicated patients. Early institution of measures to inhibit metabolism by alcohol dehydrogenase of either substance to its toxic metabolites (formic acid from methanol, oxalic and glycolic acids from ethylene glycol) and urgent dialytic removal of the alcohol and its metabolites are of paramount importance in optimizing outcome. We also recommend alcohol dehydrogenase inhibition and prophylactic hemodialysis in any intoxicated patient with an unexplained elevation of the plasma osmolal gap, especially if serum levels are not immediately available. Further complicating matters, intoxication with diethylene glycol, which is undetected by assessment for serum ethylene glycol, but is associated with elevation of the osmolal gap and development of metabolic acidosis and acute renal failure, responds to inhibition of alcohol dehydrogenase and dialytic therapy. It is thus conceivable that an inebriated patient presenting with an elevated osmolal gap but negative serum levels for ethanol, methanol, and ethylene glycol, might benefit from empiric inhibition of alcohol dehydrogenase and hemodialysis.

Isopropanol is metabolized by alcohol dehydrogenase to acetone, which is excreted through the kidneys and breath, creating a sweet smell. Clinical features of poisoning include ketonemia, ketonuria, lack of an elevated anion gap or metabolic acidosis, an elevated osmolal gap, and hemorrhagic gastritis.135 A serum isopropanol level confirms the diagnosis. Supportive measures are usually sufficient in the treatment of these patients. Gastric lavage can be helpful if performed in the first hour postingestion. Hemodialysis is indicated when lethal doses have been ingested (150 to 240 mL of 40% to 70% solution), or when lethal serum levels are detected (400 mg/dL). Refractory shock and prolonged coma are other indications for dialysis.135 Fomepizole is not indicated.

Amphetamines

Common amphetamine and amphetamine-like prescription drugs include methylphenidate, dextroamphetamine, and pemoline, used primarily for narcolepsy and attention-deficit disorder; and various anorectic medications used for weight loss, including diethylpropion and phentermine.

Illicit drugs include methamphetamine, an addictive stimulant that is made in small laboratories. Street methamphetamine is referred to by many names, such as “speed" and “meth.” When it is inhaled in powder form or by smoking it is referred to as “crank,” “crystal,” or “ice.” Over the past decade methamphetamine use has increased rapidly in the United States.141 Ecstasy or “XTC” is the street name for 3,4-methylenedioxymethamphetamine or MDMA. Ecstasy use has become common among teenagers and young adults, particularly at “rave” parties.

Amphetamines exert their toxicity via central nervous system stimulation, peripheral release of catecholamines, inhibition of reuptake of catecholamines, or inhibition of monoamine oxidase. They generally have a low therapeutic index. In overdose, they cause confusion, tremor, anxiety, agitation, and irritability. Additional features include mydriasis, tachyarrhythmias, myocardial ischemia, stroke, hypertension, hyperreflexia, hyperthermia, rhabdomyolysis, renal failure, coagulopathy, and seizures. Hepatotoxicity requiring liver transplantation has been reported with ecstasy abuse.142 Death may result from arrhythmias, status epilepticus, intracranial hemorrhage, or aspiration pneumonitis.

Treatment is supportive, including maintenance of the airway and mechanical ventilation if necessary. Hypertension generally responds to systemic vasodilation with phentolamine or nitroprusside. Tachyarrhythmias may respond to esmolol or propranolol. Benzodiazepines, droperidol, or a phenothiazine are indicated for agitation.

Gastric lavage is helpful if performed within 1 hour of ingestion and AC should be administered promptly to adsorb remaining drug. Ipecac-induced emesis is not recommended because of the risk of abrupt onset of seizures and risk of aspiration. Elimination of amphetamines may be enhanced by forced-acid diuresis; however, acidification of the urine may increase risk of nephrotoxicity when there is myoglobinuria. Dialysis and hemoperfusion are not effective. In hyperthermic patients, the role of dantrolene is controversial, particularly due to its potential for hepatotoxicity.143,144

Barbiturates

Clinical manifestations of mild to moderate barbiturate overdose include reduction in the level of consciousness, slurred speech, and ataxia. In higher doses, barbiturates cause hypothermia, hypotension, bradycardia, flaccidity, hyporeflexia, coma, and apnea. Patients with severe overdose may appear to be dead, including absence of EEG activity.

Cardiovascular depression is caused by a combination of decreased arterial tone and myocardial depression, leading to a high filling pressure, low cardiac output, and hypotension. Respiratory depression with hypercarbia and hypoxemia are common. In deep coma, the usual acid-base disturbance is a mixed respiratory and metabolic acidosis. Patients completely unresponsive to painful stimuli tend to be significantly more acidemic and hypoxemic than those who show some response, a finding that is not explained by differences in alveolar ventilation.145 Hypoxemia may be aggravated by ventilation/perfusion mismatch and/or increased capillary permeability with development of the acute respiratory distress syndrome, possibly related to aspiration pneumonitis. Local tissue hypoxia resulting from vascular stasis and arterial hypoxemia may contribute to the development of barbiturate-related skin blisters, which commonly develop over areas of increased pressure.146

The diagnosis of sedative overdose is generally made on clinical grounds. Confirmation of barbiturate ingestion is readily available by routine urine toxicology screening. Blood levels are generally available and correlate with the severity of clinical findings; however, they rarely affect management.

As in all toxic ingestions, treatment of barbiturate overdose starts with supportive measures. There is no antidote. Gastric lavage is useful in acute massive overdose; ipecac-induced vomiting should be considered immediately after ingestion, particularly in children. Activated charcoal (AC) decreases further drug absorption and increases drug elimination,147–149 but may not alter clinical course.150 Multidose AC may be useful in life-threatening overdoses.151

Alkalinization of the urine (pH >7.5) increases the elimination of phenobarbital, but not other barbiturates, and may aggravate pulmonary edema.152 Forced alkaline diuresis may be sustained by dopamine hydrochloride,153 but this is generally not required or recommended. Charcoal hemoperfusion is indicated in severe poisoning characterized by prolonged coma or refractory hypotension, although its role is disputed.154–156

When mental status changes persist, other conditions should be considered and excluded: head trauma with subdural or epidural hematoma, intracerebral hemorrhage, embolic stroke, electrolyte abnormalities, hypoxemia, hypothyroidism, liver or renal failure, central nervous system infection, seizures, and significant alterations in temperature.

Benzodiazepines

Benzodiazepines enhance the inhibitory effects of the neurotransmitter γ-aminobutyric acid (GABA), causing generalized depression of the central nervous system. Symptoms in overdose range from slurred speech and lethargy to respiratory arrest and coma, depending on the dose and compound ingested. In general, patients in coma from benzodiazepine poisoning are hyporeflexic with small to midposition pupils.

The diagnosis of benzodiazepine overdose depends on a history of ingestion or a high index of suspicion for drug overdose, combined with compatible clinical features. Confirmation of exposure is available by urine toxicology screening.

Treatment of benzodiazepine overdose consists of initial supportive measures, gastric emptying in acute ingestions, activated charcoal,157 and flumazenil. There is no role for forced diuresis, dialysis, or hemoperfusion.

Flumazenil, a specific benzodiazepine antagonist, is useful in reversing sedation in patients undergoing procedures and in patients who have taken an intentional benzodiazepine overdose. Its effect on reversal of respiratory depression is less clear.158,159 Judicious use of flumazenil provides diagnostic information, because flumazenil does not antagonize the CNS effects of alcohol, barbiturates, cyclic antidepressants, or narcotics.

Flumazenil should be considered if benzodiazepine overdose is highly suspected or confirmed and benzodiazepines have not been prescribed for a potentially life-threatening condition.160 However, the risks and benefits of flumazenil compared to supportive measures alone are not clear. Flumazenil may cause severe withdrawal or seizures in dependent patients, and in an animal model of combined cocaine-diazepam poisoning, flumazenil precipitated seizures and increased mortality. Seizures may also occur in combined cyclic antidepressant-benzodiazepine overdose; however, cautious administration of flumazenil in this setting is likely to be safe.

Flumazenil is not a recommended component of the “coma cocktail.”2 Still, in selected cases it may help to distinguish benzodiazepine overdose from mixed-drug intoxication or non–drug-induced coma, and it improves the clinical status of patients with benzodiazepine overdose. The recommended initial dose of flumazenil is 0.2 mg (2 mL) IV over 30 seconds. A further 0.3-mg (3 mL) dose can be given over 30 seconds if the desired clinical effect is not seen within 30 seconds. Additional 0.5-mg doses can be administered over 30 seconds at 1-minute intervals as needed to a total dose of 3 mg. Flumazenil dosed beyond 3 mg generally does not provide additional benefit.161 Patients should be monitored for resedation. Resedation usually occurs within 0.5 to 3.0 hours after the first flumazenil dose.162 In some cases repeat doses of flumazenil or a continuous infusion (0.1 to 0.5 mg/h) is necessary.162 Hepatic dysfunction significantly changes the pharmacokinetic profile of flumazenil, requiring downward adjustment in dosage.163

Naloxone may partially reverse the antianxiety effects of benzodiazepines,164 but it does not significantly alter motor or respiratory effects.165,166

When mental status changes persist, other conditions should be considered. These include subdural or epidural hematoma, intracerebral hemorrhage, embolic stroke, abnormalities of sodium and other electrolytes, hypoxemia, hypothyroidism, liver or renal failure, central nervous system infection, seizures, and significant alterations in temperature. A head CT scan should be performed early in the course of an obtunded patient, and there should be a low threshold to perform lumbar puncture.

Beta-Blockers

Clinical features of β-blocker overdose depend on the drug type, amount and timing of overdose, coingestions, and comorbidities. The diagnosis is usually established on clinical grounds; blood levels are available but do not correlate well with severity.167 Risk factors for cardiovascular morbidity include coingestion of another cardioactive drug and a β-blocker with myocardial membrane-stabilizing activity (acebutolol, betaxolol, pindolol, or propranolol).168 Most patients develop β-blocker toxicity within 4 hours of ingestion.169 Asymptomatic patients with a normal electrocardiogram after 6 hours generally do not require ICU monitoring.169

Cardiovascular complications of β-blockers include hypotension, bradycardia, atrioventricular block, and congestive heart failure and pulmonary edema. Hypotension is mainly due to decreased myocardial contractility rather than bradycardia. Other clinical manifestations of overdose are bronchospasm, hypoglycemia, hyperkalemia, lethargy, stupor, coma, and seizures. The risk of seizure is highest with propranolol, particularly when the QRS complex is >100 ms.170 In a large retrospective review of 52,156 cases of β-blocker overdose, there were 164 deaths.171 Propranolol was responsible for the greatest number of toxic exposures (44%) and implicated as the primary cause of death in a disproportionately higher percentage of fatalities (71%).

Treatment of β-blocker toxicity is largely supportive. Induced emesis is contraindicated because of the risk of sudden cardiovascular collapse.170 Gastric lavage may help if the procedure is undertaken within 60 minutes of ingestion. Single-dose AC is recommended; there is no clear role for multidose AC.

