General Measures

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  Supportive measures supersede 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.

  
  
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  Administer a “cocktail” of oxygen, dextrose, thiamine, and naloxone to patients with depressed mental status.

  
  
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  An increase in anion gap, osmol gap, or arterial saturation gap should raise the suspicion of intoxication.

  
  
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  An osmol gap of large magnitude (>25 mOsm/kg) suggests methanol or ethylene glycol poisoning; however, serious intoxication with either agent can occur without increasing the osmol gap, particularly in the later stages of intoxication.

  
  
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  Carbon monoxide and methemoglobin elevate the arterial oxygen saturation gap. These toxins interfere with oxygen binding to hemoglobin and decrease oxygen content without lowering PaO2. Oxygen saturation measured by pulse oximetry is falsely high in this setting.

  
  
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  Toxicology screening can provide direct evidence of intoxication, but it rarely impacts initial management.

  
  
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  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.

  
  
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  Gastric lavage only improves outcome in patients if performed within 1 hour of ingestion, although 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.

  
  
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  Activated charcoal should be administered for most acute oral ingestions if the airway is protected.

  
  
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  Whole-bowel irrigation with a polyethylene glycol electrolyte solution is only indicated for iron overdose, ingestion of sustained-release tablets, and “body packing” with illicit drugs.

  
  
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  Urinary alkalinization enhances excretion of nonpolar weak acids and is most commonly used in salicylate toxicity.

Acetaminophen

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  All overdose cases should be screened for acetaminophen poisoning.

  
  
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  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

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  Metabolic acidosis with an elevated anion gap and/or the presence of an osmol gap are classic in methanol and ethylene glycol poisoning.

  
  
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  Features of methanol poisoning include inebriation, optic papillitis, and pancreatitis.

  
  
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  Features of ethylene glycol poisoning include inebriation, acute renal failure, crystalluria, and myocardial dysfunction.

  
  
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  Treatment of methanol and ethylene glycol poisoning with fomepizole or ethanol inhibits metabolism by alcohol dehydrogenase to toxic metabolites. Dialytic removal of toxic metabolites is indicated in severe poisonings.

  
  
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  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

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  Hypothermia, hypotension, bradycardia, flaccidity, hyporeflexia, coma, and apnea are features of barbiturate overdose. Severe overdose can mimic death.

  
  
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  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. Hemodialysis should be considered in severe cases.

Benzodiazepines

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  Supportive measures, gastric emptying, activated charcoal, and flumazenil treat benzodiazepine overdose.

  
  
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  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.

  
  
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  There is no role for forced diuresis, dialysis, or hemoperfusion in benzodiazepine overdose.

β-Blockers

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  Cardiovascular manifestations of overdose are treated with fluids, vasopressors, atropine, glucagon, and hyperinsulinemia/euglycemia (HIE) therapy.

Calcium-Channel Blockers

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  Hypotension is treated with fluids, calcium chloride, and vasopressors. Glucagon and HIE therapy may decrease vasopressor requirements.

  
  
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  Intravenous lipid emulsion should be considered in the poisoned patient with cardiac arrest, terminal arrhythmia, or refractory severe hypotension.

Carbon Monoxide

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  Exposure to smoke, poorly ventilated charcoal or gas heaters, and automobile exhaust are responsible for most poisonings.

  
  
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  Carbon monoxide poisoning can present with myocardial ischemia, arrhythmias, mental status changes, headache, and generalized weakness.

  
  
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  Prompt oxygen therapy is crucial.

  
  
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  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.

  
  
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  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.

  
  
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  Delayed neurologic sequelae may occur in survivors.

Cocaine

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  Cocaine is often mixed with other substances of abuse.

  
  
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  Cocaine causes acute coronary syndromes, hypertensive crisis, seizures, rhabdomyolysis, intracranial hemorrhage, pneumomediastinum, and respiratory failure.

  
  
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  Agitation and hyperthermia should be treated rapidly with benzodiazepines and cooling strategies.

  
  
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  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.

  
  
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  Patients presenting with cocaine-associated chest pain need to be evaluated for myocardial infarction. Acute coronary syndromes should be treated with nitrates and benzodiazepines.

Cyanide

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  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.

