Acetaminophen

Acetaminophen is the most widely used analgesic and antipyretic in pediatrics, available in multiple formulations, strengths, and combinations. Consequently, acetaminophen is commonly available in the home, where it can be unintentionally ingested by young children, taken in an intentional overdose by adolescents and adults, or inappropriately dosed in all ages. Acetaminophen toxicity remains the most common cause of acute liver failure in the United States.

If a toxic ingestion is suspected, a serum acetaminophen level should be calculated 4 hr after the reported time of ingestion. For patients who present to medical care >4 hr after ingestion, a stat acetaminophen level should be obtained. Acetaminophen levels obtained <4 hr after ingestion are difficult to interpret and cannot be used to estimate the potential for toxicity. Other important baseline labs include hepatic transaminases, renal function tests, and coagulation parameters.

Any patient with a serum acetaminophen level in the possible or probable hepatotoxicity range per the Rumack-Matthew nomogram (see Fig. 58-1) should be treated with N-acetylcysteine (NAC). This nomogram is only intended for use in patients who present within 24 hr of a single acute acetaminophen ingestion with a known time of ingestion. Patients who have an initially nontoxic level and have ingested combination products or co-ingestants that can slow GI motility (e.g., diphenhydramine, opioids) should have a second acetaminophen level drawn 6-8 hr after ingestion to ensure that ongoing absorption in the setting of poor motility has not caused the acetaminophen level to cross the line into the possible or probable hepatotoxicity range.

Figure 58-1 Rumack-Matthew nomogram for acetaminophen poisoning, a semilogarithmic plot of plasma acetaminophen concentrations vs time. Cautions for the use of this chart: The time coordinates refer to time after ingestion, serum concentrations obtained before 4 hr are not interpretable, and the graph should be used only in relation to a single acute ingestion with a known time of ingestion. This nomogram is not useful for chronic exposures or unknown time of ingestion and should be used with caution in the setting of co-ingestants that that slow gastrointestinal motility. The lower solid line is typically used in the United States to define toxicity and direct treatment, whereas the upper line is generally used in Europe.

(From Rumack BH, Hess AJ, editors: Poisindex, Denver, 1995, Micromedix. Adapted from Rumack BH, Matthew H: Acetaminophen poisoning and toxicity, Pediatrics 55:871–876, 1975.)

Assessment of the patient who presents with an unknown time of ingestion or a history of chronic supratherapeutic ingestion is more complicated. One approach is to check an acetaminophen level, hepatic transaminases, and coagulation parameters. If the acetaminophen level is >10 µg/mL, even with normal liver function tests, this patient is a candidate to be treated with NAC. This practice serves to catch patients in the asymptomatic phase of toxicity, before hepatotoxicity develops, because a level of 10 µg/mL is potentially toxic at ≥20 hr after ingestion. Patients who have any signs of hepatotoxicity (elevated transaminases and international normalized ratio [INR]), even with a low or nondetectable acetaminophen level, are also candidates for antidotal therapy. However, patients who have an acetaminophen level <10 µg/mL and normal transaminases are unlikely to develop significant toxicity. Although this is a conservative approach, the benefits of treating with NAC likely outweigh the risks of treatment or missing potential hepatotoxicity in most of these cases. Consultation with the poison control center (1-800-222-1222) or a medical toxicologist is recommended in these difficult cases.

Treatment

Initial treatment should focus on the ABCs and consideration of decontamination with activated charcoal in patients who present within 1-2 hr of ingestion. The antidote for acetaminophen poisoning is NAC, which works primarily via replenishing hepatic glutathione stores. NAC therapy is most effective when initiated within 8 hr of ingestion, though it has been shown to have benefit even in patients who present in fulminant hepatic failure, likely due to its antioxidant properties. There is no demonstrated benefit to giving NAC before the 4 hr postingestion mark. Thus, patients who present early after ingestion should have a 4 hr level drawn, and decision to initiate NAC should be based on this level. Patients with a history of a potentially toxic ingestion who present >8 hr after ingestion should be given the loading dose of NAC, and decision to continue treatment should be based on the stat acetaminophen level and/or other lab parameters as noted earlier.