Cardiovascular manifestations are treated with fluid resuscitation, vasopressors, atropine, electrical pacing, and glucagon. Glucagon effectively reverses myocardial depression and bradycardia. Its positive inotropic and chronotropic effect is mediated through adenyl cyclase, which increases cyclic adenosine monophosphate and intracellular calcium influx.172 Improvements in bradycardia and hypotension occur within a few minutes and may preclude the need for high-dose catecholamine infusion.173 Glucagon is given as bolus of 5 to 10 mg IV over 1 minute followed by an infusion of 1 to 10 mg/h. Dilution in saline or dextrose as opposed to the diluent provided by the manufacturer, which contains 2 mg of phenol per 1 mg of glucagon, is recommended to avoid phenol toxicity. The use of an insulin-glucose infusion for β-blocker toxicity may prove to be superior to glucagon alone; this strategy is under investigation.174

Calcium Channel Blockers

Calcium channel blockers (CCBs) selectively inhibit the movement of calcium ions through the membrane of cardiac and vascular smooth muscle during the slow inward phase of excitation-contraction. These agents have varying degrees of cardiovascular effects. Verapamil is more of a negative inotrope; nifedipine has more vasodilatory effects. Verapamil and diltiazem depress the sinus node and slow conduction through the atrioventricular node. The most common cardiovascular effect is hypotension, which generally occurs within 6 hours of CCB overdose (except with sustained-release preparations, in which toxicity may not be evident for 12 hours). Hypotension is mainly secondary to peripheral vasodilation as opposed to myocardial depression. Conduction abnormalities are worsened with concurrent β-blocker ingestion and existing cardiovascular disease.175 Nausea, vomiting, hyperglycemia, confusion, lethargy, and coma have all been attributed to CCB overdose. Seizures are uncommon.

Gastric lavage may be useful for up to 8 hours after ingestion of a sustained-release preparation. Whole bowel irrigation has similarly been used for sustained-release preparations.176 Multidose activated charcoal and hemodialysis are not indicated. However, charcoal hemoperfusion may have a role in verapamil overdose in the setting of hepatic dysfunction.177

Hypotension is treated first with fluids and vasopressors. For refractory hypotension, calcium chloride infusions (1 to 3 g by slow IV push) are recommended.6 Additional calcium infusions (by bolus or constant infusion) are warranted in patients who demonstrate a transient response to the initial calcium infusion. Calcium gluconate (2 to 3 g total or 0.2 to 0.5 mL/kg of a 10% solution every 15 to 20 minutes to a total of 4 doses) has also been recommended.178,179 Glucagon, given as a bolus of 5 to 10 mg IV over a minute followed by an infusion of 1 to 10 mg/h, may decrease vasopressor requirements.173,180 Recently, several investigators have reported successful reversal of refractory shock in CCB toxicity with hyperinsulinemia-euglycemia therapy by continuous infusion of insulin and glucose.181,182 Larger trials are needed to confirm its safety and efficacy.

Carbon Monoxide

Carbon monoxide (CO) is a nonirritating, colorless, tasteless, and odorless gas formed by incomplete combustion of carbon-containing materials (complete oxidation produces carbon dioxide). Poisoning occurs in the setting of smoke inhalation, attempted suicide from automobile exhaust, and poorly ventilated charcoal and gas stoves. Rarely, CO is generated during hepatic metabolism of dichloromethane, a component of paint and varnish removers. Carbon monoxide is a common cause of death by poisoning in the United States.183

Carbon monoxide binds to hemoglobin with an affinity that is 240 times greater than oxygen. Fetal hemoglobin binds carbon monoxide to an even greater degree, placing the fetus at particularly high risk during CO exposure. Carboxyhemoglobin (HbCO) decreases oxyhemoglobin saturation and blood oxygen-carrying capacity, in a way that is analogous to anemia (a HbCO concentration of 50% effectively lowers hemoglobin concentration by half). However, CO poisoning causes significantly more toxicity than similar degrees of anemia because in CO poisoning (1) HbCO shifts the oxyhemoglobin dissociation curve to the left, interfering with off-loading of oxygen in peripheral tissues; (2) CO reacts with myoglobin to form carboxymyoglobin; (3) CO blocks myoglobin-facilitated diffusion of oxygen (particularly in tissues rich in myoglobin), as well as myoglobin-mediated oxidative phosphorylation, resulting in impaired cardiac contractility; (4) CO inhibits enzymes of the mitochondrial electron-transfer chain, further interfering with cellular function; and (5) CO binds and inhibits various intracellular enzymes including cytochrome P-450 and NADPH reductase.184,185 Tissues with high oxygen consumption (namely, heart and brain) are particularly vulnerable to toxic effects.

The severity of CO poisoning depends on the concentration of CO, duration of exposure, and minute ventilation. Carboxyhemoglobin levels do not correlate well with clinical severity of CO poisoning. Generally, mild exposures (HbCO 5% to 10%) cause headache and mild dyspnea. These concentrations may be seen in heavy smokers and commuters on busy highways and are generally well tolerated, even in the presence of documented coronary artery disease and ventricular ectopy.186 Carboxyhemoglobin concentrations between 10% and 30% cause headache, dizziness, weakness, dyspnea, and irritability. These concentrations may cause angina and myocardial infarction even in young and otherwise healthy patients.187 Exposures to >50% HbCO result in coma, seizures, cardiovascular collapse, and death.

Ten to thirty percent of survivors of CO poisoning develop delayed neurologic sequelae (DNS) of hypoxic brain injury.188,189 Clinical manifestations of DNS are variable, including persistent vegetative state, parkinsonism, memory deficits, behavioral changes, and hearing loss. Neurologic sequelae cannot be predicted by severity of carboxyhemoglobin exposure, age, method of exposure (accidental or intentional), or results of early neuroimaging (which may be normal or show low-density lesions in the globus pallidus or deep white matter changes).190

The diagnosis of CO poisoning is often made on clinical grounds in the setting of smoke inhalation or attempted suicide. However, the diagnosis can be missed if the history is incomplete and the clinical presentation is nondescript. There should be a high index of suspicion, particularly during cold weather months in patients with myocardial ischemia/infarction, cardiac arrhythmias, mental status changes, headache, and generalized weakness. Rarely, cherry-red skin discoloration reflecting high venous saturation (arteriolization of venous blood) provides an additional clue. Failure to diagnose CO may have disastrous consequences for the patient and other members of an affected household.

Laboratory confirmation of elevated HbCO is available by co-oximetry. Pulse oximetry is unreliable in detecting HbCO because it cannot distinguish carboxyhemoglobin from oxyhemoglobin. Pulse oximetry overestimates oxyhemoglobin by the amount of HbCO present, and may be in the normal range despite high concentrations of HbCO.191 Arterial blood gases typically demonstrate a normal PO2, contrasting with low oxyhemoglobin saturation by co-oximeter, and metabolic acidosis. Of note, patients with suspected CO poisoning can be screened by analysis of venous blood because venous HbCO levels accurately predict arterial blood levels.192

Treatment of CO poisoning consists of immediate removal of the patient from the exposure and administration of 100% supplemental oxygen. Breathing 100% oxygen reduces the half-life of HbCO from 5 to 6 hours on room air to 40 to 90 minutes. Breathing oxygen that contains 4.5% to 4.8% carbon dioxide allows for a greater minute ventilation while maintaining normocapnia and further accelerates CO clearance. In one study of seven healthy volunteers, this method decreased the half-life of CO from 78 ± 24 minutes to 31 ± 6 minutes compared to 100% O2 at resting minute ventilation.193 Hyperbaric oxygen (HBO) (2.8 atmospheres) further decreases the half-life of HbCO to 15 to 30 minutes.

The role of HBO, which can result in arterial oxygen tensions greater than 2000 mm Hg and oxygen tensions in tissue approaching 400 mm Hg, is debated.194 Several nonrandomized studies have demonstrated that HBO improves acute and delayed effects of CO poisoning.195 One trial in 343 patients comparing HBO with 100% normobaric oxygen (NBO) delivered outside a hyperbaric chamber in patients without loss of consciousness showed no significant difference between groups in acute or delayed symptoms of CO poisoning.196 Another unblinded study comparing HBO with 100% NBO in 65 patients without loss of consciousness demonstrated significantly fewer patients with DNS in the HBO group (0% versus 23%).197 HBO has also been found to be beneficial in patients (n = 26) with loss of consciousness.198 Another study comparing HBO with 100% NBO delivered in a hyperbaric chamber (i.e., blinded) in CO-poisoned patients with and without loss of consciousness showed no difference in the development of delayed neurologic sequelae, and that “normal neuropsychologic and functional outcomes are possible after severe CO poisoning without the use of HBO therapy.”199 In a recent double-blind, randomized trial, patients (76 in each group) with symptomatic CO poisoning were assigned to three HBO sessions within 24 hours or one NBO treatment plus two sessions of normobaric room air. Cognitive sequelae were less frequent in the HBO group at 6 weeks and 12 months.200 In this study, the presence of cerebellar dysfunction before treatment was associated with the occurrence of cognitive sequelae.

Although the use of HBO remains controversial, we believe that patients with potentially life-threatening exposures should receive at least one HBO treatment (if hyperbaric capability is readily available). Particularly controversial is whether a patient with severe CO poisoning should be transferred solely for the purpose of HBO, a problem that may be solved by refinement of portable HBO chambers.201 Also controversial is the relative efficacy of single versus multiple HBO treatments.202,203 Since CO poisoning may occur with other life-threatening injuries (e.g., burns or other trauma), the judgment to utilize HBO must take into consideration the patient's stability and the ability to monitor and treat during HBO therapy.

Cocaine

Cocaine may be snorted nasally, inhaled orally, or used intravenously. Body packers swallow multiple wrapped packages of cocaine in an attempt to smuggle the drug across national borders; body stuffers swallow or conceal wrapped packets of cocaine in various body cavities when law enforcement agents approach. Freebase cocaine is prepared for smoking by dissolving cocaine salt in an aqueous alkaline salt solution and then extracting the freebase form with a solvent such as ether. Heat is often used to speed this process, creating a fire hazard. The preferred freebase preparation for smoking is crack cocaine, which is a more potent, rapidly absorbed, water-soluble alkaloid form of the drug.

Cocaine is often mixed with other substances of abuse including heroin (“speedball”), phencyclidine, and various sympathomimetic drugs used to treat nasal congestion.204 In the presence of ethanol, cocaine is transesterified in the liver to cocaethylene, which has similar properties to cocaine but a longer half-life. Cocaethylene is a myocardial depressant capable of reducing stroke volume and arterial pressure while increasing pulmonary artery wedge pressure. Cocaethylene also prolongs QRS and QTc intervals.205 Individuals combine cocaine and ethanol to achieve a more pronounced and prolonged euphoria, but this combination is more toxic than either drug alone.

Toxic effects of cocaine stem from excessive central nervous system stimulation and inhibition of neuronal uptake of catecholamines. The result is generalized sympathetic overstimulation similar to that of amphetamine intoxication. Onset and duration of symptoms depend on route of administration, dose, and patient tolerance. Smoking and intravenous use produce symptoms within 1 to 2 minutes; oral use delays onset of symptoms by 20 to 30 minutes. The half-life of cocaine is approximately 60 minutes.