  
  
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  Sodium nitroprusside infusions can cause cyanide and thiocyanate poisoning.

  
  
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  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.

  
  
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  In addition to supportive measures and oxygen, several antidotes are available: amyl and sodium nitrite, sodium thiosulfate, and hydroxycobalamine.

Cyclic Antidepressants

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  Neurologic deterioration is often abrupt and has been associated with QRS prolongation >0.10 second.

  
  
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  Acidemia potentiates toxicity. Therapeutic alkalemia with sodium bicarbonate is beneficial.

  
  
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  Lidocaine should be used for ventricular arrhythmias resistant to sodium bicarbonate. Procainamide is contraindicated.

  
  
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  Physostigmine should be avoided as it has been associated with death. Flumazenil should be avoided because of risk of increased seizure activity.

Digoxin

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  Features of digitalis intoxication include fatigue, gastrointestinal symptoms, neurologic disturbances such as blurred vision, visual color changes, headache, dizziness, delirium, and cardiac arrhythmias. Significant overdose may cause hyperkalemia.

  
  
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  Supportive therapy includes rapid correction of arrhythmogenic metabolic disturbances, particularly hypokalemia if present. Hyperkalemia requires treatment unless Fab therapy is immediately available.

  
  
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  Immunotherapy with digoxin-specific antibody Fab fragments is indicated for severe intoxications.

  
  
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  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.

  
  
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  Electrical cardioversion of a digitalis toxicity–induced arrhythmia should be reserved as a last resort, using the minimum effective energy level.

γ-Hydroxybutyrate

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  Depressed mental status, emesis, bradycardia, hypotension, and respiratory depression are features of GHB overdose.

  
  
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  Treatment is supportive.

Lithium

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  Most cases of intoxication, associated with levels above 1.5 mEq/L, are caused by unintentional overdose during chronic therapy.

  
  
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  High levels of lithium decrease the anion gap.

  
  
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  Severe poisoning causes coma, seizures, and cardiovascular instability.

  
  
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  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.

  
  
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  Lithium is the prototypical dialyzable intoxicant.

Methemoglobinemia

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  Hereditary methemoglobinemia (eg, 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.

  
  
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  Methemoglobinemia decreases oxyhemoglobin saturation and blood oxygen-carrying capacity by decreasing available hemoglobin and shifting the oxyhemoglobin dissociation curve to the left.

  
  
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  Symptoms of moderate methemoglobinemia include dyspnea, headache, and weakness. Confusion, seizures, and death can occur with levels >60%.

  
  
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  Cooximetry 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.

  
  
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  Routine treatment of methemoglobinemia consists of oxygen and methylene blue.

Opioids

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  The triad of miosis, respiratory depression, and coma suggests opioid intoxication.

  
  
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  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 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

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  Organophosphates are irreversible inhibitors of acetylcholinesterase (AChE); carbamates reversibly inhibit AChE.

  
  
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  Signs of cholinergic poisoning include salivation, lacrimation, urination, diarrhea, gastrointestinal cramping, and emesis (SLUDGE). Muscle fasciculations, coma, and seizures also occur.

  
  
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  Respiratory failure results from muscle weakness, bronchorrhea, depressed respiratory drive, and bronchoconstriction.

  
  
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  The level of red blood cell cholinesterase helps diagnose organophosphate poisoning.

  
  
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  Treatment includes supportive measures, atropine, and oximes. Large doses of atropine may be needed to decrease pulmonary secretions.

Salicylates

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  The Done nomogram for predicting salicylate toxicity is of limited use in current practice.

  
  
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  Salicylate poisoning causes respiratory alkalosis and metabolic acidosis; the latter is more prominent in children.

  
  
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  Manifestations of chronic ingestion may be subtle and occur at relatively low serum salicylate levels.

  
  
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  Acidemia favors tissue penetration of salicylates. Urinary alkalinization enhances renal clearance of salicylates. Hypokalemia must be corrected to succeed in urinary alkalinization.

  
  
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  Seizures, coma, refractory acidosis, and high serum salicylate levels are indications for hemodialysis.

  
  
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  Alkalemia should be maintained in mechanically ventilated patients with salicylate poisoning

Selective Serotonin Reuptake Inhibitors

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  In combination with a number of drugs, SSRIs may cause serotonin syndrome. Toxic combinations may not be evident for days to weeks.