NAC is available in oral and intravenous forms, and both forms are equally efficacious (see Table 58-8 for the dosing regimens of the oral vs. IV form). The intravenous form is generally preferred, especially in patients with intractable vomiting, those with evidence of hepatic failure, and pregnant patients. NAC has an unpleasant taste and smell, and it should be mixed in soft drink or fruit juice or given via nasogastric tube to improve tolerability of the oral regimen. Administration of IV NAC (as a standard 3% solution to avoid administering excess free water, typically in 5% dextrose), especially the initial loading dose, is associated in some patients with the development of anaphylactoid reactions (non–immunoglobulin E [IgE] mediated). These reactions are typically managed by stopping the infusion; treating with diphenhydramine, albuterol, and/or epinephrine as indicated; and restarting the infusion at a slower rate once symptoms have resolved. IV NAC is also associated with mild elevation in measured INR (1.2-1.5 range).

Transaminases, synthetic function, and renal function should be followed daily while the patient is being treated with NAC. Patients with worsening hepatic function or clinical status might benefit from more frequent lab monitoring. Instead of a standard time course of therapy for all patients with acetaminophen poisoning, current literature suggests a more patient-tailored approach to length of NAC treatment. That is, NAC is continued for at least 21-24 hr and until the patient is clinically well, with improving transaminases, normalizing synthetic function, and acetaminophen level <10 µg/mL. Patients who develop hepatic failure in spite of NAC therapy may be candidates for liver transplantation. The King’s College criteria are used to determine which patients should be referred for consideration of liver transplant. These criteria include acidosis (pH <7.3) after adequate fluid resuscitation, coagulopathy (prothrombin time [PT] >100 sec), renal dysfunction (creatinine >3.4 mg/dL), and grade III or IV hepatic encephalopathy (Chapter 356).

Pathophysiology

Salicylates lead to toxicity by interacting with a wide array of physiologic processes including direct stimulation of the respiratory center, uncoupling of oxidative phosphorylation, inhibition of the tricarboxylic acid cycle, and stimulation of glycolysis and gluconeogenesis. The acute toxic dose of salicylates is generally considered to be >150 mg/kg. More significant toxicity is seen after ingestions of >300 mg/kg, and severe, potentially fatal, toxicity is described after ingestions of >500 mg/kg.

Clinical and Laboratory Manifestations

Salicylate ingestions are classified as acute or chronic, and acute toxicity is far more common in pediatric patients. Early signs of acute salicylism include nausea, vomiting, diaphoresis, and tinnitus. Moderate salicylate toxicity can manifest as tachypnea and hyperpnea, tachycardia, and altered mental status. The tachycardia results in large part from marked insensible losses from vomiting, tachypnea, diaphoresis, and uncoupling of oxidative phosphorylation. Thus, careful attention should be paid to volume status and early volume resuscitation in the significantly poisoned patient. Signs of severe salicylate toxicity include hyperthermia, coma, and seizures. Chronic salicylism can have a more insidious presentation, and patients can show marked toxicity at significantly lower salicylate levels than in acute toxicity.

The classic blood gas of salicylate toxicity reveals a primary respiratory alkalosis and a primary, anion gap, metabolic acidosis. Hyperglycemia (early) and hypoglycemia (late) have been described. Abnormal coagulation studies, clinically manifested as bleeding and easy bruising, may also be seen.

Serial serum salicylate levels should be closely monitored (every 2 hr initially) until they are consistently down trending. Salicylate absorption in overdose is often unpredictable and erratic, and levels can rapidly increase into the highly toxic range. The Done nomogram is of poor value and should not be used. Serum and urine pH and electrolytes should be followed closely. An acetaminophen level should be checked in any patient who intentionally overdoses on salicylates, because acetaminophen is a common co-ingestant and because people often confuse or combine their OTC analgesic medications. Salicylate toxicity can cause a noncardiogenic pulmonary edema, especially in chronic overdose; thus a chest x-ray is recommended in any patient with signs and symptoms of pulmonary edema.