Common central nervous system manifestations include euphoria, anxiety, agitation, psychosis, and delirium. Rarely, cocaine-induced ischemic cerebral infarction is mistaken for a psychiatric condition.206 Seizures are generally short-lived and self-limited unless there is ongoing drug absorption (as in body packers or body stuffers) or other central nervous system pathology. Several mechanisms are likely responsible for more serious central nervous system complications. A sudden rise in systemic arterial pressure may cause intracerebral hemorrhage and subarachnoid hemorrhage,207 particularly in association with an underlying aneurysm or arteriovenous malformation. Vasospasm, vasculitis, myocardial infarction with cardiac arrhythmias, and increased platelet aggregation may further trigger ischemic events.208 Benign angiopathy of the CNS has also been reported.209 In most cases, the time interval between drug abuse and the cerebrovascular event is less than 3 hours.210

Cardiovascular manifestations of cocaine abuse include chest pain, myocardial ischemia and infarction, sudden death, arrhythmias, congestive heart failure, pulmonary hypertension, endocarditis, and aortic dissection.211–214,144 Common findings include a significant increase in heart rate and mean arterial blood pressure consistent with sympathetic stimulation combined with a fall in ejection fraction as determined by two-dimensional echocardiography.215 The pathogenesis of these cardiovascular complications has not been fully explained, but may be related to a combination of the sympathomimetic and membrane effects (sodium and potassium channel blockade) of cocaine.

The mechanism by which cocaine induces myocardial ischemia remains controversial. Most prior studies have postulated that cocaine-induced coronary vasoconstriction limits myocardial oxygen. Platelet aggregation and increased myocardial oxygen requirements may fuel the imbalance between supply and demand. Asymptomatic cocaine abusers have been reported to have left ventricular hypertrophy, segmental wall motion abnormalities, ST-T wave changes, pathologic Q waves, and increased QRS voltage on electrocardiogram.216

Baseline electrocardiographic changes complicate decisions regarding the need to hospitalize patients with cocaine-associated chest pain. Studies have yielded conflicting data regarding the incidence of myocardial infarction in cocaine abusers, and there are no clinical parameters that reliably identify patients at very low risk for myocardial infarction. These considerations mandate that all patients with cocaine-associated chest pain are evaluated for myocardial infarction.217 Furthermore, cocaine-related mental status changes may interfere with patient reporting of cocaine-associated chest pain.218

Patients with cocaine-associated chest pain often continue to use cocaine after discharge. Cardiac stress tests or cardiac angiography may not be necessary for patients in whom myocardial infarction has been ruled out and who do not continue to have chest pain; such patients appear to have a low risk for subsequent myocardial infarction and death. Instead, efforts should emphasize cessation of cocaine abuse.219

Respiratory complications of cocaine include status asthmaticus,220 upper airway obstruction (stridor),221 pulmonary hypertension,222 barotrauma, pulmonary edema, and alveolar hemorrhage.223 Not uncommonly, crack cocaine causes an acute pulmonary syndrome characterized by dyspnea, diffuse infiltrates, and hemoptysis.224 The severity of respiratory complications ranges from mild dyspnea to severe respiratory failure requiring intubation and mechanical ventilation.

Another severe manifestation of cocaine abuse is rhabdomyolysis.225 Creatine kinase levels are often over 10,000 U/L on presentation, with values reported as high as 85,000 U/L.226 There is often concurrent hyperthermia, tachycardia, muscle rigidity, disseminated intravascular coagulation, hepatic dysfunction, and renal failure.225,226 Cocaine also has a direct toxic effect on muscles.

Cocaine-induced hyperthermia resembles neuroleptic malignant syndrome;227 both are characterized by a decrease in the number of dopamine receptors or depletion of dopamine. Contributors to hyperthermia include agitation and adrenergic stimulation causing vasoconstriction.

Rare cocaine-associated complications include ischemic colitis,228 renal infarction,229 nasal septal perforation, and localized areas of skin necrosis due to accidental subcutaneous injection. Intranasal use of cocaine has been associated with sinusitis and botulism;230 botulism also occurs with skin wounds.231 In addition, the behavioral effects of cocaine increase the likelihood of violent fatal injuries.232

Treatment of cocaine intoxication starts with the ABCDs of resuscitation and treatment of seizures, hyperthermia, and agitation. For orally ingested drug, AC should be given to decrease drug absorption. Gastric lavage and ipecac-induced vomiting are not recommended because of the risk of seizures and subsequent aspiration. In body packers whole bowel irrigation with a polyethylene glycol electrolyte solution (e.g., GoLYTELY) 1 to 2 L/h is recommended until the rectal effluent clears and there is no radiographic evidence of retained drug condoms (Fig. 102-2).233 For this purpose, abdominal ultrasound, a CT scan with contrast or a small bowel follow-through contrast study is more sensitive and specific than routine abdominal radiographs.234 Contraindications to whole-bowel irrigation include ileus, gastrointestinal hemorrhage, and bowel perforation. Polyethylene glycol electrolyte solutions may also displace cocaine from AC.235 Surgical removal of retained packages may be required, particularly if there is bowel obstruction or package perforation.236 Endoscopic approaches risk packet rupture and are not recommended. Neither dialysis nor hemoperfusion effectively removes cocaine.

Perhaps the most important treatment strategy in cocaine intoxication is rapid treatment of agitation and hyperthermia. Along these lines, patient cooling, benzodiazepines, and occasionally muscle relaxation improve outcome,237 although there are concerns that benzodiazepines may enhance cocaine-induced hyperactivity.238 For purposes of patient sedation, haloperidol has not been shown to be of benefit,237 and few data are available regarding a possible role for barbiturates.

First-line treatments of cocaine-associated chest pain are nitrates and benzodiazepines.2,6,239,240 Use of an α-adrenergic receptor blocker such as phentolamine is recommended in patients refractory to nitrates and benzodiazepines.6,241 Nonselective β-blockers should not be used alone to treat cocaine toxicity because of the potential for unopposed α-adrenergic stimulation and potentiation of coronary vasoconstriction.242 Propranolol worsens outcome in an animal model;243 esmolol produces an inconsistent antihypertensive response and may cause hypertension or hypotension.244 The use of labetalol is controversial.6 Labetalol blocks both α- and β-adrenergic receptors and may reverse cocaine-induced hypertension, but there are data that show that it is ineffective in cocaine-induced coronary vasoconstriction.245

The role of thrombolytic therapy remains unclear in patients with cocaine-associated acute myocardial infarction. Intracoronary administration of thrombolytics has been recommended over peripheral administration in refractory cases, but further studies addressing safety and efficacy are needed before firm recommendations can be made.6,246 Thrombolytics are contraindicated in uncontrolled hypertension, aortic dissection, and intracerebral hemorrhage.

Treatment of respiratory complications is supportive. Oxygen is delivered to improve arterial oxygen saturation; continuous positive airway pressure or positive end-expiratory pressure may decrease intrapulmonary shunting in patients with diffuse lung disease. Inhaled bronchodilators and corticosteroids are indicated for cocaine-associated bronchospasm. Tube thoracostomy may be required for pneumothorax; pneumomediastinum is watched expectantly.

Cyanide

Cyanide is found in a variety of synthetic and natural substances: plastics, glue removers, wool, silks, nylons, and various seeds and plants. Poisoning occurs through a number of mechanisms including (1) ingestion (e.g., the cassavabased foodstuff “gari”247 or tainted over-the-counter preparations248); (2) inhalation of hydrogen cyanide gas (HCN), a combustion by-product of cyanide-containing products; (3) sodium nitroprusside infusion; and very rarely (4) absorption of cyanide-containing solutions or gas through skin.

Cyanide is a rapidly-acting poison that binds to cellular cytochrome oxidase and interferes with aerobic oxygen utilization. Once ingested, it is detoxified by enzymatic conversion to the less toxic, renally excreted metabolite thiocyanate. The most important enzyme for cyanide conversion is rhodenase (a sulfur transferase), which forms thiocyanate in the presence of sulfane sulfur. This reaction occurs in liver, although the kidney also contains high concentrations of rhodenase. Serum albumin plays an important role in cyanide detoxification because it is a readily available source of sulfane sulfur and it has sulfurtransferase activity. A small amount of cyanide is also detoxified by the vitamin B12 precursor hydroxycobalamin. This agent binds cyanide to form nontoxic cyanocobalamin.

Clinical manifestations of cyanide poisoning depend upon the amount and rate of cyanide absorption. Patients who are asymptomatic after inhalation (which is associated with immediate absorption) do not require treatment and can be discharged after a short period of observation. Patients who ingest cyanide orally may present with progressive symptoms over minutes to hours. Oral ingestion on an empty stomach with low pH results in the rapid generation of HCN from potassium and sodium salts (KCN and NaCN). Oral ingestion into a full and alkaline stomach delays generation of HCN, resulting in progressive symptoms over 1 to 2 hours. Ingestion of plants containing cyanogenic glycosides also causes delayed and progressive toxicity.

At low concentrations, cyanide acts as a respiratory and central nervous system stimulant. Clinical manifestations include anxiety, dyspnea, headache, confusion, tachycardia, and hypertension. At higher concentrations, patients may develop stupor or coma, seizures, fixed and dilated pupils, hypoventilation, hypotension, bradycardia, heart block and ventricular arrhythmias. Patients with massive ingestion present in coma and cardiopulmonary collapse. Survival in these cases depends on the success of cardiopulmonary resuscitation, with survivors at great risk of permanent sequelae of anoxic brain injury.249,250

The diagnosis of cyanide poisoning is usually made on clinical grounds, often in the setting of smoke inhalation injury, where combined carbon monoxide and cyanide toxicity occurs. Highly suggestive is the rapid onset of coma, seizures, and cardiopulmonary dysfunction. Lactic acidosis and an elevated mixed venous oxyhemoglobin saturation provide evidence for the blocking of aerobic oxygen utilization.251 Elevated venous oxyhemoglobin is further demonstrated by arteriolization of retinal veins on funduscopic examination or venous blood on venipuncture. The bitter almond scent of HCN may also be detected.

Short-term high-dose sodium nitroprusside therapy (>10 μg/kg per minute) may result in acute cyanide poisoning characterized by anxiety, agitation, tachycardia, myocardial ischemia, metabolic acidosis, hyperventilation, seizures, and paradoxical hypertension (or difficulty in lowering blood pressure). Cyanide poisoning is uncommon at nitroprusside infusion rates less than 10 μg/kg per minute; however, toxicity has been reported at an infusion rate of 4 μg/kg per minute after 3 hours of therapy.252 Prolonged nitroprusside infusion increases the risk of thiocyanate toxicity. Thiocyanate levels should be followed in these cases, particularly when there is renal dysfunction. Thiocyanate levels greater than 50 to 100 mg/L cause confusion, somnolence, and seizures.252

When clinical features of cyanide poisoning are present, treatment should proceed before confirmation of the diagnosis by determination of whole blood cyanide levels. The laboratory should be notified prior to drawing the blood, since special instructions may be required to measure this unstable compound. Whole blood levels greater than 0.5 to 1.0 mg/L are considered toxic.253 Smokers may have cyanide levels nearing 0.1 mg/mL.

