Altered mental status is common in a toxicologic emergency. A detailed assessment of neurologic status should be made to determine if there is any alteration in level (stupor/coma or agitation) or content of consciousness (confusion/delirium).¹ The evaluation should include an assessment of pupillary reactivity, ocular movements, and motor responses. Ruling out structural versus toxic or metabolic reasons for the altered state is important. Drug-induced seizures are often difficult to treat and may respond only to specific antidotal therapy. In general, benzodiazepines are more effective in terminating drug-induced seizures than other agents.

Pupils should be assessed for size and reactivity, and ocular movements should be evaluated for the presence of sustained nystagmus. Agents associated with miosis include organophosphates/carbamates (mydriasis also seen), other cholinergic agents, opioids, acetone, clonidine, phencyclidine, phenothiazines, and nicotine. Both anticholinergics and sympathomimetics may cause mydriasis; the pupils are reactive to light with cocaine but unreactive in diphenhydramine overdose. Opioid withdrawal may also result in dilated pupils. The assessment may be difficult in the setting of multiple coingestants, whereby the response may be blocked or partially manifested. Horizontal nystagmus is commonly seen with alcohols, lithium, carbamazepine, solvents, and primidone. Phenytoin, sedative-hypnotics, and phencyclidine may cause a combination of vertical, horizontal, or rotatory nystagmus.

The clinical examination should also include evaluation of bowel sounds (decreased/hyperactive), skin (wet/dry), and mucosa (secretions).

Toxidromes

A complex of signs and symptoms may be identified by physical examination and grouped into a toxic syndrome, or “toxidrome.” In many cases, recognition of this toxic pattern is more important than identifying a specific offending agent. Identifying a toxidrome enables the clinician to initiate the assessment, derive a differential diagnosis, and formulate a treatment plan. The most typical toxidromes are listed in Table 68.2.² Importantly, the clinician should note that patients may not present with a classic toxidrome due to variable manifestations of toxins and overlapping features that exist between toxidromes.

Table 68.2

Toxidromes

BP, blood pressure; HR, heart rate; RR, respiratory rate; T, temperature; ↑, increase; ↓, decrease; ±, variable; —, change unlikely.

Adapted from Nelson NS, Lewin NA, Howland MA, et al: Initial evaluation of the patient: Vital signs and toxic syndromes. In Nelson NS, Lewin NA, Howland MA, et al (eds): Goldfrank’s Toxicologic Emergencies, 9th ed. New York, McGraw-Hill Medical, 2011, p 33.

Laboratory Tests

A laboratory test for a patient exposed to toxic agents should be helpful in diagnosis or monitoring.³ Select laboratory examinations may be used when appropriate to determine the three gaps of toxicology—the anion gap, the osmolar gap, and the oxygen saturation gap. An arterial blood gas (ABG) analysis will identify hypoxemia or hypoventilation, as well as acid-base abnormalities. Agents associated with a gap in oxygen saturation (>5% difference between measured and calculated saturation) include carbon monoxide (CO) and methemoglobin inducers. In these exposures, a pulse oximeter inaccurately reflects the oxygen saturation of tissues and co-oximetry is necessary to identify abnormal hemoglobins. Determination of electrolytes with blood urea nitrogen (BUN) and creatinine will detect renal abnormalities and allow calculation of the anion gap. Some common drugs associated with an anion gap acidosis are listed in Box 68.2. Hypoperfusion must also be considered as a cause of metabolic acidosis. An osmolar gap (>10 mOsm/L) may be caused by any small particle (toxin) that increases the measured osmolarity as measured by freezing point depression. Such agents include ethanol, ethylene glycol, glycerol, isopropyl alcohol, mannitol, methanol, propylene glycol, and sorbitol. An electrocardiogram (ECG) should be obtained when potential cardiac toxicity exists.

A qualitative urine drug screen is a combination of tests that serves to identify common drugs encountered in overdoses. However, a “tox screen” is usually unnecessary because the results rarely alter management, many toxins are not detectable, and positive results do not assess severity of exposure. Quantitative determination of drug/toxin concentrations in blood is indicated by history and clinical examination to diagnose the intensity of toxicity, monitor the treatment or course of a patient, or define indications for specific interventions. Serum concentration measurements may be required as criteria for therapy or to assess the effectiveness of therapy. Because of the ubiquity of acetaminophen in over-the-counter and prescription preparations and the potential for significant morbidity and even death, a level should be obtained in any suspected polydrug ingestion.