Treatment

For the patient who presents soon after an acute ingestion, initial treatment should include gastric decontamination with activated charcoal. Salicylate pills occasionally form concretions called bezoars, which should be suspected if serum salicylate concentrations continue to rise many hours after ingestion or are persistently elevated in spite of appropriate management. Gastric decontamination is typically not useful after chronic exposure.

Initial therapy focuses on aggressive volume resuscitation and prompt initiation of sodium bicarbonate therapy in the symptomatic patient, even before obtaining serum salicylate levels. Therapeutic salicylate levels are 10-20 mg/dL, and levels >30 mg/dL warrant treatment.

The primary mode of therapy for salicylate toxicity is urinary alkalinization. Urinary alkalinization enhances the elimination of salicylates by converting salicylate to its ionized form, “trapping” it in the renal tubules, and thus enhancing elimination. In addition, maintaining an alkalemic serum pH decreases CNS penetration of salicylates because charged particles are less able to cross the blood-brain barrier. Alkalinization is achieved by administration of a sodium bicarbonate infusion at approximately 1.5 times maintenance fluid rates. The goals of therapy include a urine pH of 7.5-8, a serum pH of 7.45-7.55, and decreasing serum salicylate levels. Careful attention should be paid to serial potassium levels, because hypokalemia impairs alkalinization of the urine. Multiple doses of charcoal may be beneficial if a salicylate bezoar is suspected.

In cases of severe toxicity, dialysis may be required. Indications for dialysis include serum salicylate concentrations of >90-100 mg/dL in acute ingestions and >60 mg/dL in chronic ingestions, altered mental status, seizures, pulmonary edema, cerebral edema, renal failure, and worsening clinical status in spite of appropriate alkalinization.

Pathophysiology

NSAIDs inhibit prostaglandin synthesis by reversibly inhibiting the activity of cyclo-oxygenase (COX), the primary enzyme responsible for the biosynthesis of prostaglandins. In therapeutic use, side effects include GI irritation, reduced renal blood flow, and platelet dysfunction. In an attempt to minimize these side effects, NSAID analogs have been developed that are more specific for the inducible form of COX (the COX-2 isoform) than the constitutive form, COX-1. However, overdose of the more selective COX-2 inhibitors (e.g., celecoxib [Celebrex]) is treated the same as overdose of nonspecific COX inhibitors (e.g., ibuprofen) because at higher doses, COX-2–selective agents lose their COX inhibitory selectivity.

Ibuprofen, the primary NSAID used in pediatrics, is well tolerated, even in overdose. In children, acute doses of <200 mg/kg rarely cause toxicity, but ingestions of >400 mg/kg can produce more serious effects, including altered mental status and metabolic acidosis.

Clinical and Laboratory Manifestations

Symptoms usually develop within 4-6 hr of ingestion and resolve within 24 hr. If toxicity does develop, it is typically manifested as nausea, vomiting, and abdominal pain. Though GI bleeding and ulcers have been described with chronic use, they are rare in the setting of acute ingestion. After massive ingestions, patients can develop marked CNS depression, anion gap metabolic acidosis, renal insufficiency, and (rarely) respiratory depression. Seizures have also been described, especially after overdose of mefenamic acid. Specific drug levels are not readily available nor do they inform management decisions. Renal function studies, acid-base balance, complete blood count, and coagulation parameters should be monitored after very large ingestions. Co-ingestants, especially acetaminophen, should be ruled out after any intentional ingestion.