Treatment begins by identifying and treating life-threatening problems. Survival depends on prompt and successful CPR.254 Oxygen therapy at 100% fraction of inspired oxygen (FiO2) is effective in cyanide poisoning and should be administered immediately.255–258 Hyperbaric oxygen is of unproven benefit in cyanide poisoning (in part because of the time element involved).259

Several antidotes are available to treat cyanide poisoning. Amyl and sodium nitrite induce formation of methemoglobin. Cyanide has a high affinity for the ferric iron contained in methemoglobin, thereby rendering methemoglobin an effective scavenger of unbound cyanide. Amyl nitrite is administered by inhalation of crushable ampules. Ampules are inhaled for 15 to 30 seconds; effects last approximately 2 to 3 minutes. This therapy can be used in spontaneously breathing patients and in patients receiving ventilatory support by face mask or endotracheal tube until administration of sodium nitrite. Sodium nitrite is administered intravenously at a dose of 300 mg over 3 minutes to convert hemoglobin to methemoglobin. Half this dose may be repeated after 2 hours if there is persistent toxicity and a tolerable degree of methemoglobinemia. Conversion of 25% to 30% of hemoglobin to methemoglobin effectively treats cyanide poisoning,260 although in usual practice, methemoglobin levels generally remain less than 20%.261 Induction of methemoglobinemia of course has several disadvantages, including the reduction of circulating hemoglobin available for oxygen transport (which may be further aggravated by concurrent carboxyhemoglobinemia in the setting of smoke inhalation) and the risk of hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient patients.262 In one study evaluating serial cyanide, methemoglobin, and carbon monoxide levels in seven critically ill smoke inhalation patients receiving sodium nitrite, peak measured methemoglobin levels did not occur until a mean of 50 minutes following administration of sodium nitrite.261 The total oxygen-carrying capacity reduced by the combination of carboxyhemoglobin and methemoglobin was never more than 21% (range = 10% to 21%). Of note, methylene blue should be avoided to treat methemoglobinemia because it will release free cyanide.

Sodium thiosulfate is safe and effective in cyanide poisoning. It acts as a sulfur donor to rhodenase and other sulfurtransferases thereby enhancing conversion of cyanide to thiocyanate.263,264 The dose is 12.5 g IV (50 mL of a 25% solution) over 10 minutes. Half this dose may be repeated in 2 hours for persistent toxicity. Coadministration of thiosulfate with nitroprusside (in a ratio of 1:10 thiosulfate to nitroprusside) effectively eliminates the possibility of cyanide intoxication without altering the efficacy of nitroprusside.265 Treatment with sodium thiosulfate can cause thiocyanate toxicity, particularly in the setting of renal insufficiency. Fortunately, thiocyanate is readily dialyzable.

Hydroxycobalamin is a cyanide antidote capable of reducing red blood cell and plasma cyanide concentrations. Little is known, however, about the safety, efficacy, and pharmacokinetics of hydroxycobalamin in human cyanide poisoning. Acute allergic reactions have been reported,266 and hydroxycobalamin may interfere with several chemistry methodologies affecting measurement of aspartate aminotransferase, total bilirubin, creatinine, magnesium, and iron.267 In healthy adult smokers, hydroxycobalamin 5 g IV resulted in transient reddish discoloration of skin, mucous membranes, and urine, slight elevation in blood pressure, and a decrease in heart rate.268 It did, however, decrease whole blood cyanide levels by 59% and increase urinary cyanide excretion. As with thiosulfate, coadministration of hydroxycobalamin (25 mg/h IV) with nitroprusside may protect against nitroprusside-induced cyanide toxicity.269,270 The currently recommended dose of hydroxycobalamin in acute cyanide poisoning is 4 to 5 g IV administered as a one-time dose.270–272

Intravenous dicobalt ethylenediamine tetraacetic acid (EDTA) is a potent cyanide antidote. When cyanide binds to cobalt a stable and nontoxic compound is formed. The initial dose is 300 to 600 mg IV over 1 minute, followed by an additional 300 mg if the patient fails to improve. Side effects from EDTA include cardiac arrhythmias, hypotension, nausea, vomiting, and severe allergic reactions.273

Additional treatment strategies include removal and isolation of all contaminated clothing. Health care workers should avoid contact with cyanide-containing solutions and vapors. Gastric emptying is recommended for acute ingestions, followed by AC. Induced emesis is not recommended because of the risk of rapid cyanide-induced deterioration in clinical status (and subsequent risk of aspiration). There is no role for hemodialysis or hemoperfusion except to clear high levels of thiocyanate.

Cyclic Antidepressants

Cyclic antidepressant drugs (including the tricyclics, tetracyclics, bicyclics, and monocyclics) are among the most commonly encountered causes of self-poisoning.2 Tricyclic antidepressants include amitriptyline, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and amoxapine. In overdose, these drugs primarily affect the central nervous and cardiovascular systems. Lesser effects are seen in the gastrointestinal tract. Central nervous system toxicity results from anticholinergic effects and inhibition of neural reuptake of norepinephrine or serotonin. Cardiovascular manifestations stem from anticholinergic effects, inhibition of neural uptake of norepinephrine or serotonin, peripheral α-adrenergic blockade, and membrane depressant effects. Most patients develop symptoms within the first 6 hours after ingestion or not at all.

Clinical presentation is divided into anticholingeric effects, cardiovascular effects, and seizures. Mydriasis, blurred vision, fever, dry skin and mucous membranes, lethargy, delirium, coma, tachycardia, ileus, myoclonus, and urinary retention are manifestations of anticholinergic toxicity. These symptoms are described by the common mnemonic: “hot as a hare, dry as a bone, red as a beet, mad as a hatter.”

Cardiovascular effects consist of sinus tachycardia with prolongation of the QRS, QTc, and PR intervals. Occasionally, sinus tachycardia with QRS prolongation is difficult to distinguish from ventricular tachycardia. Torsades de pointes is rare. Various forms of atrioventricular block may accompany cyclic antidepressant overdose. Right bundle-branch block is common.

A maximal limb-lead QRS interval longer than 0.10 second reliably predicts serious intoxication (except in cases of amoxapine overdose) requiring monitoring until resolution.274 QRS duration <0.1 second is rarely associated with arrhythmias or seizures. Patients with QRS >0.10 second are at risk for seizures and arrhythmias. In one prospective trial seizures occurred at any QRS duration ≥0.10 second, but ventricular arrhythmias were seen only with a QRS duration ≥0.16 second.274 Serum drug levels in this study did not predict complications.

Hypotension is relatively common (although hypertension also occurs). It results from venodilation and decreased myocardial contractility. In severe cyclic antidepressant overdose, hypotension may be refractory to fluid administration and vasopressors and associated with pulmonary edema.

Seizures are common in cyclic antidepressant overdose. They may be short-lived and self-limited or prolonged and refractory to treatment. Neurologic deterioration may be abrupt and unpredictable. A “downward spiral” occurs when seizures or arrhythmias cause metabolic acidosis. Metabolic acidosis increases the fraction of free drug and enhances drug toxicity.

The diagnosis of cyclic antidepressant overdose depends on a history of ingestion or a high index of suspicion and compatible clinical features. Cyclic antidepressant overdose should be considered in all patients with QRS prolongation. Confirmation of cyclic antidepressant exposure is rapidly available by urine toxicology screening.

Treatment of cyclic antidepressant overdose starts with identifying and treating life-threatening problems. Sodium bicarbonate (1 to 2 mEq/kg IV) is indicated if there is widening of the QRS interval to decrease the fraction of free drug. Sodium bicarbonate should be continued until there is narrowing of the QRS interval or serum pH exceeds 7.5 to 7.55. In intubated patients, hyperventilation can achieve the same target pH, but hypertonic sodium usually provides greater benefit.6 The electrocardiogram (ECG) should be followed closely in all cases for 48 to 72 hours.275 In general patients should remain in an ICU for 12 hours after discontinuation of all therapy and be asymptomatic with a normal ECG and pH before transfer.276,276a

Lidocaine is the drug of choice when ventricular arrhythmias are refractory to sodium bicarbonate.6 Class 1a antiarrhythmics (e.g., procainamide) are contraindicated in cyclic antidepressant overdose because of added cardiac toxicity. Anecdotal reports have also suggested a primary role for phenytoin; however, convincing data are not available to support the use of phenytoin in the setting of cyclic antidepressants as either a prophylactic or therapeutic drug. Physostigmine should not be used in cyclic antidepressant overdose because of possible worsening of cardiac conduction disturbances.

Hypotension refractory to sodium bicarbonate should be treated with vasopressors. A pulmonary artery catheter rarely helps direct therapy and may be arrhythmogenic. Norepinephrine and phenylephrine are the preferred vasopressors because cyclic antidepressants deplete presynaptic catecholamine stores, limiting the effectiveness of dopamine. Dopamine and other vasopressors may cause an exaggerated vasopressor response in the presence of cyclic antidepressants because of inhibition of catecholamine reuptake. An enhanced hypertensive response to phenylephrine can be also seen in anticholinergic overdose because anticholinergics interfere with phenylephrine-induced reflex bradycardia.

Seizures should be treated with intravenous diazepam or lorazepam. Phenytoin may be administered cautiously in refractory cases. Paralysis may be indicated when seizures are refractory (as may be seen in amoxapine overdose) to control temperature and muscle breakdown. After paralysis, an EEG monitor should be placed to guide subsequent therapy.

Because delayed gastric emptying is extremely common, gastric lavage may be considered during the first 12 hours after a large ingestion. Syrup of ipecac is contraindicated in cyclic antidepressant overdose because patients may suddenly seize or develop a lethal arrhythmia at any time after dosing. Single-dose AC is effective, although anticholinergic-induced ileus increases risk of charcoal-induced bowel obstruction. Because these drugs are lipid-soluble and protein-bound, dialysis and hemoperfusion are not effective.

Gamma-Hydroxybutyrate

Gamma-hydroxybutyrate (GHB), also known as “liquid ecstasy,” “liquid G,” “date-rape drug,” or “fantasy,” has become a popular drug of abuse among young individuals. In the 1980s, the drug was promoted to bodybuilders as a growth hormone stimulator and muscle-bulking agent. Recreationally, it was claimed to cause euphoria without a hangover and to increase sensuality and disinhibition. In 1990 GHB was banned outside of clinical trials approved by the FDA. However, products such as Revivarant, containing a precursor of GHB (gamma-butyrolactone), continued to be available until a recent ban by the federal government.277,278

GHB is derived from γ-aminobutyric acid (GABA) and is thought to function as an inhibitory transmitter through specific brain receptors for GHB and possibly through GABA receptors.279 GHB increases stage IV of non–rapid eye movement sleep (slow-wave deep sleep).280 In narcoleptics it decreases cataplexy, sleep paralysis, hallucinations, and daytime sleep attacks.281 Clinical manifestations of GHB depend on the dose ingested. Regular use causes tolerance and dependence, and abrupt discontinuation can result in delirium and psychosis.282 Low doses of GHB can induce a state of euphoria. Higher doses can cause coma and death.283 Emesis, bradycardia, hypotension, and respiratory acidosis have all been described.284

Treatment of GHB poisoning is mainly supportive. It is important to keep in mind that coingestions are common, especially with ethanol and amphetamines.284 Mechanical ventilation may be required for brief periods, as most patients regain consciousness spontaneously within 5 hours.284

Yates and Viera have described two patients with GHB overdose who awoke in less than 5 minutes after a single dose of physostigmine.285 Whether physostigmine will prove to be useful in this setting is unclear since rapid recovery is the norm and there are risks in its use, particularly when there is coingestion of a cyclic antidepressant.

