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Information

  1. Drug overdoses can present in a variety of settings, from intentional (eg, suicide or recreational) to unintentional (eg, child ingesting pills), iatrogenic (eg, unintentional overdose of acetaminophen from multiple products), and work related (eg, chemical plant exposures).
  2. Acetaminophen (APAP) is the leading cause of acute liver failure (ALF) in the United States and was associated with more than 100 deaths in 2019. APAP ingestion should be suspected in all patients being evaluated for suspected overdose, given its wide availability and the large number of combination products that contain APAP.
    1. The majority of damage occurs when CYP2E1 metabolizes APAP to the active metabolite, N-acetyl-p-benzoquinone-imine (NAPQI). NAPQI is normally neutralized by glutathione; however, toxicity ensues when NAPQI depletes endogenous glutathione stores. Excess NAPQI binds mitochondrial proteins in hepatocytes, which inhibits cellular respiration. This leads to necrosis and apoptosis, ultimately causing ALF.
    2. Patients may present without obvious illness, but then rapidly deteriorate to fulminant liver failure within 24 to 96 hours of ingestion. Initial symptoms can include nausea, vomiting, malaise, and anorexia. If untreated, these symptoms may progress to right upper quadrant abdominal pain, profound encephalopathy, hepatorenal syndrome, and metabolic acidosis. Lab abnormalities typically correlate with the severity of the ingestion and may include elevated AST/ALT, elevated PT/INR, and elevated bilirubin. The King’s College Criteria can be used to help predict the need for liver transplantation among patients with ALF from both APAP overdoses and non-APAP ALF as shown in Table 31.1. Please note that there is a modified King’s College Criteria that incorporates lactate and phosphate to increase the sensitivity (not shown).
    3. To determine whether patients require treatment for their APAP ingestion, serum APAP levels are plotted on the Rumack-Matthew nomogram (see Figure 31.1). This nomogram should only be used following an acute, single ingestion of immediate-release APAP. The APAP level should be plotted on the nomogram as early as possible, but at least 4 hours postingestion. There is minimal utility in obtaining APAP levels between 0- and 4-hour postingestion, aside from confirming if APAP was the substance ingested. Because absorption and distribution are still occurring, this level cannot reliably predict which patients will need to be treated.
    4. N-acetylcysteine (NAC) should be administered in the following circumstances:
      1. An APAP level above the treatment line on the Rumack-Matthew nomogram
      2. Unknown time of APAP ingestion with an APAP level greater than 10 μg/mL or evidence of liver injury
      3. History of chronic supratherapeutic APAP ingestion and evidence of liver injury
    5. Administration of IV NAC is generally well tolerated by most patients, although adverse effects include nausea, vomiting, flushing, and anaphylactoid reactions. Anaphylactoid reactions are significantly more common in patients without a toxic APAP level. Despite the risks, it is generally better to overtreat with NAC and discontinue the infusion if it is not indicated. If administered within 8 hours postingestion, NAC is nearly 100% effective in avoiding liver transplantation. This is because the body’s glutathione stores can last approximately 6 to 8 hours following a toxic ingestion. Therefore, waiting for the results of an APAP level between the 4- to 8-hour time frame before starting NAC won’t change a patient’s outcome. The use of IV NAC is far more common than PO NAC, given its ease of administration, potentially shorter treatment course, and increased tolerability. Discontinuation of NAC is typically recommended when the APAP level is undetectable, AST/ALT has significantly decreased for at least two consecutive draws, metabolic acidosis is resolved, serum creatinine is at baseline, and the INR is less than 2.0. Dosing can be found in Table 31.2.
  3. Salicylates are available in many over-the-counter products. The most commonly encountered agent is aspirin, which is used for the prevention and treatment of cardiovascular disease, as well as many other conditions.
    1. Salicylates are primarily absorbed in the stomach. Absorption is variable and can be delayed due to the formation of a bezoar, delayed release formulations, or salicylate-induced pylorospasm. The half-life is 2 to 4 hours, but this is prolonged up to 20 hours or longer with high doses or enteric-coated formulations. The volume of distribution is 0.2 to 0.3 L/kg and it is normally 90% protein bound, but this decreases to less than 75% following toxic ingestions. At physiologic pH (7.35-7.45), salicylate primarily exists in the ionized form. In an alkaline environment, salicylate does not easily cross the cellular membrane into organs, such as the blood-brain barrier. However, as the blood pH decreases, significantly more salicylate becomes nonionized and can therefore cross into organs leading to significant toxicity.