Treatment

Meticulous supportive care, including use of antiemetics and acid blockade as indicated, is the primary therapy for NSAID toxicity. Decontamination with activated charcoal should be considered if a patient presents within 1-2 hr of a potentially toxic ingestion. There is no specific antidote for this class of drugs. Given the high degree of protein binding and excretion pattern of NSAIDs, none of the modalities used to enhance elimination are particularly useful in managing these overdoses. Unlike in patients with salicylate toxicity, urinary alkalinization is not helpful for NSAID toxicity. Patients who develop significant clinical signs of toxicity should be admitted to the hospital for ongoing supportive care and monitoring. Patients who remain asymptomatic for 4-6 hr after ingestion may be considered medically cleared.

Pathophysiology

Methadone is a lipophilic synthetic opioid with potent agonist effects at µ-opioid receptors, leading to both its desired analgesic effects and undesired side effects including sedation, respiratory depression, and impaired GI motility. Methadone is thought to cause QTc interval prolongation via interactions with the human ether-a-go-go–related gene (hERG)-encoded potassium rectifier channel. Methadone has an average half-life of >25 hr, which may be extended to >50 hr in overdose or with chronic use.

Suboxone is a combination of buprenorphine, a potent opioid with partial agonism at µ-opioid receptors and weak antagonism at κ-opioid receptors, and naloxone. Naloxone has poor oral bioavailability but is included in the formulation to discourage diversion for intravenous use, during which it precipitates withdrawal. Suboxone is formulated for buccal or sublingual administration; consequently, toddlers can absorb significant amounts of drug even by sucking on a tablet. Buprenorphine has an average half-life of 37 hr.

Clinical and Laboratory Manifestations

In children, methadone and suboxone ingestions can manifest with the classic opioid toxidrome of respiratory depression, sedation, and miosis. Signs of more-severe toxicity can include bradycardia, hypotension, and hypothermia. Even in therapeutic use, methadone has been associated with a prolonged QTc interval and risk of torsades de pointes. Accordingly, an ECG should be part of the initial evaluation after ingestion of methadone or any unknown opioid. Neither drug is detected on routine urine opiate screens, though some centers have added a separate urine methadone screen. Levels of both drugs can be measured, though this is rarely done clinically and is seldom helpful in the acute setting. An exception may be in the cases involving concerns about neglect or abuse, at which point urine for gas chromatography/mass spectroscopy (GC/MS), the legal gold standard, should be sent to confirm and document the presence of the drug.

Treatment

Patients with significant respiratory depression or CNS depression should be treated with the opioid antidote, naloxone (see Table 58-8). In pediatric patients who are not chronically on opioids, the full reversal dose of 0.1 mg/kg (max, 2 mg/dose) should be used. In contrast, opioid-dependent patients should be treated with smaller initial doses (0.01 mg/kg), which can then be repeated as needed to achieve the desired clinical response, hopefully avoiding abrupt induction of withdrawal. Because the half-lives of methadone and suboxone are far longer than that of naloxone, patients can require multiple doses of naloxone. These patients might benefit from a continuous infusion of naloxone, typically started at 2/3 of the reversal dose/hr and titrated to maintain an adequate respiratory rate and level of consciousness. Patients who have ingested methadone should have serial ECGs to monitor for the development of a prolonged QTc interval. If a patient does develop a prolonged QTc, management includes close cardiac monitoring, repletion of electrolytes (potassium, calcium, and magnesium), and having magnesium readily available should the patient develop torsades de pointes.

Given the potential for clinically significant and prolonged toxicity, any toddler who has ingested methadone, even if asymptomatic, should be admitted to the hospital for at least 24 hr of monitoring. Some experts advocate a similar approach to management of suboxone ingestions, even in the asymptomatic patient. As we gain more experience with pediatric suboxone exposures, some patients who remain absolutely asymptomatic for 6-8 hr after ingestion and have a stable social setting may be candidates for earlier discharge. In the meantime, these cases should be discussed with a poison control center or medical toxicologist before determining disposition.