Normal toxicologic screens do not include GHB. However, when documentation is important in cases of sexual assault, GHB can be detected in urine and blood by special laboratories using gas chromatography-mass spectroscopy.286,287 GHB can also be detected by hair analysis.288

Digoxin

Digitalis is a cardiac glycoside clinically used for treatment of systolic myocardial dysfunction and supraventricular arrhythmias. Two formulations are commercially available: digoxin and digitoxin. These compounds differ importantly in their routes of metabolism: digoxin depends upon renal excretion (60% to 70% unchanged, including filtration and some tubular secretion), whereas digitoxin is hepatically metabolized (to form renally excreted metabolites, including digoxin). They share the important property of prolonged half-life (42 hours for digoxin, 7 days for digitoxin). Digoxin is extensively tissue bound (mostly in muscle), resulting in a massive apparent volume of distribution (4 to 7 L/kg). Digoxin intoxication may occur accidentally during chronic therapy. Diminished clearance because of renal insufficiency, which often increases half-life to 80 to 180 hours, is the most common precipitant of such episodes. Drug interactions may also elevate digoxin levels by impairing renal excretion (e.g., verapamil, other calcium channel blockers, quinidine, or cyclosporine) or hepatic biotransformation (e.g., cyclosporine, verapamil, other calcium channel blockers, or amiodarone), or decreasing digoxin tissue binding and Vd (e.g., quinidine). Finally, increased oral bioavailability because of antibiotic-induced sterilization of digoxin-metabolizing gut flora may also precipitate digoxin toxicity.289 Variability between digoxin preparations is no longer a major problem.290 Digitalis may also be ingested in toxic amounts as an unsuspected component of herbal preparations291 or as a deliberate self-overdose.

The clinical manifestations of digitalis intoxication include fatigue, gastrointestinal symptoms (anorexia, nausea, vomiting, diarrhea, and abdominal pain), neurologic disturbances (blurred vision, visual color changes, headache, dizziness, and delirium), and cardiac arrhythmias (including any category, classically supraventricular tachycardia with AV block). Massive digoxin overdose also causes hyperkalemia, because of inhibition of cellular Na-K-ATPase function. Plasma digoxin levels correlate generally with therapeutic and toxic effects, but interindividual variability in response to a particular digoxin level is common.292–294 In addition, several factors aside from excess total body digoxin can precipitate digitalis toxicity, even in the therapeutic range, by increasing myocardial digitalis sensitivity. Such factors include hypokalemia, hypomagnesemia, myocardial disease, old age, hypothyroidism, and a variety of other metabolic disturbances (hypoxemia, acid-base abnormalities, hypercalcemia, and hypernatremia). More commonly, digitalis intoxication during chronic therapy results from renal insufficiency or drug interactions (see above).

To be most informative, a digoxin level should be taken when steady-state conditions are in effect. This occurs after approximately 1 week when renal function is normal. The timing of blood sampling is also crucial. To allow time for distribution a sample should be obtained at least 6 hours after the last dose. Based on data demonstrating benefit of low serum digoxin concentrations in heart failure,295 many laboratories have lowered the therapeutic range for digoxin to 0.5 to 1.0 ng/mL.

Supportive therapy of overdose includes rapid correction of arrhythmogenic metabolic disturbances, particularly hypokalemia. As noted above, hyperkalemia may also require treatment unless Fab therapy is immediately available. Severe bradyarrhythmias that are unresponsive to atropine may require electrical pacing. Ventricular tachycardia should be treated with lidocaine or phenytoin. Electrical cardioversion of any digitalis toxicity–induced arrhythmia should be reserved as a last resort, using the minimum effective energy level.

Gastrointestinal decontamination measures should include emesis or lavage and should be followed by activated charcoal. Charcoal doses may be repeated to minimize enterohepatic recirculation of active digitalis metabolites; orally administered cholestyramine has also been used for this purpose. Timely elimination of digoxin may be difficult to achieve in the face of significant renal insufficiency. Hemodialysis or hemoperfusion can remove only small amounts of total body digitalis (because of extensive tissue binding), but HD may still be indicated for correction of hyperkalemia or other acid-base derangements in renally impaired patients. Fortunately, immunotherapy with digoxin-specific antibody Fab fragments is widely available. These sheep-derived antibodies bind intravascular digoxin, also competitively removing digoxin bound to cellular Na-K-ATPase sites.296–298 Indications and protocol for Fab therapy are contained in Table 102-24.

Following intravenous administration, plasma free digoxin levels and toxic effects (hyperkalemia and arrhythmia) decrease almost immediately, and the Fab fragments and bound digoxin are eliminated by glomerular filtration (Fab molecular weight is 50,000 Da). Standard digoxin levels can be misleading after treatment. Fab fragments have also been successfully used to treat digoxin toxicity in patients with renal insufficiency, including chronic hemodialysis patients; the potential late complication of rebound intoxication because of impaired Fab-digoxin complex excretion is not commonly seen even in such circumstances.299 Nevertheless, monitoring of free (rather than total) plasma digoxin levels, and consideration of follow-up plasmapheresis to remove Fab-digoxin complexes has been advocated to prevent late rebound toxicity in renal failure patients.300

Lithium

Lithium (Li) is used for treatment of bipolar affective disorders. Chronic use is associated with development of nephrogenic diabetes insipidus, renal insufficiency, hypothyroidism, and leukocytosis. Lithium has a low therapeutic index (target range = 0.5 to 1.25 mEq/L). Most cases of intoxication, associated with levels above 1.5 mEq/L, are caused by unintentional overdose during chronic therapy. Volume depletion (aggravated by underlying diabetes insipidus) and renal insufficiency are the common precipitants of lithium overdose. Li is a low-molecular-weight monovalent cation (7 Da), has a small volume of distribution (0.66 L/kg), and is eliminated by glomerular filtration. Li has a prolonged elimination half-life that is increased by advancing age, renal insufficiency, and duration of therapy: 18 hours in adults with normal renal function; up to 36 hours in the elderly; and increased up to twofold in chronically treated subjects.301 Lithium is predominantly (80%) reabsorbed in the proximal renal tubule, and the other 20% of filtered load is excreted. Any stimulus which augments proximal tubular sodium reabsorption tends to cause increased Li reabsorption in parallel and may precipitate Li intoxication; volume depletion, congestive heart failure, cirrhosis, and other salt-avid states all reduce Li clearance in this manner, independently of effects on glomerular filtration rate. Deliberate acute lithium overdose by ingestion with suicidal intent also commonly occurs.302

Serum levels following acute Li ingestion correlate poorly with intracellular Li levels and clinical symptoms. A closer correlation exists between serum levels and clinical symptoms in chronic and acute-on-chronic intoxications. Thus severe toxicity may occur at lower serum levels in the setting of chronic Li ingestion than following acute ingestion without previous use.

Clinical manifestations of overdose are primarily neurologic. Clinical features of mild (1.5 to 2.5 mEq/L) and moderate (2.5 to 3.5 mEq/L) intoxication include nausea, vomiting, diarrhea, weakness, and neurologic dysfunction (confusion, tremor, nystagmus, dysarthria, ataxia, and other signs of cerebellar dysfunction), and choreiform and Parkinsonian movements reflecting basal ganglia involvement. Severe toxicity (>3.5 mEq/L) is characterized by worsening neurologic dysfunction (seizures and coma) and cardiovascular instability (sinus bradycardia and hypotension). Decreased serum anion gap (<6 mEq/L, because of excess cation) is an interesting consequence of severely elevated (>3.5 mEq/L) Li levels. Both hypothermia and hyperthermia have been reported to occur in Li-intoxicated patients. Acute overdose has a 25% mortality, and 10% of survivors have permanent neurologic deficits.

Treatment of Li intoxication is guided by a combination of clinical features and serum levels. Supportive care includes seizure control and use of vasopressors for hypotension refractory to fluids. Gastrointestinal decontamination following excessive lithium ingestion is the subject of a number of in vitro and animal research projects and is particularly important because sustained-release preparations are usually involved. Induction of emesis or gastric lavage should be performed initially. Oral activated charcoal is ineffective in preventing Li absorption, because it adsorbs Li poorly.303–305 However, it is not harmful in this setting, and should be administered to limit absorption of other potential ingested poisons. Animal and in vitro studies suggest that oral sodium polystyrene sulfonate (Kayexalate) impairs absorption of ingested Li,304 and that a form of gastrointestinal dialysis using multiple doses also lowers serum Li levels, but this therapy is unproven in human subjects.306 Polyethylene glycol whole bowel irrigation has also been used to limit absorption of an acute overdose of sustained-release lithium in normal volunteers.307 Elimination of Li is enhanced by volume loading (with normal saline) of hypovolemic patients, but this therapy has limited efficacy after normovolemia has been restored and risks precipitating hypernatremia in the presence of excessive ongoing water losses because of underlying diabetes insipidus. Lithium is the prototypical dialyzable intoxicant, owing to its hydrophilicity, low molecular weight, complete absence of protein binding, small apparent volume of distribution (0.66 L/kg, reflecting distribution in the total body water space), and prolonged half-life.

HD indications include: (1) Serum level >4 mEq/L; (2) serum level >2.5 mEq/L with symptoms or renal insufficiency (the latter making timely endogenous clearance unlikely); (3) serum level <2.5 mEq/L but following a large ingestion, so that rising levels are anticipated; (4) serum level <2.5 mEq/L if levels not anticipated to be <0.6 mEq/L at 36 hours after ingestion (this assessment is made by plotting three or more 2-hourly Li levels on a log-linear scale to estimate half-life). HD (clearance 70 to 170 mL/min) is preferred to peritoneal dialysis (clearance 15 mL/min, compared to 10 to 40 mL/min by renal excretion in normal subjects).301,302,308 Rebound increase of serum levels often occurs several hours after dialysis; this phenomenon is mostly attributable to slow extracellular transfer of intracellular lithium,301,309 although delayed absorption from slow-release preparations may also be contributory.310 Prolonged dialysis (8 to 12 hours) with a large surface area dialyzer is generally performed initially, with repetition as needed for levels in excess of 1.0 at 6 to 8 hours after treatment. Alternatively, there are advocates of the use of continuous arteriovenous or venovenous hemofiltration/hemodialysis (14 to 44 hours) to attain both dialytic clearance of extracellular Li and effective mobilization and removal of intracellular stores,95,96 but the obtained clearances of 20.5 to 62 mL/min (highest with continuous venovenous hemodialysis) were inferior to reported results with standard HD. Rebound of serum Li levels was prevented by prolonged therapy in the latter report,96 even in chronic intoxications, suggesting some utility in such cases. Acute hemodialysis followed by a period of continuous venovenous hemodialysis to prevent rebound is a potentially useful combination approach.