  
  
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  Serotonin syndrome is characterized by combinations of specific neurologic and autonomic abnormalities best outlined in diagnostic criteria.

  
  
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  Treatment is supportive and includes benzodiazepines for symptomatic control. Cyproheptadine has been used without convincing experimental evidence supporting its use.

Envenomations

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  The majority of poisonous snake bites in the United States involve the Crotalidae or pit viper family of snakes (eg, rattlesnakes, copperheads, and water moccasins).

  
  
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  Treatment of rattlesnake bite consists of immobilizing the bitten extremity below the level of the heart. Surgical consultation may be required for local wound management.

  
  
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  Unstable patients with pit viper envenomation should be treated with equine Crotalidae antivenin. Any patient with confirmed Elapidae bite should be treated with antivenin, as symptoms may be delayed and life threatening.

  
  
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  In North America, only the widow spiders (Latrodectus species) and the recluse spiders (Loxosceles species) are medically important.

  
  
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  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.

  
  
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  Treatment of black widow spider bite consists of supportive measures, analgesia, and sedation, and in severe cases, equine-derived antivenin.

  
  
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  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, but antivenin is selectively available.

In their 2008 annual report, the American Association of Poison Control Centers reported 2,491,049 human toxic exposure cases. Four percent of these cases, or more than 93,000 patients, required critical care. There were 1315 fatalities, associated most commonly with prescription pharmaceuticals.¹

Intentional overdose or accidental exposure may be the chief complaint at the time of initial 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 the 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/decontamination) 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 general guidelines of life support should be followed as in any medically unstable patient, but the care of critically ill poisoned patients has been identified as a “special situation” by the American Heart Association. Their recommendations in the 2010 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care are included in this chapter.²

With cervical spine precautions in place (unless trauma has been reasonably excluded), airway patency must be established. In obtunded patients with spontaneous respirations and without signs of facial trauma, a nasal trumpet is acceptable to assist in oxygen delivery. An oral airway may be used to facilitate bag-mask ventilation prior to endotracheal intubation in patients without a gag reflex. 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 124-1).

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, clear secretions, maintain gas exchange, or sustain an adequate blood pressure. Intubation decreases but does not eliminate the risk of aspiration, which occurs in approximately 10% of comatose patients with drug overdose.^3,4 Intubation further allows for administration of high concentrations of oxygen and, in some patients, provides access for drug delivery.

Selected causes of hypoxemia in drug overdose and toxic ingestion are listed in Table 124-2. 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 with pressure support). If intubation is performed solely to protect the airway or to provide supplemental oxygen, the endotracheal tube may be connected to a T-piece. Alternatively low levels of pressure support ventilation (5 to 8 cm H₂O) can be applied to overcome endotracheal tube resistance and decrease inspiratory work of breathing. Positive end-expiratory pressure (PEEP) recruits atelectatic and fluid-filled alveoli, but should be used cautiously in hypotensive patients to avoid decreasing cardiac preload. Special attention must be paid to the acid-base status in the poisoned patient on mechanical ventilation (as discussed separately in the section “Salicylates”).

Circulatory manifestations of drug overdose are common and varied. Bradycardia and/or atrioventricular (AV) block can result from cholinergic excess (eg, with organophosphate, carbamate, physostigmine, and digoxin toxicity), sympatholytic drugs (eg, β-blockers, clonidine, and opioids), membrane-depressant agents (eg, type 1a and 1c antiarrhythmic drugs, quinidine, and cyclic antidepressants), calcium-channel blockers, and lithium overdose (Table 124-3). Bradycardia can also occur from a reflex response to α-adrenergic–induced hypertension (eg, phenylpropanolamine).