Pathophysiology

In overdose, β-blockers decrease chronotropy and inotropy in addition to slowing conduction through AV nodal tissue. Clinically, these effects are manifested as bradycardia, hypotension, and heart block. Patients with reactive airways disease can experience bronchospasm due to blockade of β₂-mediated bronchodilation. β₂-Blockers interfere with glycogenolysis and gluconeogenesis, which can lead to hypoglycemia, especially in patients with poor glycogen stores (e.g., toddlers).

Clinical and Laboratory Manifestations

Toxicity typically develops within 6 hr of ingestion, though it may be delayed after ingestion of sotalol or sustained-release preparations. The most common features of severe poisoning are bradycardia and hypotension. Lipophilic agents, including propranolol, can enter the CNS and cause altered mental status, coma, and seizures. Overdose of β-blockers with membrane-stabilizing properties (e.g., propranolol) can cause QRS interval widening and ventricular dysrhythmias.

Evaluation after β-blocker overdose should include an ECG and frequent reassessments of hemodynamic status. Hypoglycemia may be seen, especially in children, and blood glucose should be measured in all patients. Serum levels of β-blockers are not readily available for routine clinical use and are not useful in management of the poisoned patient.

Treatment

In addition to supportive care and GI decontamination as indicated, glucagon is the antidote of choice for β-blocker toxicity (see Table 58-8). Glucagon stimulates adenyl cyclase and increases levels of cyclic AMP independent of the β receptor. Glucagon is typically given as a bolus and, if this is effective, followed by a continuous infusion. Other potentially useful interventions include atropine, calcium, vasopressors, and high-dose insulin. Seizures are managed with benzodiazepines, and QRS widening should be treated with sodium bicarbonate. Children who ingest 1 or 2 water-soluble β-blockers are unlikely to develop toxicity and can typically be discharged to home if they remain asymptomatic over a 6-hr observation period. Children who ingest sustained-release products, highly lipid soluble agents, and sotalol can require longer periods of observation before safe discharge. Any symptomatic child should be admitted for ongoing monitoring and directed therapy.

Pathophysiology

CCBs antagonize L-type calcium channels, inhibiting calcium influx into myocardial and vascular smooth muscle cells. This results in depressed myocardial contractility and conduction as well as peripheral vasodilation, with subsequent development of hypotension and bradydysrhythmias. Though receptor selectivity is often lost in overdose, ingestion of certain CCBs with more peripheral activity (e.g., nifedipine) can result in an initial reflex tachycardia or normal heart rate. Metabolic acidosis develops in the setting of poor perfusion.

Clinical and Laboratory Manifestations

The onset of symptoms typically is soon after ingestion, though it may be delayed with ingestions of sustained-release products. Overdoses of CCBs lead to hypotension, accompanied by bradycardia, normal heart rate, or even tachycardia, depending on the agent. One unique characteristic of CCB overdose is that patients can exhibit profound hypotension with preserved consciousness.

Initial evaluation should include an ECG, continuous and careful hemodynamic monitoring, and rapid measurement of serum glucose levels. Both the absolute degree of hyperglycemia and the percentage increase in serum glucose have been correlated with the severity of CCB toxicity in adults. The development of hyperglycemia can even precede the development of hemodynamic instability. Blood levels of CCBs are not readily available and are not useful in guiding therapy.

Treatment

Once initial supportive care has been instituted, GI decontamination should begin with activated charcoal as appropriate. WBI may be beneficial after ingestion of a sustained-release product. Calcium channel blockade in the smooth muscles of the GI tract can lead to greatly diminished motility; thus, any form of GI decontamination should be undertaken with careful attention to serial abdominal exams. High-dose insulin therapy is considered the antidote of choice for CCB toxicity. An initial bolus of 1 U/kg of regular insulin is followed by an infusion at 0.5-1 U/kg/hr (see Table 58-8). Blood glucose levels should be closely monitored, and supplemental glucose may be given to maintain euglycemia, though this is rarely necessary in the severely poisoned patient. Calcium salts are typically administered in an overdose setting, although they might not provide substantial clinical benefit. Additional therapies include IV fluid boluses, vasopressors, and cardiac pacing. In extreme cases, extracorporeal membrane oxygenation (ECMO), cardiac assist devices, and lipid emulsion therapy may be lifesaving. Given the potential for profound and sometimes delayed toxicity in toddlers after ingestion of 1 or 2 CCB tablets, hospital admission and 24 hr of monitoring for all of these patients is strongly recommended.