Methemoglobinemia

Reduced (Fe2+) hemoglobin (ferrihemoglobin) is capable of binding oxygen; oxidized (Fe3+) hemoglobin (methemoglobin or ferrihemoglobin) is not. In health, a small amount of methemoglobin is formed by auto-oxidation of circulating red blood cells continuously exposed to high concentrations of oxygen. Reduced cytochrome b5 reacts with circulating methemoglobin to restore hemoglobin and oxidized cytochrome b5. The red cell enzyme NADH-cytochrome b5 reductase (methemoglobin reductase) is responsible for regenerating reduced cytochrome b5, thereby ensuring insignificant concentrations of methemoglobin in circulating blood.311

Hereditary methemoglobinemia develops when circulating methemoglobin cannot be reduced (e.g., hemoglobin M) or there is a deficiency in red cell cytochrome b5 reductase. These hereditary conditions are of little clinical significance and usually do not require treatment, although individuals with cytochrome b5 reductase deficiency and G6PD deficiency are at increased risk of developing acquired methemoglobinemia. Acquired methemoglobinemia, which can be life threatening, occurs in the setting of oxidant drugs or toxin exposure (Table 102-25). Many of these drugs, such as commonly used analgesics, sulfonamides, sulfones, and local anesthetics, are derivatives of aniline, originally called “blue oil” which may beget “blue people” (those with methemoglobinemia).312 Aniline drugs, particularly if taken in combination, are the most common cause of methemoglobinemia today.312

Methemoglobinemia decreases oxyhemoglobin saturation and blood carrying capacity in a way that is analogous to carbon monoxide poisoning. Not only does 50% methemoglobinemia effectively decrease hemoglobin concentration by half, methemoglobinemia also shifts the oxyhemoglobin dissociation curve to the left, thereby interfering with off-loading of oxygen in peripheral tissues. In mild methemoglobinemia (<15% of the total hemoglobin) patients generally remain asymptomatic despite exam evidence of cyanosis. One possible exception is the patient with critical coronary artery disease, who may develop angina or myocardial infarction in the presence of mild functional anemia. Higher methemoglobin concentrations result in dyspnea, headache, and weakness. Severe methemoglobinemia (>60%) causes confusion, seizures, and death.

Laboratory confirmation of elevated methemoglobin is available by co-oximetry, which directly measures oxygen saturation and methemoglobin saturation. Of note, the antidote methylene blue (see below) causes falsely elevated methemoglobin levels by co-oximetry (a dose of 2 mg/kg methylene blue gives a falsely elevated methemoglobin level of 15%).313 Pulse oximetry is unreliable in patients with methemoglobinemia. Pulse oximeter saturation may fall, but it is falsely high in patients with methemoglobinemia and falsely low after methylene blue.314–316 Another clue is the finding of chocolate-colored venous blood.317

Treatment of methemoglobinemia starts with supportive measures and removal of the inciting drug or toxin. This may involve removal of contaminated clothing, washing of contaminated skin, gastric emptying, and AC, depending on the nature of the intoxication. Methylene blue, a dye capable of reversing drug- or toxin-induced methemoglobinemia by increasing conversion of methemoglobin to hemoglobin, should be considered in symptomatic patients. A dose of 1 to 2 mg/kg (0.1 to 0.2 mL/kg of a 1% solution) IV administered over 5 minutes generally results in a significant reduction in methemoglobin level within 30 to 60 minutes. A repeat dose of methylene blue may be given after 60 minutes if needed. Additional doses may be required in patients who have taken a long-acting oxidant drug such as dapsone; however, higher doses of methylene blue may paradoxically increase oxidant stress and methemoglobinemia. Contraindications to methylene blue include G6PD deficiency (in which methylene blue may trigger hemolytic anemia), renal failure (because the antidote is renally excreted), and reversal of nitrite-induced methemoglobinemia during treatment of cyanide poisoning.318 Failure to respond to methylene blue suggests cytochrome b5 reductase deficiency, G6PD deficiency, or sulfhemoglobinemia. Additional therapies of possible value in severe conditions include exchange transfusion and hyperbaric oxygen.

Opioids

Opioid stimulation of opiate receptors causes generalized depression of the central nervous system. Symptoms in cases of overdose range from lethargy to respiratory arrest and coma, depending on the dose, agent ingested, and patient tolerance. The majority of deaths occur in chronic abusers of IV heroin.319,320 Ethanol appears to enhance the acute toxicity of heroin and may contribute to deaths in infrequent users of heroin with low tolerance to its acute toxic effects.321

Opioids cause respiratory failure through a number of mechanisms such as alveolar hypoventilation, aspiration, and acute noncardiogenic pulmonary edema (which occurs most notably with heroin).322 Noncardiogenic pulmonary edema often occurs after successful resuscitation and administration of naloxone, which itself has been reported to induce pulmonary edema in certain individuals. By inhalation, heroin may trigger an acute exacerbation of asthma.323,324

Other features of opioid intoxication include hypotension, bradycardia, decreased gut motility, rhabdomyolysis, muscle flaccidity, hypothermia, and seizures. Seizures are most common with propoxyphene 325 and meperidine. The meperidine metabolite normeperidine may cause seizures in the therapeutic dosing range, particularly if there is renal insufficiency.326

Pupils are commonly small or pinpoint-sized and respond to naloxone; however, the lack of miosis does not rule out opioid poisoning, as coexisting toxins or other conditions such as anoxic brain injury may influence pupil size.

The diagnosis of opioid overdose depends on a history of ingestion or a high index of suspicion for drug overdose, combined with compatible clinical features. The combination of a Glasgow Coma Scale score ≤12 with one of the following: respiratory rate ≤12, miotic pupils, or circumstantial evidence of drug use, has a sensitivity of 92% and a specificity of 76% for opioid overdose.327 Rapid response to naloxone corroborates the diagnosis, which can be confirmed by urine or blood toxicology screening. However, certain opioids such as fentanyl are not detected by routine urine toxicology screening.328

Treatment of opioid overdose involves initial supportive measures and naloxone (see below). Gastric emptying may be helpful acutely, but extreme care must be taken not to empty the stomach in lethargic or comatose patients unless the airway has been adequately protected. Although gastric lavage is most useful when it is performed within 1 hour of ingestion, this time limit may be extended several hours because of decreased gut motility. Activated charcoal should be administered once the airway has been protected;329 there is a small risk of small-bowel obstruction in the setting of decreased bowel motility.330 There is no role for forced diuresis, dialysis, or hemoperfusion.

Naloxone, a specific opioid antagonist with no opioid agonist properties, reverses opioid-induced sedation, hypotension, and respiratory depression. The initial dose is 0.4 mg IV or 0.8 mg IM or SC. Endotracheal administration has been described.331 Lower doses should be given to opioid-dependent patients and when there is a concurrent stimulant overdose. Larger initial doses may be required when there is abuse of naloxone-resistant opioids. If naloxone does not produce a clinical response after 2 to 3 minutes, an additional 1 to 2 mg IV may be administered to a total dose of 10 mg. In general, a lack of response to 6 to 10 mg naloxone is required to exclude opioid toxicity; rarely doses >10 mg are required to antagonize the effects of propoxyphene, diphenoxylate, methadone, and pentazocine. Continuing naloxone beyond a total dose of 10 mg is reasonable if there is a very high index of suspicion for opioid overdose or a partial response has been achieved. In general, opioid antagonism occurs within minutes of naloxone administration and lasts for 1 to 3 hours. Repeat boluses may be needed every 20 to 60 minutes to maintain an adequate clinical response. Alternatively, a continuous naloxone infusion may be used (0.4 to 0.8 mg/h, or two thirds of the initial dose needed to achieve a response, given each hour intravenously).

Noncardiogenic pulmonary edema may be initially difficult to distinguish from aspiration pneumonitis with the acute respiratory distress syndrome; however, improvement is generally more rapid in opioid-induced pulmonary edema. Supplemental oxygen, positive end-expiratory pressure, and mechanical ventilatory support may all be required to achieve adequate arterial oxygen saturation.322 Since central venous pressure is low, diuresis may aggravate hypotension.

Seizures unresponsive to naloxone may be treated with intravenous diazepam or lorazepam. Refractory seizures suggest either body packing or a secondary process.

Organophosphate and Carbamate Insecticides

Most insecticides in the United States are organophosphates or carbamates. Organophosphates act as irreversible acetylcholinesterase (AChE) inhibitors. Carbamates are reversible AChE inhibitors. Insecticides can be absorbed through the mouth, skin, conjunctiva, gastrointestinal tract, or respiratory tract. Toxicity occurs within 12 to 24 hours after exposure from excess acetylcholine at neural end-plates due to inhibition of AChE.332

The diagnosis of organophosphate poisoning is made on clinical grounds and by measurement of cholinesterase activity in the blood. The history may suggest attempted suicide, accidental ingestion, industrial/agricultural exposure, or rarely ingestion of contaminated food.333,334 Emergency department personnel have also been inadvertently poisoned through contact with poisoned patients.335 The signs and symptoms of poisoning by both classes of insecticides are virtually identical except that carbamates do not readily cross the blood-brain barrier to cause CNS toxicity. Clinical features include miosis (85%), vomiting (58%), excessive salivation (58%), respiratory distress (48%), abdominal pain (42%), depressed mental status (42%), and muscle fasciculations (40%).336 In one large study, tachycardia occurred more often than bradycardia (21% versus 10% of cases). In early poisoning, there is a transient period of intense sympathetic tone causing tachycardia, followed by heightened parasympathetic tone and bradycardia, heart block, and ST- and T-wave abnormalities.336 An odor of garlic may be noted from the breath or sweat.

Clinical features of organophosphate poisoning result from overstimulation of muscarinic, nicotinic, and central receptors (Table 102-26). Muscarinic overstimulation results in sustained toxicity characterized by the mnemonic SLUDGE (salivation, lacrimation, urination, diarrhea, gastrointestinal cramps, and emesis). Blurred vision, miosis, bradycardia, and wheezing are also muscarinic effects. Nicotinic effects are less sustained and characterized by fasciculations, muscle weakness (that can progress to paralysis), hypertension, and tachycardia. Organophosphates penetrate the blood-brain barrier to cause anxiety, confusion, psychosis, seizures, and ataxia.

The two principal cholinesterases are RBC cholinesterase (also called acetylcholinesterase or AChE), which is present in red blood cells and nerve endings, and pseudocholinesterase (PChE), which is found primarily in liver and serum. Carbamates and organophosphates inhibit both. Clinical toxicity is due primarily to inhibition of AChE, but PChE is more readily quantified. Levels may not correlate with the severity of poisoning.337 A falsely low PChE may be seen in liver disease, anemia and malnutrition, and as a normal genetic variant (familial succinylcholine sensitivity). Normal levels of enzyme activity do not exclude poisoning because of wide variations in normal levels. In the absence of a baseline AChE level, serial measurement helps confirm the diagnosis.338

During initial patient stabilization, attention should be paid to the respiratory status. Bronchoconstriction, excess secretions, muscle weakness and an altered mental status all increase the risk of respiratory failure requiring intubation and mechanical ventilation. In agricultural exposures it is extremely important to remove all contaminated clothing and cleanse hair and skin thoroughly to decrease skin absorption. Health care workers must protect themselves from accidental exposure by wearing appropriate gloves and gowns. Activated charcoal is indicated to limit further absorption. Gastric lavage may be useful if done immediately after ingestion.

Symptomatic patients should receive atropine immediately. Treatment should not await results of AChE or PChE levels. Atropine competitively blocks acetylcholine at muscarinic receptors but has no effect on nicotinic receptors. Thus atropine should not worsen fasciculations, hypertension, or tachycardia. Atropine crosses the blood-brain barrier and can cause CNS toxicity that is difficult to distinguish from organophosphate toxicity. In this situation, glycopyrrolate (which does not penetrate the CNS) is a reasonable alternative to atropine.339 The dose of atropine required to achieve atropinization (mydriasis, dry mouth, and tachycardia) varies depending on the severity of poisoning. Doses of up to 40 mg/d are not uncommon. If atropinization occurs after 1 to 2 mg of atropine, the diagnosis of acetylcholinesterase inhibitor poisoning should be questioned. The initial dose of atropine is 2 mg IV followed by 2 mg every 15 minutes until adequate atropinization has occurred.