Gastrointestinal Decontamination

GI decontamination techniques in the poisoned patient with an oral ingestion have included gastric emptying procedures (ipecac-induced emesis, gastric lavage), adsorption of drugs (activated charcoal), and increasing transit through the GI tract (cathartics, whole bowel irrigation [WBI]). Use of these interventions has decreased due to uncertain evidence of benefit and recognition of adverse effects of the techniques.⁴ The consideration of a GI decontamination technique depends on the toxicity of the substance ingested, potential for deterioration in respiratory and mental status, severity of symptoms, dose, time since ingestion, presence of spontaneous emesis, and contraindications of the procedure.

Ipecac, which contains emetic alkaloids, stimulates gastric mucosal sensory receptors and the chemoreceptor trigger zone in the brain to produce vomiting. The amount of ingested drug removed by ipecac-induced emesis is highly variable, and no benefit of ipecac has been confirmed even when administered less than 60 minutes after ingestion. Currently, ipecac is not used in the management of adult poisoning victims.⁵ Complications that have been associated with ipecac administration include aspiration pneumonitis, esophageal rupture, Mallory-Weiss tear, pneumomediastinum, and protracted vomiting that can delay administration of activated charcoal.

Gastric lavage with a large bore (36- to 40-French) orogastric tube is a technique used to empty the stomach of orally ingested substances that can be associated with significant complications. After insertion of the tube, lavage is accomplished with sequential 250 mL aliquots of normal saline or water until no pill fragments are retrieved. Intubation for airway protection is required before the procedure in patients with a depressed level of consciousness or potential for sedation. No clear benefit of gastric lavage has been demonstrated, even when instituted in obtunded patients presenting within 1 hour of ingestion.⁶ Gastric lavage should not be employed routinely in the management of poisoned patients.⁷ In rare circumstances, gastric lavage may be considered with ingestion of a life-threatening amount of toxin when the procedure can be instituted within 60 minutes of ingestion or a significant amount of toxin is still likely to be present in the stomach. The clinician must consider contraindications and the potential risks before performing gastric lavage in an overdose patient. Serious complications include aspiration pneumonitis, esophageal perforation, and cardiovascular instability. Gastric lavage is contraindicated with ingestions of substances such as acid, alkali, or hydrocarbons when the risk of aspiration is increased. Patients with a risk of GI perforation or severe bleeding diathesis or who are combative should also not be subjected to gastric lavage.

Single-dose activated charcoal is one of the more frequently used interventions for GI decontamination. Activated charcoal potentially adsorbs the toxin in the GI tract and minimizes systemic absorption. The optimum dose of activated charcoal has not been established, but the usual dose for adults is 25 to 100 g (1 g/kg). Activated charcoal is not effective in adsorbing iron, lithium, cyanide, strong acids and bases, alcohols, and some hydrocarbons. Some clinical studies examining the use of activated charcoal versus no intervention found no improvement in outcomes.8,9 Volunteer studies suggest that the greatest benefit of administering activated charcoal may be within 1 hour of ingestion.¹⁰ Use of activated charcoal may be considered when a potentially toxic amount of a substance adsorbed by charcoal has been ingested within 1 hour.^11,12 Later administration may be appropriate if clinical factors suggest the ingested substance has not yet been completely absorbed. Activated charcoal is contraindicated in patients with a depressed level of consciousness unless intubated, when administration increases the risk of aspiration, or the patient is known or suspected to have a GI perforation. Few complications are associated with the appropriate use of single-dose activated charcoal. Emesis has been reported but may be related to sorbitol administered with charcoal or the ingested toxin.