Pathophysiology

Clonidine is a centrally acting α₂ agonist with a very narrow therapeutic index. Agonism at central α₂ receptors decreases sympathetic outflow, producing lethargy, bradycardia, and hypotension. Toxicity can develop after ingestion of as little as 1 pill or after sucking on or swallowing a discarded transdermal patch.

Clinical and Laboratory Manifestations

The most common clinical manifestations of clonidine toxicity include lethargy, miosis, and bradycardia. Hypotension, respiratory depression, and apnea may be seen in severe cases. Very early after ingestion, patients may be hypertensive in the setting of agonism at peripheral α receptors and resulting vasoconstriction. Symptoms develop relatively soon after ingestion and typically resolve within 24 hr. Serum clonidine concentrations are not readily available and are of no clinical value in the acute setting. Though signs of clinical toxicity are common after clonidine overdose, death from clonidine alone is extremely unusual.

Treatment

Given the potential for significant toxicity, most young children warrant referral to a health care facility for evaluation after unintentional ingestions of clonidine. Gastric decontamination is usually of little value owing to the small quantities ingested and the rapid onset of serious symptoms. Aggressive supportive care is imperative and is the cornerstone of management. Naloxone, often in high doses, has shown variable efficacy in treating clonidine toxicity. Other potentially useful therapies include atropine, IV fluid boluses, and vasopressors. Symptomatic children should be admitted to the hospital for close cardiovascular and neurologic monitoring.

Pathophysiology

Digoxin blocks the Na⁺, K⁺-ATPase pump, leading to intracellular loss of K⁺ and gain of Na⁺ and Ca²⁺. This resulting rise in Ca²⁺ available to the contractile myocardium improves inotropy. An increase in myocardial automaticity leads to subsequent atrial, nodal, and ventricular ectopy. Digoxin also affects nodal conduction, leading to a prolonged refractory period, decreased sinus node firing, and slowed conduction through the AV node. Impaired Na-K exchange results in dangerously high levels of serum potassium. Overall, digoxin overdose manifests as a combination of slowed or blocked conduction and increased ectopy.

Digoxin has a very narrow therapeutic index. Therapeutic plasma digoxin concentrations are 0.5-2.0 ng/mL; a level of >2 ng/mL is considered toxic and a level of >6 ng/mL is considered potentially fatal. Numerous drug interactions have been shown to affect plasma digoxin concentrations. Medications known to increase serum digoxin concentrations include the macrolides, erythromycin and clarithromycin, spironolactone, verapamil, amidarone, and itraconazole.

Clinical and Laboratory Manifestations

Nausea and vomiting are common initial symptoms of acute digoxin toxicity, manifesting within 6 hr of overdose. Cardiovascular manifestations include bradycardia, heart block, and a wide variety of dysrhythmias. CNS manifestations consist of lethargy, confusion, and weakness. Chronic toxicity is more insidious and manifests with GI symptoms, altered mental status, and visual disturbances.

Initial assessment should include an ECG, serum digoxin level, serum potassium, and kidney function tests. The serum digoxin level should be assessed at least 6 hr after ingestion and carefully interpreted in the setting of clinical symptoms because the digoxin level alone does not entirely reflect the severity of intoxication. In acute ingestions, serum potassium is an independent marker of morbidity and mortality, with levels >5.5 mEq/L predicting poor outcomes. In chronic toxicity, serum potassium is less useful as a prognostic marker and may be altered due to concomitant use of diuretics.