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 and clonidine 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.⁵ If transcutaneous pacing is used successfully, a prophylactic transvenous pacemaker is not routinely recommended because of theoretical risk of triggering ventricular arrhythmias by irritating the susceptible myocardium.⁶ However, if transcutaneous pacing is poorly tolerated or ineffective, transvenous pacing has been shown to be safe in certain overdose settings.⁷

Table 124-3 includes selected drugs and toxins causing tachycardia. Sinus tachycardia and supraventricular arrhythmias commonly result from sympathetic overstimulation (eg, with cocaine, theophylline, amphetamines, or phencyclidine) or inhibition of parasympathetic tone (eg, 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 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 that prolong the QT interval (eg, 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.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 the setting of sympathomimetic-induced Vt or VF is unknown; if used, the working group of the AHA recommends increasing the interval between doses and avoidance of high-dose epinephrine.⁶ This group also recommends more prolonged cardiopulmonary resuscitation (CPR) in poisoning cases because of case reports of good neurologic recovery after prolonged CPR (eg, 3-5 hours).⁶

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 (eg, 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 (eg, 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 (5-20 µg/kg/min by continuous IV infusion) 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.^8-10 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 (eg, agitated patients often respond well to benzodiazepines alone). When hypertension is severe in chronically hypertensive patients, 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 and titratable agent such as nitroprusside, as hypertension may be a precursor to drug-induced cardiovascular collapse (as in MAOI toxicity). 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. Despite recent research in the area, nonselective β-blockers are currently not recommended particularly in cocaine-associated hypertension because they may worsen α-adrenergic–induced hypertension.^11,12

“COMA COCKTAIL”

A “cocktail” of oxygen, dextrose, thiamine, and naloxone should be administered to patients with depressed mental status (see Table 124-1). These relatively innocuous drugs are helpful diagnostically and therapeutically. Although not well supported in the literature,¹³ 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 in the hypoglycemic patient, although in alcoholic patients, it is recommended to at least give them concomitantly if Wernicke-Korsakoff is suspected as the cause of coma.^13-15

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.¹³

Naloxone is an opioid antagonist with no opioid agonist properties. It can rapidly reverse opioid-induced coma, hypotension, respiratory depression, and analgesia.¹⁶ Naloxone is traditionally administered intravenously, intramuscularly, or subcutaneously; although use of nebulized and intranasal naloxone has been studied.^17,18 Initial low doses (0.4 mg IV or 0.8 mg IM or SC) are preferred to avoid symptoms of severe withdrawal in patients with chronic opioid dependence or in patients with accompanying stimulant use.⁶

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.¹⁹ 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. Even higher doses may be required to antagonize the effects of longer acting and synthetic opioids such as meperidine, propoxyphene, and methadone.² 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 has a serum half-life of 30 to 80 minutes. The effects of naloxone do not last as long as those of heroin or methadone, so repeat boluses may be required to maintain an adequate clinical response. Alternatively, a continuous naloxone infusion may be started (0.4-0.8 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.^20,21 In a rat model of combined cocaine-diazepam poisoning, flumazenil precipitated seizures and increased mortality.²²

Seizures may occur in the setting of cyclic antidepressant coingestion; however, prospective data demonstrate that cautious administration of flumazenil is safe in this setting.²³ 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.²⁴

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.

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.

Haloperidol (1-5 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 1-2 mg IV). Haloperidol also has anticholinergic effects that are undesirable in anticholinergic overdose. Adding a benzodiazepine (eg, lorazepam 1 mg IV) to each dose of haloperidol may accelerate control of the difficult patient.

Seizures are a cause of drug-related morbidity and mortality. Multiple drugs and toxins (Table 124-4) 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 (eg, cocaine) may be observed without further evaluation provided the patient is alert and has a normal neurologic examination. Recurrent seizures from cocaine 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 isoniazid toxicity (requiring treatment with pyridoxine). Patients with seizures refractory to all above therapy should be considered for paralysis with continuous electroencephalographic (EEG) monitoring to prevent hyperthermia and rhabdomyolysis.

ALTERATIONS IN TEMPERATURE

Drugs and toxins have the potential to alter body temperature through a number of mechanisms (Table 124-5). Hypothermia is caused by peripheral vasodilation, inhibition of shivering, depression of metabolic activity, and environmental exposure. 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 is exposed to 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.²⁵ Specifics regarding complications and treatment of hypo- and hyperthermia are included in chapters 131 and 63. 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. Routine treatment consists of withdrawal of the offending agent, supportive care, and benzodiazepines. Other therapeutic options such as bromocriptine, amantadine, dantrolene, and electroconvulsive therapy have been used in severe cases.²⁶ Malignant hyperthermia is an inherited disorder characterized by hyperthermia, rigidity, and metabolic acidosis. It occurs in response to inhalational anesthetic agents and succinylcholine, and is treated with dantrolene.