Cathartics have been administered in poisoning ingestions based on the hypothesis that absorption and overall bioavailability of the agent are decreased by reducing contact time in the GI tract. Sorbitol (70% solution with activated charcoal) is the most commonly used cathartic, but magnesium citrate and magnesium sulfate have also been used. No clinical studies have demonstrated beneficial effects of cathartics in poisoned patients. A cathartic alone has no role in the management of poisonings, and even the routine use of a cathartic in combination with activated charcoal cannot be recommended.¹³ If a cathartic is used, only a single dose should be administered. A cathartic should not be administered in patients with ileus, GI obstruction or perforation, recent GI surgery, or hemodynamic instability. Complications of cathartics include nausea, vomiting, and abdominal cramping. Multiple doses of magnesium-containing cathartics may result in significant dehydration and electrolyte abnormalities.

WBI has been proposed as a technique to prevent absorption of ingested poisons by rapidly expelling the bowel contents. WBI involves the enteral administration (usually by nasogastric tube) of large volumes (1 to 2 L/hour in adults) of polyethylene glycol electrolyte lavage solution; this is continued until the rectal effluent is clear or elimination of the toxin has been confirmed. During the procedure, the head of the bed should be elevated to 45 degrees to decrease the likelihood of vomiting and aspiration. No clinical trials have assessed the impact of WBI on patient outcomes. Currently, there are no established indications for WBI, but it may be considered for potentially toxic ingestions of sustained-release or enteric-coated drugs, iron, and illicit drug packets.¹⁴ WBI is contraindicated in the presence of ileus, GI obstruction or perforation, GI bleeding, hemodynamic instability, or intractable vomiting. In the patient with decreased level of consciousness or respiratory depression, the airway must be protected before instituting WBI.

Enhanced Elimination

Multiple-dose activated charcoal (MDAC) therapy involves the repeat oral administration of activated charcoal to prevent absorption of drug that persists in the GI tract and to enhance elimination of drugs already absorbed into the body by functioning as an adsorbent “sink” at several sites in the gut.¹⁵ First, it can interrupt enterohepatic circulation of drugs or metabolites that are actively secreted into bile. Second, it can adsorb drugs or metabolites that enter the gut by active secretion or passive diffusion and prevent reabsorption. Finally, it may prevent desorption of drugs, particularly acidic substances that bind two to three times less avidly to activated charcoal in the alkalotic milieu of the intestinal lumen than in the acidic environment of the stomach. Drugs with a prolonged elimination half-life after overdose and small volume of distribution are more likely to have elimination enhanced significantly by MDAC.

There is no convincing evidence that MDAC reduces morbidity and mortality rates in poisoned patients.¹⁶ However, MDAC may be considered if the patient has ingested a life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine, or theophylline and may obviate the need for invasive extracorporeal techniques. Insufficient evidence exists to support routine use of MDAC in ingestions of other substances.

Forced diuresis involves the intravenous (IV) administration of large volumes of isotonic fluids and diuretics to enhance renal excretion of drug or metabolite. This method is of limited clinical benefit and should not be used because of the potential for fluid overload and acid-base disturbances.

Urinary alkalinization is beneficial in increasing renal clearance of weak acids such as salicylates and phenobarbital. These weak acids are ionized at alkaline urine pH, trapped in the renal tubules, and not reabsorbed. Alkalinization can be initiated by adding 88 to 132 mEq sodium bicarbonate to 1 L of 5% dextrose in water (D₅W). Urine pH should be tested every hour, and the rate of the bicarbonate infusion should be titrated to achieve a urine pH of 7.5 to 8.5. Alkalinization may be difficult to achieve if metabolic acidosis is present. Hypokalemia is a common complication and requires correction to facilitate urinary alkalinization. Increasing the urine pH with carbonic anhydrase inhibitors such as acetazolamide is not recommended because metabolic acidosis will worsen. Urine alkalinization can be considered in patients with significant salicylate ingestions who do not require hemodialysis. Phenobarbital poisonings are more effectively treated with MDAC.¹⁷