Treatment

Initial treatment includes good general supportive care and gastric decontamination with activated charcoal if the ingestion was recent. An antidote for digoxin, digoxin-specific Fab antibody fragments (Digibind or Digifab) is available (see Table 58-8). Fab fragments bind free digoxin in both the intravascular and the interstitial spaces to form a pharmacologically inactive complex that is subsequently renally eliminated. Indications for Fab fragments include life-threatening dysrhythmias, K⁺ value of >5-5.5 mEq/L in the setting of acute overdose, serum digoxin level of >15 ng/mL at any time or >10 ng/mL 6 hr after ingestion, and ingestion of >4 mg in children or >10 mg in adults. If Digibind or Digifab are not readily available, phenytoin or lidocaine may be beneficial in managing ventricular irritability. Atropine is potentially useful in managing symptomatic bradycardia. Consultation with a cardiologist is recommended in the management of patients chronically on digoxin, because administration of Fab fragments can lead to recurrence of the patient’s underlying dysrhythmias or dysfunction.

Pathophysiology

TCAs achieve their desired antidepressant effects primarily via blockade of norepinephrine and serotonin reuptake. TCAs have complex interactions with other receptor types. Antagonism at muscarinic acetylcholine receptors leads to clinical features of the anticholinergic toxidrome. Antagonism at peripheral α-receptors leads to hypotension and syncope. Key to the toxicity of TCAs is their ability to block fast sodium channels, leading to impaired cardiac conduction and arrhythmias.

Clinical and Laboratory Manifestations

Cardiovascular and CNS symptoms dominate the clinical presentation of TCA toxicity. Symptoms typically develop within 1-2 hr of ingestion, and serious toxicity usually manifests within 6 hr of ingestion. Patients can have an extremely rapid progression from mild symptoms to life-threatening arrhythmias. Patients often develop features of the anticholinergic toxidrome, including delirium, mydriasis, dry mucous membranes, tachycardia, hyperthermia, mild hypertension, urinary retention, and slow GI motility. CNS toxicity can include lethargy, coma, myoclonic jerks, and seizures. Sinus tachycardia is the most common cardiovascular manifestation of toxicity; however, patients can develop widening of the QRS complex, premature ventricular contractions, and ventricular arrhythmias. Refractory hypotension is a poor prognostic indicator and is the most common cause of death in TCA overdose.

An ECG is a readily available bedside test that can help determine the diagnosis and prognosis of the TCA-poisoned patient (see Fig. 58-2). A QRS duration of >100 ms identifies patients who are at risk for seizures and cardiac arrhythmias. An R wave in lead aVR of >3 mm is also an independent predictor of toxicity. Both of these ECG parameters are superior to measured serum TCA concentrations in identifying patients at risk for serious toxicity, and obtaining levels is rarely helpful in management of the acutely ill patient.

Figure 58-2 Electrocardiographic findings in tricylic antidepressant toxicity. Note the tachycardia, widened QRS interval (144 ms), and prominent R wave in lead aVR. These findings are consistent with blockade of fast sodium channels.

Treatment

Initial attention should be directed to supporting vital functions, including airway and ventilation support as needed. Gastric decontamination can be accomplished with activated charcoal in appropriate patients. Because mental status can deteriorate rapidly, airway protective reflexes must be carefully assessed and the airway must be protected, if necessary, before decontamination. Treating clinicians should obtain an ECG as soon as possible and follow serial ECGs to monitor for progression of toxicity.

Sodium bicarbonate is the antidote of choice for TCA toxicity and works via overcoming the sodium channel blockade by providing a sodium load and via inducing an alkalosis to decrease drug binding to sodium channels. Indications for sodium bicarbonate include a QRS duration >100 ms, ventricular dysrhythmias, and hypotension. An initial bolus of 1-2 mEq/kg of sodium bicarbonate is given followed by initiation of a continuous infusion. Additional boluses may be given if the QRS duration continues to widen, with the goals of therapy being a serum pH of 7.45-7.55, improved hemodynamic stability, and narrowing of the QRS complex. Hypertonic (3%) saline, lidocaine, or lipid emulsion therapy may be beneficial in the setting of refractory arrhythmias. Consultation with a poison control center or medical toxicologist is suggested in these cases. Sodium bicarbonate therapy should be continued for at least 12-24 hr after the patient is stabilized because TCAs have the propensity to redistribute from the tissues back into the serum.