    2. Salicylate toxicity may initially present with nausea, vomiting, and tinnitus. Following larger ingestions, patients typically go on to develop a respiratory alkalosis secondary to salicylates directly stimulating the respiratory center in the brainstem. Salicylates can also cause uncoupling of oxidative phosphorylation, which leads to an anion gap metabolic acidosis and hyperthermia refractory to antipyretics. Altered mental status, gastrointestinal bleeding, pulmonary edema, seizures, and coma may also be seen.
    3. Salicylate levels greater than 30 to 40 mg/dL are typically considered toxic whereas patients with levels greater than 90 to 100 mg/dL should receive emergent hemodialysis (HD). Following an acute salicylate ingestion, administration of oral activated charcoal may prevent significant absorption and avoid more invasive therapies. Multidose activated charcoal may also be considered if there is a concern for bezoar formation or if an extended-release formulation was ingested. Practically, each time a serum concentration is higher (or the same) as the previous one, another dose of activated charcoal may be considered, if safe to do so, as this likely represents continued absorption. It is recommended that pertinent labs, such as salicylate concentrations and blood gases (venous or arterial), be monitored at least every 2 to 4 hours until salicylate levels are decreasing on two sequential lab draws. For patients who develop symptoms of salicylate toxicity, alkalinization of blood and urine via administration of IV sodium bicarbonate should be considered. The typical alkalinization regimen includes a 1 to 2 mEq/kg bolus of IV sodium bicarbonate followed by an isotonic sodium bicarbonate infusion titrated to a urine pH greater than or equal to 7.5 and a blood pH 7.45 to 7.55. Alkalinization of the urine increases salicylate excretion by decreasing the relative concentration of nonionized salicylate to the blood and trapping the ionized salicylate in the urine. Patients critically ill secondary to salicylate ingestion should be discussed with a toxicologist and nephrologist and may require immediate HD. Potential indications for HD include:
      1. Blood pH less than 7.2 despite aggressive alkalinization therapy
      2. Altered mental status, seizures, persistent central nervous system (CNS) disturbances
      3. Pulmonary edema or acute lung injury
      4. Acute renal failure
      5. Coagulopathy
      6. Serum salicylate level greater than 100 mg/dL
      7. Serum salicylate level greater than 90 mg/dL with impaired renal function
  4. Cardiovascular medications, such as β-blockers (BB), calcium-channel blockers (CCB), and cardiac glycosides (eg, digoxin), can lead to significant morbidity and mortality when ingested in toxic amounts. With an aging population and the associated increases in prescriptions for cardiovascular drugs, overdoses of these medications are expected to increase in the United States.
    1. BBs are used for a variety of medical conditions. They work by blocking β-adrenergic receptors, thus antagonizing catecholamines and decreasing intracellular cAMP. Across the BB class, the β-receptor-binding affinity and selectivity vary significantly. Drugs blocking β1 receptors reduce the inotropic and chronotropic effects on the heart, whereas drugs blocking β2 receptors reduce bronchodilatation and gluconeogenesis. However, in cases of overdose, BBs may lose β-receptor selectivity. Drugs such as labetalol and carvedilol also block α1 receptors, leading to a decrease in blood pressure.
      1. Overdose can result in severe bradycardia and hypotension (cardiogenic shock) as well as hypoglycemia, atrioventricular (AV) block, bronchospasm, and seizures (eg, propranolol). Following ingestion of an immediate-release BB, symptoms should develop within 6 hours and if patients are still asymptomatic at that time then the patient can be medically cleared. Patients who ingest an extended- release formulation or sotalol require a longer period of observation (12-24 hours).