Hemodialysis is useful to increase the clearance of certain drugs and metabolites, as well as to correct metabolic acidosis induced by some substances. The concentration gradient of the unbound toxin provides the driving force for clearance. The following criteria should be applied to a drug to determine the potential for enhanced elimination by hemodialysis: low volume of distribution (<1 L/kg), single-compartment kinetics, low endogenous clearance (<4 mL/minute/kg), molecular weight less than 500 daltons, water solubility, and low plasma protein binding. Drugs for which hemodialysis should be considered in the presence of a significant intoxication include methanol, ethylene glycol, salicylates, lithium, valproic acid, boric acid, and thallium. The usual complications of hemodialysis may occur, particularly in unstable patients. Hemoperfusion is a form of extracorporeal toxin removal, whereby whole blood is passed through an adsorbent-containing (charcoal) cartridge. In general, if a compound is well adsorbed by activated charcoal, then charcoal hemoperfusion clearance may exceed that of hemodialysis. In contrast to hemodialysis, substances with a high degree of plasma protein binding can be removed. However, advancements in hemodialysis and the limited availability of hemoperfusion cartridges have resulted in decreased utilization of hemoperfusion. Charcoal hemoperfusion is effective for elimination of carbamazepine, phenobarbital, phenytoin, and theophylline. Lithium and other heavy metals are not well removed by hemoperfusion. Charcoal hemoperfusion is generally performed for 4 to 6 hours at flow rates of 250 to 400 mL/minute. The risks of hemoperfusion are similar to those of hemodialysis. Additionally, hypoglycemia, hypocalcemia, and hypothermia may occur.

Continuous renal replacement therapies have been used less frequently for drug removal in the treatment of poisoning.¹⁸ Clearance rates achieved with these techniques are considerably lower than those achieved with hemodialysis. Such therapy may be instituted after hemodialysis or hemoperfusion to further remove the drug after it slowly redistributes from tissue to blood. This is a potential option for agents such as lithium or procainamide. Continuous renal replacement techniques may be advantageous in hemodynamically unstable patients who cannot tolerate conventional hemodialysis or hemoperfusion. Despite many case reports demonstrating significant drug clearance, there are no data demonstrating that these techniques affect outcome.

Specific Poisonings

Alcohols

Ethylene Glycol and Methanol

Methanol and ethylene glycol are toxic alcohols that have similar properties in overdose. Toxicity can occur through ingestion, inhalation, or dermal absorption. Cardiopulmonary and central nervous system (CNS) symptoms are common, and both agents can produce an anion gap metabolic acidosis and an osmolar gap. However, absence of an osmolar gap or anion gap does not exclude a toxic ingestion. The osmolar gap may be normal if all alcohol is metabolized to acid metabolites, and an anion gap may be normal if metabolism of alcohol has not yet produced acid metabolites (e.g., concomitant ethanol ingestion or early presentation). If toxic alcohol ingestion is suspected, regardless of whether the patient is symptomatic, blood should be immediately sent for serum methanol, ethylene glycol, and ethanol levels, and definitive treatment initiated based on the clinical history and acid-base status. Significant toxicity is associated with methanol and ethylene glycol levels greater than 50 mg/dL. The severity of pH, serum bicarbonate, and anion gap abnormalities appears to be directly correlated with the likelihood of survival.

Ethylene glycol is found in antifreeze and deicing solutions. Ethylene glycol causes acidemia as a result of metabolism by alcohol dehydrogenase to glycolic and oxalic acid. Oxalate crystals in the urine may be detected with a Wood’s lamp or on microscopic examination, but they may not be present in the majority of exposed patients. Three classic phases of ethylene glycol toxicity have been described: neurologic, cardiopulmonary, and renal. During the first 0.5 to 12 hours after ingestion, ethylene glycol produces transient inebriation without the usual odor of ethanol, along with GI symptoms (nausea, vomiting). After toxic metabolites form (4 to 12 hours after ingestion), a metabolic acidosis develops along with CNS depression. The CNS symptoms may progress to coma associated with hypotonia, hyporeflexia, and occasionally seizures, meningismus, and cerebral edema. In the second stage (12 to 24 hours after ingestion), tachycardia and hypertension often occur along with progression of metabolic acidosis. Hypoxia may result from aspiration, heart failure, or acute respiratory distress syndrome. Death is most common in this stage. In the third stage (24 to 72 hours after ingestion), oliguria, flank pain, acute tubular necrosis, and renal failure develop.