Pralidoxime (2-PAM) reverses nicotinic and muscarinic effects of organophosphate poisoning by reactivating AChE and protecting the enzyme from further inhibition. In carbamate poisoning, pralidoxime is generally not needed because of the more rapid resolution of symptoms and reversible nature of enzyme inhibition. Moreover, pralidoxime may enhance carbaryl (or Sevin, a carbamate insecticide) toxicity.340 To be effective pralidoxime should be given within the first 6 hours of poisoning (although treatment in the first 24 to 48 hours may still be effective), prior to irreversible phosphorylation of cholinesterase (a process referred to as “aging”). After this critical period, restoration of normal cholinesterase function requires regeneration of the enzyme, a process that may take weeks to complete. Antimuscarinic effects allow for atropinization more quickly, and with lower doses of atropine. The initial dose of pralidoxime is 1 to 2 g IV given over approximately 10 to 20 minutes. Clinical response should be evident within 30 minutes. If there is no improvement in fasciculations or weakness the dose may be repeated once. A continuous infusion is then administered at a rate of 200 to 500 mg/h, titrated to achieve the desired effect. Continuous infusion of pralidoxime may be necessary for over 24 hours, depending on the half-life and lipid solubility of the poison, after which the dose may be gradually reduced and stopped while the patient is observed for signs of recurrent muscle weakness.

Phencyclidine

Phencyclidine (PCP) or “angel dust” is a dissociative anesthetic agent that is similar in many ways to ketamine. It decreases the perception of pain and has variable anticholinergic, opioid, dopaminergic, CNS stimulant, and α-adrenergic effects. PCP is usually smoked; however, it can also be nasally snorted, orally ingested, or intravenously injected. PCP is often mixed with other substances including ethanol, marijuana, and LSD. The long-term outlook for chronic abusers is characterized by unemployment, financial dependence on others, and repeated need for hospitalization.342

Persons intoxicated with PCP may demonstrate fluctuating, bizarre, and violent behavior that occasionally lasts for days following exposure.343,344 In one study of 1000 patients evaluated in the ED for PCP intoxication, violence was present in 35% of cases, bizarre behavior in 29%, and agitation in 34%.345 Forty-six percent of patients were alert and oriented; others demonstrated alterations in mental status ranging from lethargy to coma. Nystagmus (vertical or horizontal) and hypertension occurred in 57% of cases. Diaphoresis, hypersalivation, bronchospasm, and urinary retention occurred in less than 5% of cases. Grand mal seizures, muscle rigidity, dystonic reactions, catalepsy and athetosis occurred but were rare. Twenty-eight cases (2.8%) were apneic, and three cases (0.3%) presented in cardiac arrest. Hypoglycemia and elevated serum CPK, uric acid, and SGOT/SPGT were common. Rhabdomyolysis results in renal failure in 50% of cases.346 Other features of PCP intoxication include self-inflicted injuries, aspiration pneumonia, hypertensive crisis, and intracranial and subarachnoid hemorrhage.347–349

The diagnosis of PCP intoxication is usually made on clinical grounds (fluctuating behavior, signs of sympathomimetic overstimulation, and vertical nystagmus). Particularly suggestive is the finding of pinpoint pupils in an agitated patient. Confirmation of PCP exposure is available through qualitative urine screening. PCP levels do not correlate with the severity of the clinical findings.345

Treatment of PCP intoxication involves initial supportive measures aimed at identifying and treating life-threatening problems. Few data are available regarding safety and efficacy of gastric emptying in PCP toxicity; however, this strategy is unlikely to be of significant benefit in patients presenting more than 1 hour after oral ingestion, and gastric emptying carries significant risk. Ipecac-induced vomiting should be avoided because of the risk of wide fluctuations in mental status, and the placement of a nasogastric tube may result in extreme agitation. Activated charcoal is effective in reducing intoxication. Acidifying the urine with NH4Cl and diuresis enhances drug elimination.350–352 However, the benefits of urinary acidification are small,353 and urinary acidification may exacerbate myoglobinuric renal failure. Therefore urinary acidification is not recommended for routine use in PCP overdose. Neither hemoperfusion nor dialysis effectively eliminates PCP because of its large volume of distribution.

Violent or acutely psychotic patients unresponsive to verbal feedback and reduction in environmental stimuli require immediate pharmacologic treatment or physical restraints to establish adequate patient and staff safety. A common error in the management of the agitated patient is to delay treatment, allowing patients to harm themselves or others; another error is premature discharge of PCP-intoxicated patients after they demonstrate a period of normal behavior. Haloperidol appears to be the drug of choice to treat PCP psychosis.354 Haloperidol (2 to 5 mg IM) may be repeated every 30 to 60 minutes to a total dose not exceeding 100 mg. Haloperidol prolongs the QT interval and therefore should be used with continuous monitoring. In addition, haloperidol lowers the seizure threshold and is associated with neuroleptic malignant syndrome, tardive dyskinesia, and the development of extrapyramidal symptoms. Adding a benzodiazepine (e.g., lorazepam 1 mg) to each dose of haloperidol may expedite control of the difficult patient. Data are limited regarding the use of chlorpromazine and opioids in PCP psychosis.355 Other causes of agitation including head trauma, intracerebral or subarachnoid hemorrhage, CNS infection, thyrotoxicosis, pheochromocytoma, hyperthermia, and acute psychiatric illnesses should be considered.

Hypertension often responds to haloperidol or benzodiazepine therapy. In cases of severe hypertension, nitroprusside or labetalol may be required. β-Blockers should be avoided as sole drugs because of the risk of worsening hypertension as β2 sites are blocked.

Salicylates

Acetylsalicylic acid or aspirin is converted rapidly to salicylic acid, its active moiety. Salicylic acid is readily absorbed from the stomach and small bowel. At therapeutic doses, it is metabolized by the liver and eliminated in 2 to 3 hours. Chronic ingestion can increase the half-life to more than 20 hours.356 Overdose can be accidental or deliberate, acute or chronic. A number of over-the-counter combination formulations and herbal remedies contain salicylates. The use of alternate analgesics, child-resistant containers, and package size restrictions has decreased the incidence of poisoning.357,358

Therapeutic serum levels of salicylates are 10 to 30 mg/dL. Clinical features of intoxication occur in most individuals with serum levels above 40 to 50 mg/dL; in chronic intoxication, severe poisoning occurs at lower serum levels (particularly in elderly patients). In toxic amounts, salicylates are metabolic poisons that affect a number of organ systems by uncoupling oxidated phosphorylation and interfering with the Krebs cycle.359

Minor intoxication causes tinnitus, vertigo, nausea, vomiting, and diarrhea. More significant ingestions cause acid-base disturbances. Respiratory alkalosis is caused by direct central ventilatory stimulation. Organic acids (including lactate and ketoacids) accumulate with uncoupling of oxidative phosphorylation to cause an elevated anion gap metabolic acidosis. Salicylic acid itself contributes only minimally to the measured anion gap (only 3 mEq/L with a 50-mg/dL level). Adults commonly present with respiratory alkalosis or combined metabolic acidosis and respiratory alkalosis.360,361 Children may develop pure metabolic acidosis. Severe poisoning also causes noncardiogenic pulmonary edema, mental status changes, seizures, coma, gastrointestinal bleeding, liver failure, renal failure, and death.362 Low cerebrospinal fluid glucose is a characteristic finding.362

Thisted and colleagues reported the clinical findings in 177 consecutive admissions to an ICU with acute salicylate poisoning.363 Neurologic abnormalities occurred in 61% of cases, acid-base disturbances in 50%, pulmonary complications in 43%, coagulation disorders in 38%, fever in 20%, and hypotension in 14%. In a separate 2-year review of salicylate deaths in Ontario, 31.4% of patients were dead on arrival.364 ICU mortality has been reported to be 15%.363 The clinical features of salicylate intoxication are reviewed in Tables 102-27 and 102-28.

The lethal adult dose is approximately 10 to 30 g (35 tablets or more). Lethality correlates poorly with serum levels. The Done nomogam may be of little value, particularly if the time of ingestion is incorrectly estimated, more than a single dose is taken, or an enteric-coated preparation is used.356,365,366 These caveats hold particularly true for chronic salicylism, which commonly occurs unintentionally in elderly patients receiving long-term analgesic therapy.367 These patients are more likely to present with CNS injury368 or noncardiogenic pulmonary edema;369 isolated mild elevation of the prothrombin time is another telltale sign. Salicylate ingestion is usually diagnosed by serum level measurements, which are less helpful in chronic intoxication. Urine tests with Phenistix or ferric chloride can also be used to detect salicylate poisoning.370

Optimal management of a salicylate-intoxicated patient requires appreciation of the toxicokinetics of ingestion and the importance of serum pH in determining disposition of this drug. At therapeutic levels, salicylic acid is 90% protein-bound. Most (75%) is partially glycinated in the liver to form salicyluric acid, a less toxic and more water-soluble renally excreted metabolite. Proximal organic anion secretion, rather than glomerular filtration, is normally responsible for the bulk of salicylate excretion, since salicylate is a highly proteinbound drug; and pH-dependent nonionic back-diffusion from the tubular lumen occurs at alkaline urine pH. At toxic levels, however, only 50% of salicylic acid is protein-bound, so that (with increased tissue distribution) the customary metabolic pathway via salicyluric acid becomes saturated, and elimination half-life increases from 3 to 12 hours to 15 to 30 hours.

Supportive care includes empiric administration of dextrose to treat low CSF glucose level. Treatment of an acute ingestion starts with gastric lavage and AC. These strategies are not helpful in chronic salicylism, although there is debate regarding the efficacy of multidose AC.371

The extent of tissue distribution of absorbed salicylate is influenced by plasma pH. For instance, CNS toxicity may be ameliorated by administration of bicarbonate to raise plasma pH to 7.45 to 7.5 (of course, such therapy may be contraindicated in the presence of alkalemia caused by salicylate-induced hyperventilation). Systemic alkalinization has the additional salutary effect of augmenting renal salicylate excretion. Raising urinary pH from 6.1 to 8.1 results in an over 18-fold increase in renal clearance by preventing nonionic tubular back-diffusion.372 This decreases the half-life of salicylates from 20 to 24 hours to <8 hours. To accomplish urinary alkalinization, it is vital to avoid hypokalemia that prevents excretion of alkaline urine by promoting distal tubular potassium reabsorption in exchange for hydrogen ion. Forced diuresis appears not to add additional clearance to such therapy and tends to precipitate volume overload. Treatment with acetazolamide has also been used to induce alkaline diuresis, but we do not recommend this approach because “overshoot” acidemia may increase drug entry into the CNS and salicylate toxicity.

Indications for hemodialysis are listed in Table 102-29.356,365 They include a serum level >120 mg/dL acutely, >100 mg/dL 6 hours postingestion, refractory acidosis, coma, seizures, noncardiogenic pulmonary edema, and renal failure. In chronic overdose, hemodialysis may be necessary for symptomatic patients with serum levels over 60 mg/dL.373

Selective Serotonin Reuptake Inhibitors

The SSRIs, which include sertraline, citalopram, nefazodone, venlafaxine, paroxetine, fluoxetine, escitalopram, trazodone, and fluvoxamine, are noncyclic antidepressant agents that selectively inhibit the presynaptic neural uptake of serotonin.374 These drugs are indicated for treatment of patients with affective disorders. They are relatively nontoxic when taken alone, but when taken in combination with a number of other drugs (listed in Table 102-30), there is the potential for excessive stimulation of 5-HT1A and 5-HT2 receptors and development of the serotonin syndrome.375–380 Because of the long half-life of some of these drugs, toxic combination therapy may not be apparent for days to weeks.