      2. Initial treatment in overdose may include charcoal, IV fluids, and supporting the heart rate with the use of atropine or electrical pacing. Depending on the quantity of BB ingested, catecholamines (eg, epinephrine, norepinephrine) may be beneficial and sufficient to support patients until they recover without needing additional treatments. Glucagon is traditionally considered the first-line antidote for BB toxicity, though high-dose insulin is becoming increasingly popular and preferred. Glucagon increases intracellular cAMP and may be administered as a bolus of 3 to 5 mg IV push followed by an infusion at 3 to 5 mg/h. Patients frequently develop nausea and vomiting so care should be taken to prevent aspiration; ondansetron is often coadministered. Data increasingly support the use of high-dose insulin therapy for BB toxicity. Care should be taken when implementing this regimen, especially in BB overdose as these patients may already be hypoglycemic, so a concentrated dextrose solution should always be initiated concomitantly with the insulin bolus and infusion. Patients should receive an insulin bolus of 1 u/kg followed by an infusion of 1 u/kg/h, titrated to markers of organ perfusion. Doses up to 10 u/kg/h may be required. High-dose insulin improves cardiac function by improving cardiac myocyte glucose uptake and utilization. Venous-arterial extracorporeal membrane oxygenation (VA ECMO) may effectively be used for cardiac support if other treatment options are ineffective.
    2. CCBs are used for numerous indications. CCBs antagonize L-type voltage-gated calcium channels in myocardial cells, smooth muscle cells, and β-islet cells in the pancreas, thus inhibiting calcium entry into the cells. Dihydropyridines (eg, amlodipine and nifedipine) act peripherally and cause systemic vasodilation, whereas nondihydropyridines (eg, verapamil and diltiazem) act primarily within the heart, reducing inotropy and chronotropy. In the pancreas, CCBs decrease insulin secretion, leading to hyperglycemia.
      1. CCB overdoses present with hypotension (cardiogenic shock), sinus bradycardia, AV block, and hyperglycemia. As in BB overdose, CCBs may lose their selectivity and all agents may lead to hypotension and bradycardia.
      2. The treatment of CCB toxicity is similar to a BB overdose. Initial treatment may include activated charcoal, IV fluids, atropine, and IV calcium. Catecholamines, such as epinephrine or norepinephrine, may also be used to improve perfusion. High-dose insulin therapy is typically the first-line therapy for CCB toxicity causing significant hemodynamic compromise. Initial insulin dosing is a bolus of 1 u/kg followed by an infusion at 1 u/kg/h titrated up to a maximum of 10 u/kg/h based on markers of organ perfusion. A concentrated dextrose solution should be initiated concomitantly to avoid hypoglycemia, but the dextrose requirement is likely to be lower than with a BB overdose as patients with CCB toxicity are frequently already hyperglycemic.
    3. Digoxin is still used for the treatment of atrial fibrillation and congestive heart failure. Digoxin is a sodium-potassium ATPase inhibitor that increases intracellular sodium, leading to increased calcium and improved inotropy. It also stimulates the vagus nerve which causes decreased cardiac conduction velocity. Toxicity can occur with normal serum digoxin levels in the setting of hypokalemia, hypomagnesemia, or hypothyroidism. Conversely, serum digoxin levels can increase while on a stable dose if drugs such as amiodarone, verapamil, or erythromycin are coadministered or if renal elimination is decreased secondary to dehydration or other causes.
      1. Toxicity leads to increased automaticity and dysrhythmias, including frequent premature ventricular contractions (PVCs), atrial fibrillation with a slow ventricular response, bidirectional ventricular tachycardia, or complete AV block. Scooping of the ST segment may be seen on an ECG but is not indicative of toxicity. Other symptoms include nausea, vomiting, abdominal pain, altered mental status, and visual disturbances, including the classic yellow halos around sources of light. Hyperkalemia is present in acute overdoses and is correlated to mortality. Digoxin’s distribution in the body is bimodal; therefore, serum concentrations obtained less than 6 hours after ingestion may overestimate the severity of the overdose. Additionally, following the administration of digoxin immune antigen-binding fragments (Fab), digoxin is pulled from the tissue into the circulation and bound to the antidote. This may cause total digoxin serum concentrations to appear higher after administering this treatment, but this does not signal worsening toxicity. Therefore, we do not recommend following digoxin serum concentrations after antidote administration.