Methanol is found in windshield washer fluid, solvents, and bootleg whiskey. It is metabolized by alcohol dehydrogenase to formaldehyde, which is then metabolized by aldehyde dehydrogenase to formic acid. Uncoupling of the mitochondrial oxidative metabolism produces lactic acid. The metabolic derangements are caused by lactic and formic acid; the latter is responsible for ocular disturbances. When methanol is ingested, peak levels occur within 30 to 60 minutes but there is often a latent period of about 24 hours (range 1 to 72 hours) before the development of toxic symptoms or metabolic acidosis. GI (abdominal pain, nausea, vomiting), CNS (dizziness, headache, seizures, coma), and ocular toxicities (blurred vision, photophobia, retinal edema, disc hyperemia, blindness) are seen.

Practice guidelines are available for the treatment of ethylene glycol and methanol intoxication.19,20 If the patient has symptoms and is significantly acidemic, sodium bicarbonate may be administered as a temporizing measure to enhance formate and oxalate elimination by ion trapping. Fluid overload and hyperosmolarity may become significant problems as a result of bicarbonate administration. Hydration is helpful because ethylene glycol is well excreted by the kidney as long as renal function is maintained. The definitive treatment of intoxication with methanol or ethylene glycol is inhibition of the alcohol’s metabolism and hemodialysis to remove the alcohol and toxic metabolites and to correct metabolic abnormalities. Hemodialysis should be considered for the following conditions: deteriorating vital signs despite intensive supportive care, significant metabolic acidosis (pH < 7.25 to 7.3), blood level of methanol or ethylene glycol higher than 25 mg/dL, or any evidence of renal failure or electrolyte imbalances unresponsive to conventional therapy.^19,20

Antidotal treatment of significant poisoning involves inhibition of alcohol dehydrogenase to prevent metabolism of the alcohols to toxic metabolites with ethanol or fomepizole. Ethanol (IV or oral) allows preferential metabolism of ethanol over methanol and ethylene glycol. Ethanol should be administered to maintain a blood level of 100 to 150 mg/dL. A loading dose should be followed by a maintenance infusion according to the established dosing requirements for nondrinkers, drinkers, and during hemodialysis (Table 68.3).²¹ Problems encountered during ethanol administration include CNS depression, hypoglycemia, dehydration, and fluctuating serum concentrations. A second IV line using 0.9% sodium chloride may be necessary to avoid development of hyponatremia because of the large free water content and significant hypertonicity (1713 mOsm/L) of 10% ethanol solution. Advance notice should be given to the pharmacy to allow sufficient time to locate enough ethanol for administering and preparing the solution. If IV ethanol is not available, oral ethanol can be used.

Table 68.3

Intravenous Administration of 10% Ethanol

^*A 10% vol/vol concentration yields approximately 100 mg/mL.

^†For a 5% concentration, multiply the amount by 2.

^‡Infusion to be started immediately after the loading dose. Concentrations above 10% are not recommended for intravenous administration. The dose schedule is based on the premise that the patient initially has a zero ethanol level. The aim of therapy is to maintain a serum ethanol level of 100 to 150 mg/dL, but constant monitoring of the ethanol level is required because of wide variations in endogenous metabolic capacity. Ethanol will be removed by hemodialysis.

^§Rounded to the nearest milliliter.

Adapted from Howland MA: Antidotes in depth: Ethanol. In Nelson NS, Lewin NA, Howland MA, et al (eds): Goldfrank’s Toxicologic Emergencies, 9th ed. New York, McGraw-Hill Medical, 2011, p 1419.

Fomepizole, a competitive inhibitor of alcohol dehydrogenase, is approved for use in ethylene glycol and methanol overdose.²² It is easier to administer than ethanol, does not cause sedation, and is associated with fewer severe and serious adverse events.²³ Fomepizole administration should be considered instead of ethanol if the patient develops altered consciousness, seizures, or a significant metabolic acidosis. Although fomepizole appears to be equally effective, there are no data to demonstrate its comparative efficacy or cost-effectiveness. Administration of ethanol or fomepizole should continue after dialysis until the serum ethylene glycol or methanol concentration is undetectable or less than 20 mg/dL or acidosis is resolved and the patient is asymptomatic. In the absence of renal dysfunction and a significant metabolic acidosis, the use of fomepizole potentially could obviate the need for hemodialysis, even though the serum ethylene glycol or methanol concentration exceeds 50 mg/dL.²⁴ If patients with high serum concentrations of ethylene glycol are not treated with hemodialysis, then their acid-base balance should be monitored closely and hemodialysis instituted if a metabolic acidosis develops.¹⁹