Features of the serotonin syndrome include various combinations of confusion, agitation, coma, shivering, flushing, hyperthermia, diaphoresis, mydriasis, tachycardia, disseminated intravascular coagulation, convulsions, muscle rigidity, myoclonus, hyperreflexia, involuntary movements, autonomic instability, nausea, diarrhea, orthostatic hypotension, and rhabdomyolysis, which may not develop until 6 to 12 hours after overdose.28,375,378 Trazodone, which also acts as an α-adrenergic blocker, may cause a hypotensive response. Other findings include hyponatremia and SIADH.381,382 Death is rare.

The diagnosis of serotonin syndrome should be considered in any patient with compatible clinical features, particularly if there is a history of depression. Blood levels are not helpful because the syndrome is a result of increased concentrations at nerve endings.

Treatment of serotonin syndrome starts with identifying and treating life-threatening problems. Gastric emptying should be considered in patients with acute ingestion. Ipecac-induced vomiting may be useful in the early management of children outside the hospital setting. Activated charcoal with a cathartic should be administered. Dialysis and hemoperfusion are not effective. Prognosis is generally good in mild cases, with resolution within 24 to 36 hours with supportive therapy alone. In severe cases, anecdotal reports suggest that serotonin antagonists (methysergide and cyproheptadine) may be beneficial.383 Chlorpromazine, diphenhydramine, and benzodiazepines have also been used to treat serotonin syndrome.384,385

Theophylline

Theophylline has a low therapeutic index, with a recommended therapeutic range of plasma levels between 10 and 20 mg/L. Toxicity can occur in the therapeutic range, but is more frequently associated with plasma levels >20 mg/L. Intoxication may result from either acute massive ingestion or chronic overmedication. The latter scenario may result from diminishing theophylline clearance on a stable chronic regimen. Drug interactions, smoking cessation, congestive heart failure, and hepatic dysfunction all diminish theophylline clearance. Chronic intoxication is associated with more severe clinical sequelae at any given plasma level due to larger body stores.386,387

Clinical features of theophylline toxicity are neurologic, cardiovascular, and metabolic.388 Seizures occur at lower serum levels in chronic intoxication than in acute overdose.389 For reasons unknown, seizures occur several hours after peak serum levels in acute intoxication. Uncontrolled seizures can lead to hyperthermia and rhabdomyolysis. Tachyarrhythmias, both supraventricular and ventricular, are common at theophylline levels of 20 to 30 mg/L;390 cardiovascular collapse can occur at levels over 50 mg/L. Metabolic abnormalities include hypokalemia, hypomagnesemia, hyperglycemia, hypophosphatemia, hypercalcemia, and respiratory alkalosis.391

Initial treatment should include gastric lavage and activated charcoal. Emesis is contraindicated because of the risk of seizures. Since theophylline undergoes enterohepatic circulation, multidose AC can enhance elimination.69

Seizures should be treated with benzodiazepines. Refractory seizures are an indication for the addition of phenobarbital or other antiepileptics. Phenytoin can worsen theophylline-induced seizures and should be avoided.392,393 Supraventricular tachyarrhythmias are best controlled by a cardioselective β-blocker (metoprolol or esmolol), but these must be used with care in patients with underlying obstructive airways disease and not at all in patients who are actively wheezing. Calcium channel blockers may be useful in supraventricular tachycardia.394,395 However, hypotension due to β2-adrenergic stimulation should be treated with fluids and phenylephrine. Interestingly, refractory hypotension has been treated with a nonselective β-blocker such as esmolol.396–398 Lidocaine and other standard agents are suitable for therapy of ventricular arrhythmias. Electrolyte repletion may be required.

Patients presenting with seizures or arrhythmias are candidates for extracorporeal drug removal (ECR). Other indications are a plasma level >100 mg/L at 2 hours after initial charcoal therapy, a level >50 mg/L in chronic ingestion, a 2-hour level >35 mg/L associated with clinical instability (shock), and a high risk of adverse outcome and/or prolonged intoxication. High-risk characteristics include: (1) chronic intoxication; (2) intolerance of oral charcoal; (3) impaired theophylline metabolism (congestive heart failure, cirrhosis, or severe hypoxemia [PO2 <40 mm Hg]); (4) susceptibility to cardiovascular toxicity (elderly or coronary artery disease), seizures (epilepsy or coingestion of other convulsant drugs), or respiratory failure (severe pulmonary disease).

Extracorporeal therapy is best achieved by use of “in-series” hemodialysis (HD) and hemoperfusion (HP).389,399,400 The physical and disposition characteristics of theophylline allow fairly effective clearance by HD, which has an extraction ratio (ER) of 0.5, achieving a clearance of up to 150 mL/min at a 300 mL/min blood flow rate. HP is more effective, with ERs of 0.6 to 0.9, allowing clearance twice that of HD. Cartridge replacement is required every 2 hours during isolated HP, because of adsorption saturation and declining ER (0.99 at initiation of therapy, decreasing to 0.5 by 2 hours). Placement of a hemodialyzer in series proximal to the HP cartridge in the extracorporeal circuit delays development of system saturation, adds additional clearance by HD, and allows for more rapid correction of metabolic derangements. Peritoneal dialysis does not add to endogenous clearance, even though this is low in nonsmokers (0.7 to 1.0 mL/min). Continuous extracorporeal therapies are of some utility and are indicated only in the absence of available HD or HP. Other techniques such as plasmapheresis and exchange transfusion have been successfully used in pediatric patients.

Envenomations

Snake Bite

The majority of poisonous snake bites in the United States involve the Crotalidae (pit viper) family of snakes (e.g., rattlesnakes, copperheads, and water moccasins) in the southwest, west, and southeast. Pit vipers are named for a small pit between their eyes and nostrils. Large venom glands located in the temporal region result in a triangular shaped head; a horny rattle on the tail is vibrated when the rattlesnake is agitated.

Most bites involve native, noncaptive snakes, and are considered accidental. Accidental bites are more common in the summer months, in the afternoon or evening, and during recreational activities.401 Young men are the most frequent victims.

Rattlesnakes strike when they are disturbed. Telltale fang marks appear as paired puncture wounds or lacerations a few millimeters deep, although atypical wounds consisting of single or multiple puncture sites or scratches are also seen. Twenty-five percent of bites do not result in envenomation (i.e., “dry bites”); half of all bites result in minimal or no envenomation.401,402 Dry bites are generally benign, although there is potential for infection due to bacteria in the snake's mouth or on the victim's skin. When envenomation occurs, a variety of toxic proteins and enzymes are introduced into the victim that are capable of producing serious local and systemic reactions. Local effects develop within minutes and consist of stinging, burning, swelling, erythema, ecchymosis, and hemorrhagic blebs. Extremities swell over the next several hours, occasionally resulting in compartment syndrome. Facial bites with severe local swelling may obstruct airways.403 Systemic effects of rattlesnake venom include fever, nausea, vomiting, delirium, seizures, muscle cramps, jaundice, disseminated intravascular coagulation, acute renal failure, and shock. Death is rare but may occur hours to days after envenomation. Of note, the Mojave rattlesnake is unique in causing minimal local tissue damage and serious delayed systemic effects.

Treatment of rattlesnake bite consists of splinting and immobilizing the bitten extremity at heart level to slow the spread of venom.404 A loose fitting tourniquet should be placed above the bite site to impede lymph flow and rate of venom spread. Surgical consultation should be obtained for management of serious wounds. Débridement of necrotic wounds may be necessary. If compartment syndrome is suspected, tissue pressure should be measured. Surgery should be reserved only for severe and refractory cases and may not improve outcome.405 Tetanus prophylaxis should be provided.

Rapid volume infusion is indicated in the initial management of hypotensive patients. Several liters of isotonic fluid may be required. One animal study suggests that in severe cases colloid infusion is more effective than crystalloid.406 Patients with significant envenomations with progressive local or systemic effects should be considered for specific treatment with equine-derived Crotalidae antivenin. Antivenin is a lyophilized protein product derived from horses immunized with venom pooled from several members of the Crotalidae family of snakes. Prior to antivenin administration, patients should be skin tested with a 1:10 dilution of antivenin (or per instructions in the commercially available antivenin kit). Patients with a positive skin test should be reconsidered for supportive care only; however, in the setting of severe envenomation, diluted antivenin may still be administered slowly after pretreatment with diphenhydramine and corticosteroids. This situation mandates large-bore IV access and epinephrine at the bedside in anticipation of anaphylaxis. A negative skin test is reassuring but does not exclude the possibility of anaphylaxis or the need for close monitoring and bedside availability of antihistamines and epinephrine. Antivenin is dosed by vial. Minimal envenomations with progressive symptoms can be treated effectively with five vials. Severe envenomations with hypotension and coagulopathy should receive 15 to 20 vials as guided by the instructions in the antivenin kit.407 Most patients respond to the initial antivenin infusion, but some patients require additional infusions every few hours. Patients should be monitored closely for immediate hypersensitivity reactions and delayed hypersensitivity reactions (i.e., serum sickness) which commonly occur 5 to 14 days later. Of note, commercially available equine antivenin is also available for eastern coral snake (Micrurus fulvius) and Texas coral snake (Micrurus fulvius tenere) envenomation.

Spider Bite

In North America, only the widow spiders (Latrodectus species) and the recluse spiders (Loxosceles species) are medically important. The female black widow spider (Latrodectus mactans) has a shiny black body approximately 1 cm in diameter with a red hourglass mark on the abdomen. This spider, which favors woodpiles, dimly lit sheds, greenhouses, basements, and outdoor toilets, is most often encountered during the summer months. It bites aggressively to introduce potent venom into its victim. Envenomation results in local pain and erythema followed by muscle cramps and muscle fasciculations near the bite site. Painful cramps may generalize to the abdomen, back, and chest, mimicking myocardial infarction or an acute surgical abdomen.284 Cramps may last for several days. Hypertension, tachycardia, tremor, fever, agitation, diaphoresis, and nausea are also common. Rarely, black widow spider bite results in hypertensive crisis or cardiopulmonary arrest. Treatment of black widow spider bite consists of general supportive measures combined with adequate analgesia and sedation. Intravenous calcium and methocarbamol effectively treat muscle cramps. Rare patients with significant signs and symptoms not responding to conservative measures should be considered for specific treatment with equine antivenin. As with other equine-derived antivenins, skin testing should be performed prior to antivenin administration, and precautions should be taken for anaphylaxis.284

Recluse spider bite (loxoscelism) is characterized by pain and burning at the bite site followed by localized swelling, erythema, and formation of bullae. A bull's eye–shaped lesion ranging from 1 to 5 cm may develop, consisting of an erythematous or hemorrhagic center, surrounded by a blanched ring that is enclosed in an ecchymotic ring. Central necrosis may develop and last for weeks to months. Some patients develop systemic symptoms including fever, myalgias, headache, and nausea. Rare patients develop intravascular hemolysis, disseminated intravascular coagulation, acute renal failure, and the acute respiratory distress syndrome. Treatment of loxoscelism is largely supportive. Cool compresses have been recommended for the bite site. Systemic steroids and dapsone have been advocated in severe cases, but convincing evidence supporting the use of these agents is lacking, and they should be considered experimental. Antivenin is not currently available.