HISTORY AND PHYSICAL EXAMINATION

Clinical features mandating consideration of drug overdose or poisoning are listed in Table 124-6. 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, herbal medications, dietary supplements, 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.²⁷

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—however, coingestions should still be considered in patients presenting with a classic toxidrome. Common toxidromes are listed in Table 124-7.

When initial signs and symptoms are less specific, we find it is useful to categorize patients as physiologically depressed (Table 124-8), or agitated and hyperadrenergic (Table 124-9). This categorization narrows the list of possible ingestions and impacts initial treatment strategies (see below). When confusion or delirium dominate, drugs listed in Table 124-10 deserve consideration.²⁸ 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 124-11) alter pupil size. Combining the patient’s physiologic state (ie, agitated or depressed) with pupil size provides for rapid assessment of the dominant ingestion. For example, the constellation of agitation, tachycardia, and rotator nystagmus is suspicious for phencyclidine intoxication; lethargy, pinpoint pupils, and slow and deep respirations are characteristic of opioid overdose.^28,29

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 124-12.²⁵ Dystonic reactions characterized by torticollis, tongue movements, and trismus are classic in haloperidol, phenothiazine, or metoclopramide overdose. Dyskinesias (eg, myoclonus, hyperkinetic activity, and repetitive activity) are seen with anticholinergics, PCP, and cocaine. Muscle rigidity with hyperthermia is the 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 osmol 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 HCO−3):

with a normal value of approximately 12 ± 4 mEq/L.³⁰

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 (hence the difference of approximately 12 mEq/L).³¹ 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.³²

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 HCO−3. 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 124-13.

Toxic ingestions may increase unmeasured anions and elevate the anion gap (eg, 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.^33,34 Drugs associated with an elevated anion gap are included in Table 124-14.

Rarely, toxic ingestion decreases the anion gap (<6 mEq/L). Causes of decreased anion gap are listed in Table 124-15. Note the presence of lithium on this list.

Osmol Gap: Certain drugs and toxins of low molecular weight (Table 124-16) produce a discrepancy between measured osmolality and calculated plasma osmolarity, commonly referred to as the osmol gap (osmol gap equals measured osmolality minus calculated osmolarity). The plasma osmol gap can thus be used to detect the presence of these toxins in the blood. Normal plasma osmolarity, determined by the concentrations of major solutes in plasma, is approximately 285 to 295 mOsm/L and is calculated as:

where Na⁺ (in mmol/L) is multiplied by 2 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 into mmol/L. Dividing ethanol concentration by 4.6 accounts for the effect of a measured plasma ethanol concentration (in mg/dL) on calculated plasma osmolarity. Of note, measured osmolality has units of mOsm/kg and calculated osmolarity has units of mOsm/L; subtracting one from the other, however, generally does not cause a critical error in analysis because 1 L ∼ 1 kg in human serum. Further note that spuriously low serum sodium values (pseudohyponatremia) due to hyperlipidemia or hyperproteinemia may cause a factitious osmol gap.

Methanol and ethylene glycol are unique in producing both severe metabolic acidosis with elevated anion gap and an elevated osmol gap. Isopropanol intoxication can elevate the osmol 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 osmol 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.^35,36 Although 10 mOsm/L is often used as the upper limit of normal, osmol gaps may range from −9 mOsm/L to +5 mOsm/L in normal individuals (using the standard formula for calculations).³⁷ Thus, an osmol gap of 10 mOsm/L in a patient whose baseline value is −2 mOsm/L could represent the presence of significant amounts of low-molecular-weight substances (eg, ethylene glycol level over 70 mg/dL).^38,39 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/L using the standard formula, including the contribution of measured ethanol concentrations.⁴⁰ Large variations existed in the range of osmol gap that was very dependent on the equation used. Because of the large range of values, the authors noted that small osmol gaps in no way exclude the possibility of toxic alcohol ingestion. Furthermore, as ethylene glycol/glycoaldehyde and methanol/formaldehyde are metabolized, the osmol gap may fall into the normal range in the continued presence of toxic metabolites.⁴¹ By contrast, concurrent ethanol ingestion may prevent early development of metabolic acidosis, so that the presence of an osmol gap greater than expected from the measured ethanol level may be the only clue to the presence of a nonethanol alcohol.⁴² Lactic acidosis and ketoacidosis have also been reported to cause elevation of the osmol gap.⁴³ Finally, chronic (but not acute) renal failure is a cause of increased osmol gap, a phenomenon corrected by dialysis.⁴⁴