Additional therapeutic measures for ethylene glycol ingestions may include thiamine 100 mg IV and pyridoxine 50 mg every 6 hours until the ethylene glycol level is zero and no acidosis persists. If the patient becomes hypocalcemic as a result of precipitation of calcium oxalate crystals, calcium should be replaced. In methanol overdose, it may be reasonable to also administer IV folate (folinic or folic acids) at 50 to 75 mg IV every 4 hours for at least 24 hours to provide the cofactor for enhancing formic acid elimination.

Isopropyl Alcohol

Isopropyl alcohol may also be ingested, particularly by chronic alcoholics with no access to ethanol. It is found in rubbing alcohol and some hand sanitizers in high concentrations. Oral absorption occurs rapidly (within 0.5 hour), and it undergoes metabolism to acetone, carbon dioxide, and water. Symptoms may include severe abdominal pain, GI bleeding, nausea, and vomiting. Isopropyl alcohol is two to three times more potent than ethanol as a CNS depressant, and acetone is comparable with ethanol. Patients frequently present with headache, lethargy, ataxia, or coma. Respiratory depression occurs secondary to the CNS depression. Laboratory findings include an osmolar gap without a metabolic acidosis. Patients may, however, have a fruity odor on their breath from acetone, and ketonemia and ketonuria may also be present. Treatment is supportive with fluid administration for significant dehydration. Hemodialysis should be considered when isopropyl alcohol levels exceed 400 to 500 mg/dL, evidence of hypoperfusion exists, coma is present, or a failure to respond to supportive therapy is noted.

Propylene Glycol

Propylene glycol is another alcohol that can cause toxicity in critically ill patients receiving high doses of IV medications containing the alcohol as a solvent. Medications that contain propylene glycol include lorazepam, diazepam, phenobarbital, pentobarbital, nitroglycerin, phenytoin, esmolol, etomidate, and sulfamethoxazole/trimethoprim. Propylene glycol toxicity is more commonly observed with lorazepam because of the use of high doses in some patients, the frequency of use for sedation in ICUs, and the high concentration of propylene glycol—approximately 830 mg/mL.²⁵ Common manifestations of propylene glycol accumulation are anion gap metabolic acidosis and increased osmolar gap.²⁶ Additional toxicities include renal dysfunction, hemolysis, cardiac arrhythmias, seizures, and CNS depression or agitation. Clinical studies suggest that an elevated osmolar gap correlates with propylene glycol accumulation. Accumulation can occur when doses of lorazepam exceed 0.1 mg/kg/hour and when renal or hepatic insufficiency is present. Although toxicity is more common after long periods of lorazepam infusion (>3 days), toxicity has occurred with short-term, high-dose use. The treatment of choice is to stop the lorazepam infusion and sedate with an agent that does not contain propylene glycol. Hemodialysis removes propylene glycol but is usually not required unless severe renal dysfunction develops.

Analgesics

Acetaminophen

Acetaminophen (N-acetyl-p-aminophenol [APAP]) is present in a large number of prescription and over-the-counter medications and is frequently a coingestant with other drugs. In addition, unintentional overdoses result from patients unknowingly ingesting multiple products containing acetaminophen (particularly acetaminophen-narcotic combinations). Because APAP overdose may result in significant hepatotoxicity and even death that is preventable, it is important to recognize and initiate appropriate therapy. With higher doses of APAP, a greater proportion is hepatically metabolized by the cytochrome P-450 system of mixed function oxidases (CYP450) to the toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which can result in cell injury and death. Hepatic glutathione facilitates detoxification and elimination of NAPQI with therapeutic doses of APAP, but glutathione supply is overwhelmed in APAP overdoses. The clinical course of APAP toxicity has been divided into stages on the basis of the development of hepatotoxicity (Table 68.4).²⁷

Table 68.4

Stages of Acetaminophen Toxicity

Stage	Time Course (after Ingestion)	Characteristics
I	0-24 hours	Asymptomatic or nausea, vomiting; normal LFTs
II	24-72 hours (latent stage)	Right upper quadrant pain; abnormal LFTs and PT; renal dysfunction possible
III	72-96 hours (hepatic stage)	Encephalopathy, jaundice, bleeding, renal dysfunction; maximal hepatic injury, synthetic dysfunction
IV	4 days-2 weeks (recovery stage)	Recovery of liver function

LFT, liver function tests; PT, prothrombin time.