      2. Treatment of acute or chronic digoxin toxicity typically begins with supportive care, atropine for bradydysrhythmias, and potentially multidose activated charcoal, as dioxin undergoes enterohepatic recirculation. Both hypokalemia and hyperkalemia can worsen toxicity. Patients with hypokalemia should receive IV potassium repletion until their potassium is within the normal range, and digoxin immune Fab should not be administered until the hypokalemia is corrected. Similarly, hyperkalemia should be corrected by the usual means. IV calcium in the context of hyperkalemia associated with digoxin toxicity is controversial, but recent data do not support the universal avoidance of IV calcium. Hypomagnesemia may also occur with digoxin toxicity, and correction may temporarily help stabilize the patients; therefore, it is generally recommended to administer 2 g of IV magnesium sulfate and give additional magnesium as needed based on the patient’s magnesium concentration. Tachydysrhythmias may be managed with IV lidocaine; all Class IA antidysrhythmics are contraindicated. Ultimately, the administration of IV digoxin immune Fab is necessary for life-threatening toxicity. The dose may be calculated based on either the reported amount of digoxin ingested or on the digoxin serum concentration. Additionally, empiric doses may be given if this information cannot be obtained. Indications for digoxin immune Fab include:
        1. Life-threatening dysrhythmias secondary to digoxin
        2. Potassium level greater than 5 mEq/L following an acute digoxin ingestion
        3. Chronic ingestion of digoxin associated with dysrhythmias, significant GI symptoms, or altered mental status
        4. Total digoxin level greater than 15 ng/mL at any point or greater than 10 ng/mL at least 6 hours postingestion
        5. Ingestion of 10 mg of digoxin in adults or 4 mg of digoxin in children
  5. Antipsychotics and Antidepressants
    1. Antipsychotics include traditional (aka “typical antipsychotics”) medications, such as haloperidol and chlorpromazine, and newer classes (aka “atypical antipsychotics”) of antipsychotics such as quetiapine, olanzapine, and risperidone, which have less antidopaminergic effects. All antipsychotics can produce adverse reactions such as neuroleptic malignant syndrome (see Section IV), extrapyramidal side effects (ie, parkinsonism and dystonia), and tardive dyskinesia (irreversible, purposeless movements of the face and neck), though atypical antipsychotics produce these less frequently. In overdose, patients develop stupor and hypotension with reflex tachycardia, prolongation of the QT interval on electrocardiogram (ECG). Treatment of an antipsychotic overdose involves supportive care, IV benztropine or diphenhydramine if the patient develops extrapyramidal side effects, and IV magnesium for prolonged QTc.
    2. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), atypical antidepressants (eg, bupropion), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). Ingestion of SSRIs, SNRIs, and MAOIs may lead to serotonin toxicity (see Section IV). Bupropion overdose may be complicated by tachycardia, hypertension, agitation, seizures, and QRS prolongation. Bupropion-related seizures should be treated with IV benzodiazepines. Patients with a prolonged QRS should receive IV sodium bicarbonate. TCAs block cardiac sodium channels causing a prolonged QRS and lead to dysrhythmias such as wide-complex ventricular tachycardia and ventricular fibrillation. Treatment of a QRS greater than 100 ms or hypotension secondary to a TCA ingestion should include administration of a 1 to 2 mEq/kg sodium bicarbonate bolus repeated every 3 to 5 minutes until symptoms improve. Hypertonic saline (3%) may also be used in place of sodium bicarbonate if the latter is not available. TCA toxicity may also include the development of delirium, agitation, and seizures, which should be treated initially with IV benzodiazepines.
  6. Lithium is used for the long-term treatment of bipolar disorder but has a narrow therapeutic window with several adverse side effects.
    1. Acute lithium ingestions can present with nausea, vomiting, and diarrhea initially, and progress to the development of CNS depression and cardiac manifestations (eg, T-wave flattening and QTc prolongation). Early management includes aggressive fluid hydration with normal saline; activated charcoal does not bind lithium and should be avoided unless other medications are also ingested. Serum lithium levels should be obtained upon presentation and regularly every few hours to monitor absorption and elimination. In severe cases of lithium toxicity, emergent hemodialysis may be required. Initiation of hemodialysis should be discussed with a toxicologist and potential indications include:
      1. Impaired renal function with lithium level greater than 4 mEq/L
      2. Decreased level of consciousness, confusion, seizures, or life-threatening dysrhythmias
      3. Lithium level greater than 5 mEq/L
      4. Expected time to reach lithium level less than 1 mEq/L of more than 36 hours
    2. Chronic lithium toxicity results in significantly different symptoms than those associated with acute ingestions. These symptoms include tremor, hyperreflexia, clonus, dysarthria, nystagmus, ataxia, altered mental status, and seizure. These symptoms occur because lithium is directly neurotoxic. Treatment is limited to discontinuation of lithium, and many of these symptoms may be irreversible.