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 osmol gap, particularly of large magnitude (>25 mOsm/L), 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 osmol 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 cooximetry. 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) or show evidence for body packing (see below). Sustained-release preparations may be detected more easily through digital enhancement of the radiograph.⁴⁵

TOXICOLOGY SCREENING

Toxicology screening provides direct evidence of ingestion, but it rarely impacts initial management, and supportive measures should not await results of such analysis. In Brett’s review of 209 cases of intentional drug overdose,⁴⁶ 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.⁴⁷ Management changes followed drug screening in only 16 (4.4%) of cases.

Toxicology screening provides evidence for select intoxications quickly (see below) and may establish the 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.⁴⁸ 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 (eg, trauma patients). Urine screens used in the ED are aimed at detecting common drugs of abuse (Table 124-17). Results are generally available in 30 minutes. Many more drugs are included in the expanded screening panel (Table 124-18), the results of which should be available in several hours. Table 124-19 lists some drugs not included in routine drug screening.

Toxicologic screening of blood is generally not additive to comprehensive urine testing, 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).⁴⁹ Quantitative blood analysis of suspected drugs can be useful for diagnostic and therapeutic reasons, particularly in overdoses involving alcohols, acetaminophen, and salicylates. And a strong argument can be made for checking acetaminophen and salicylate 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 by nurses, pharmacists, pharmacologists, and physicians trained in clinical toxicology. They provide information regarding substance identification, drug interactions, adverse drug reactions, and management of poisoned patients. These centers maintain current references and information about toxins and 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.⁵⁰ The national toll-free emergency phone number is 1-800-222-1222.

GASTRIC EMPTYING

Historically gastric emptying has been attempted by gastric lavage (GL) or syrup of ipecac. There is no role for ipecac in the hospital setting as it has no proven efficacy, it is associated with multiple risks, and it can delay or decrease the effectiveness of other methods of decontamination. In the out-of-hospital setting, the recommended use of ipecac has been narrowed to an incredibly select patient population that meets the following requirements: ipecac is not contraindicated (eg, the ingested substance is not a corrosive, the substance will not cause altered mental status); the ingestion poses a sincere life threat; there is no alternative therapy available; the patient will not be able to reach a hospital in under 1 hour; ipecac can be given within 90 minutes of ingestion; and it will not adversely impact definitive therapy.^51,52

GL can be attempted in the management of select ingestions. Like the use of ipecac, 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 most patients. The indication for GL is recent ingestion (under 60 minutes) of a highly toxic substance for which there is no reliable alternative therapy (such as antidote).⁵³ 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 (eg, anticholinergics, opioids), and patients who have taken agents that are readily absorbed from the gastrointestinal tract (eg, alcohols). 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.

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.

Prior to inserting a large-bore orogastric tube (Ewald tube), the mouth should be inspected for foreign material and equipment should be readied for suctioning. Large gastric tubes (37F-40F) 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. In the adult patient, lavage is performed by instilling 200-mL aliquots of warmed tap water or normal saline until there is clearing of aspirated fluid. In children, normal saline is preferred, because tap water has been associated with severe hyponatremia.⁵³ In adults, tap water is preferred over normal saline because it avoids unnecessary salt loading, and neither irrigant significantly alters blood cell concentrations or electrolyte concentrations.⁵⁴ 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 binds intraluminal drugs and interferes with their absorption.⁵⁵

The use of activated charcoal (AC) in acute overdose has become a source of heated debate in the last few years. The largest prospective randomized clinical trial to date, published by Eddleston et al in 2008, failed to show difference between poisoned patients given AC, multidose AC, and supportive care only⁵⁶; although the study has been criticized for its mean length from time of ingestion to hospital presentation and AC administration (greater than 4 hours) and the frequent use of forced emesis prior to presentation. Other prospective trials, large retrospective studies, and meta-analyses, however, show effective absorption of drug and improvement in clinical outcome measures.^57-59