If possible, an estimate of the quantity and dosage form of APAP ingested and the time of ingestion should be obtained. In adults, hepatic toxicity can occur after ingestion of more than 7.5 to 10 g during 8 hours or less but has been reported with exposures of 4 g. The maximum daily dose of acetaminophen has been reduced to 3 g because of concerns for toxicity.²⁸ The risk of toxicity may be increased in patients with low glutathione stores (malnutrition, fasting state, chronic alcoholism) or induction of CYP450 enzymes (chronic alcoholism, phenytoin or carbamazepine use). For patients with a recent single, acute ingestion, an acetaminophen level should be obtained at least 4 hours after ingestion. Liver enzymes only need to be evaluated if the APAP level indicates potential toxicity or the clinical examination suggests hepatic injury. If the time of ingestion is unknown, an APAP level should be obtained on admission. An APAP level and liver function tests should be determined in patients presenting late, patients with multiple ingestions over time, or chronic ingesters of APAP.

Activated charcoal does adsorb acetaminophen, and it is reasonable to administer charcoal up to 2 hours after ingestion. Acetaminophen is absorbed rapidly from the GI tract, so later use of charcoal is not warranted unless gastric emptying is likely to be delayed. Administration of activated charcoal will not interfere with subsequent administration of oral N-acetylcysteine (NAC) therapy.

NAC is the antidote for APAP poisoning, but the optimal route and duration of treatment are still debated.²⁹ NAC limits toxicity by combining with NAPQI and by serving as a precursor of glutathione, which inactivates NAPQI. For patients with a single, acute ingestion of APAP, the serum acetaminophen level assessed at least 4 hours after ingestion is compared with the Rumack-Matthew nomogram. Treatment with NAC is initiated in the United States if the value falls above the lower possible hepatotoxicity line. Only the initial APAP level is used in making the decision to initiate or continue NAC treatment. Subsequent levels are unnecessary unless extended-release preparations are ingested (see following). The Rumack-Matthew nomogram is not useful for patients with multiple ingestions of APAP over time, chronic ingesters, or those ingesting extended-release forms (see following discussion). If acetaminophen levels are not available, NAC treatment should be initiated if more than 150 mg/kg or 10 g acetaminophen is ingested. For extended-release APAP, a second level 4 hours after an initial nontoxic level should be evaluated to assess for delayed absorption. If the second value is above the lower line on the Rumack-Matthew nomogram, NAC is initiated.

NAC is most effective in preventing toxicity if administered within 8 hours of ingestion. NAC therapy can be initiated pending results of the acetaminophen level if the patient is presenting late or APAP level results will be delayed. The oral regimen for NAC includes a loading dose of 140 mg/kg followed by 17 oral maintenance doses of 70 mg/kg administered 4 hours apart (72-hour regimen). Due to the odor of the oral form, a nasogastric tube may need to be placed for administration, and antiemetic therapy may be necessary to control vomiting that occurs in up to 50% of patients. If the patient vomits the loading dose or any maintenance dose within 1 hour of administration, the dose should be repeated. IV NAC is administered as a loading dose of 150 mg/kg over 60 minutes followed by 50 mg/kg infused over 4 hours and then 100 mg/kg infused over 16 hours (21-hour regimen). Anaphylactoid reactions may occur in 14% to 18% of patients with IV NAC. Oral and IV regimens of administering NAC are similar in efficacy.³⁰ However, the oral regimen may be more appropriate in patients who present later after ingestion (>18 hours) and when large amounts of APAP are ingested due to the higher dose of administered NAC.^31,32 If the patient has a serum APAP level in the potentially toxic range, the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level should be evaluated daily. If abnormal, additional tests such as bilirubin, prothrombin time, creatinine, BUN, blood glucose, and electrolytes should also be obtained. In patients with elevated liver enzymes, NAC may be continued beyond the full course of therapy until transaminases are decreasing.