In light of these conflicting studies, the routine use of single-dose activated charcoal in every poisoned patient is not recommended.⁶⁰ Those patients who should receive single-dose activated charcoal include those that have no contraindications for AC use and have a potentially toxic/fatal ingestion of drugs that can bind to AC.⁶¹

If AC is administered, it should be done in a timely fashion after ingestion, as efficacy has been shown to decrease over time. While classically taught that AC should be given within 1 hour of ingestion, there is evidence that it continues to significantly reduce drug absorption for up to 4 hours.⁵⁹ Activated charcoal should be avoided in stuporous, comatose, or convulsing patients unless an endotracheal tube protects the airway and a gastric tube is in place to administer the charcoal. Aspiration of this particulate has been associated with pneumonia,⁶² bronchiolitis obliterans,⁶³ acute respiratory distress syndrome,⁶⁴ and death.⁶⁵

Activated charcoal is generally given as a single dose. The dose is based on patient weight (1 g/kg added to four parts water to form an aqueous slurry). Mixing AC with juice, soda, or chocolate milk may improve patient acceptance of this unpleasant adsorbent.

Multiple-dose AC (MDAC) can enhance the elimination of selected toxins that have been absorbed.⁶⁶ 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. 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 pK_a (negative logarithm of the acid ionization constant), which maximizes transport across mucosal membranes into the gastrointestinal tract.⁶⁷ Based on experimental and clinical studies, the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists recommend it should be considered only in life-threatening ingestions of selected drugs: carbamazepine, dapsone, phenobarbital, quinine, or theophylline.⁶⁸

In their position statement, the AACT/EAPCCT reported that MDAC increases drug elimination, but has not been shown to reduce morbidity and mortality in controlled trials.⁶⁸ 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.⁶⁹ 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 three doses. Multiple doses should be used with caution in patients with decreased bowel sounds, abdominal distension, and emesis. Contraindications for MDAC use are the same as those for single-dose AC.

Combining AC with a cathartic may facilitate evacuation of the toxin and avoid 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.⁷⁰ McNamara and colleagues found no benefit to adding sorbitol to a simulated acetaminophen overdose.⁷¹ 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.⁷²

WHOLE-BOWEL IRRIGATION

The routine use of whole-bowel irrigation (WBI) is not recommended, as efficacy has not been established in controlled clinical trials.⁷³ Based on case reports, its use can be considered in a few cases: (1) potentially fatal or otherwise highly toxic ingestion of sustained-release or enteric-coated drugs, (2) ingestion of a large amount of iron, and (3) ingestion of large number of packets of illicit drugs (in the case of body packers).⁷³ WBI is performed with a polyethylene glycol electrolyte solution (eg, GoLYTELY) 1 to 2 L/h by mouth or nasogastric tube. Irrigation is generally continued until the rectal effluent is clear or there is radiographic evidence of clearance. 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 and lead to fluid overload (pulmonary or cerebral edema).⁷⁴

Therapeutic manipulation of urinary pH can enhance elimination of some intoxicants (Table 124-20). 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.

Currently, urinary alkalinization is most frequently recommended in moderate salicylate toxicity not yet meeting criteria for hemodialysis, although it may also be useful in enhanced elimination of chlorpropamide, 2,4-dichlorophenoxyacetic acid, diflunisal, fluoride, mecoprop, methotrexate, and phenobarbital.⁷⁵

Urinary alkalinization (pH >7) is usually achieved by administration of intravenous sodium bicarbonate (1-2 mEq/kg every 3-4 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.⁷⁶

Complications of urinary alkalinization 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 alkaline urine, yet increases the risk of alkalemia. Since urinary alkalinization can cause hypokalemia 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.⁷⁷ 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 to enhance elimination of weak bases, such as phencyclidine and amphetamines, is not recommended. It is not an effective elimination technique and carries with it the real risk of increased renal injury and systemic metabolic 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 lifesaving for such patients, although clear proof that ECR favorably alters the course of any intoxication is generally lacking.⁷⁸ 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.^79-81 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.^82-86

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.^87,88

   
   
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 3-4 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.

   
   
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.⁸⁷ 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 vs 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 vs 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:

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