Chronic ingesters of APAP or patients with multiple ingestions over time are problematic when determining the need to administer NAC. Presentation beyond 24 hours after ingestion makes the APAP level essentially useless, and there are no established guidelines for administration of NAC in these circumstances. A marker of toxicity that may be useful is the evaluation of AST and ALT. If enzymes are elevated at the time of presentation (>50 IU/L) or the APAP level is greater than 10 µg/mL (>10 µmol/L), a course of NAC should be strongly considered.³³ A course of NAC should also be administered to patients with hepatic failure caused by APAP.

Patients with evidence of toxicity from APAP should be monitored for signs and symptoms of hepatic failure. This includes evaluating mental status and frequently assessing blood glucose. In cases in which fulminant hepatic failure develops, appropriate consultation with a hepatologist should be obtained. Transplant may be an option in severe cases.

Opioids

Illicit and prescription opioids can result in a toxidrome characterized by depressed level of consciousness, respiratory depression, and miosis. However, manifestations may be variable depending on the drug used and presence of other drugs or alcohol. Miosis is not seen with meperidine, propoxyphene, and tramadol toxicity. Additional clinical findings may include hypotension, pulmonary edema, bronchospasm (heroin), ileus, nausea, vomiting, and pruritus. Seizures may be a manifestation of toxicity with meperidine, propoxyphene, and tramadol. Methadone use is associated with QT interval prolongation and ventricular arrhythmias.

Prescription opioids obtained from physicians or illicitly now account for almost 40% of all poisoning deaths in the United States and affect all age groups.³⁴ The agents most commonly involved in deaths include methadone, oxycodone, and hydrocodone.³⁵ Toxicity depends on the potency of the agent, dose ingested, tolerance of the individual, and concomitant use of other drugs. These prescription opioids have overshadowed deaths due to heroin. Heroin is rapidly absorbed by all routes of administration including IV, intranasal, intramuscular, subcutaneous, and inhalation, but most fatal overdoses occur with IV administration. IV fentanyl (sometimes extracted from analgesic patches) is also associated with fatalities. Diagnosis of an opioid overdose is made by characteristic clinical findings, exposure history, qualitative urine toxicology assay, and response to naloxone. Qualitative urine assays may not detect all opioid derivatives (e.g., fentanyl).

The immediate priorities in a patient with opioid toxicity are support of ventilation, correction of hypotension, and reversal of the toxic effects with an opioid antagonist. If reversal of respiratory depression cannot be accomplished quickly, intubation may be necessary. Isotonic fluids should be administered for hypotension. Naloxone, a potent competitive opioid antagonist, is the antidote for opioid toxicity. It can be administered intravenously, intramuscularly, subcutaneously, by sublingual injection, or through an endotracheal tube. The initial dose of naloxone in a suspected opioid overdose is 0.04 to 2 mg; the lower dose should be considered in patients suspected of chronic addiction to avoid precipitating acute withdrawal symptoms. The goal of therapy is to restore adequate spontaneous respirations rather than complete arousal. Doses of naloxone up to 10 to 20 mg may be required to reverse the effects of synthetic opioids such as pentazocine, methadone, and fentanyl. The effects of naloxone last approximately 60 to 90 minutes, necessitating continued observation of the patient for resedation. Patients may require continuous infusion of naloxone to maintain adequate respirations, particularly with long-acting opioids. The dose for infusion is typically one half to two thirds of the initial amount of naloxone that reversed the respiratory depression administered on an hourly basis. Adjustments of the dose should be made to achieve clinical end points and avoid withdrawal symptoms. Nalmefene, a long-acting opioid antagonist, has also been used to treat opioid overdoses, but prolonged withdrawal symptoms may be a concern.³⁶ Potential acetaminophen toxicity should be considered in patients ingesting opioids formulated with acetaminophen. Patients should also be observed for potential complications of opioid overdose including aspiration pneumonitis and noncardiogenic pulmonary edema. Noncardiogenic pulmonary edema is usually self-limited (24 to 36 hours) and managed with supportive care that may include intubation and mechanical ventilation.³⁷ Other complications that may be related to injection drug use include wound botulism, endocarditis, rhabdomyolysis, and compartment syndrome.