Hypotension can require vasopressor therapy, with direct-acting agents such as norepinephrine being the preferred pressors. Physostigmine, once promoted as an “antidote” for TCA toxicity, can cause seizures or dysrhythmias, especially in the setting of impaired cardiac conduction. Thus, physostigmine is currently considered relatively contraindicated in management of TCA ingestions. In the few patients who demonstrate prominent anticholinergic signs without any evidence of cardiac conduction abnormalities or seizures, use of physostigmine may be considered in consultation with a medical toxicologist. Seizures are typically brief and can be managed with benzodiazepines.

Asymptomatic children should be observed with continuous cardiac monitoring and serial ECGs for at least 6 hr. If any manifestations of toxicity develop, the child should be admitted to a monitored setting. Children who remain completely asymptomatic with normal serial ECGs may be candidates for discharge after 6 hr of close observation.

Pathophysiology

SSRIs selectively block the reuptake of serotonin in the CNS. In contrast to TCAs and atypical antidepressants, SSRIs do not directly interact with other receptor types.

Clinical and Laboratory Manifestations

In overdose, the principal manifestations of toxicity are sedation and tachycardia. Cardiac conduction abnormalities (primarily QTc prolongation) and seizures have been described in significant overdoses, especially after ingestions of citalopram. An ECG should be part of the initial assessment after SSRI ingestion.

Though development of the serotonin syndrome is seen more often after therapeutic use or overdose of several serotoninergic agents in combination, it has also been described in ingestions of SSRIs alone (Table 58-13). Clinically, serotonin syndrome is a triad of altered mental status, autonomic instability, and neuromuscular hyperactivity (hyperreflexia, tremors, clonus in the lower extremities more than the upper extremities) (see Figure 58-3).

Table 58-13 DRUGS ASSOCIATED WITH THE SEROTONIN SYNDROME

From Boyer EW, Shannon M: The serotonin syndrome, N Engl J Med 352:1112–1120, 2005.

Figure 58-3 Findings in a patient with moderately severe serotonin syndrome. Hyperkinetic neuromuscular findings of tremor or clonus and hyperreflexia should lead the clinician to consider the diagnosis of the serotonin syndrome.

(From Boyer EW, Shannon M: The serotonin syndrome, N Engl J Med 352:1112–1120, 2005.)

Treatment

Initial management includes a careful assessment for signs and symptoms of serotonin syndrome and an ECG. Most patients simply require supportive care and observation until their mental status improves and tachycardia, if present, resolves. Management of serotonin syndrome is directed by the severity of symptoms; possible therapeutic interventions include benzodiazepines in mild cases and intubation, sedation, and paralysis in patients with severe manifestations (e.g., significant hyperthermia). Because agonism at the 5-HT_2A serotonin receptor is thought to be primarily responsible for the development of serotonin syndrome, use of the 5HT_2A receptor antagonist cyproheptadine has also been shown to be beneficial. Cyproheptadine is only available in an oral form.

Clinical and Laboratory Manifestations

In overdose, venlafaxine and other SNRIs have been associated with cardiac conduction defects, including QRS and QTc prolongation, and seizures. Bupropion is one of the most common etiologies of toxicant-induced seizures in the United States. After ingestion of sustained or extended-release preparations, seizures can occur as late as 18-20 hr after ingestion. In addition, bupropion can cause tachycardia, agitation, and QRS and QTc prolongation. The structure of bupropion contains an amphetamine moiety, which can cause a false-positive result on the urine amphetamine screen. In addition to sedation and signs of serotonin excess, trazodone overdose may be associated with hypotension due to blockade of peripheral α-receptors.

Treatment

Management is directed to clinical signs and symptoms. QRS interval prolongation may be treated with IV sodium bicarbonate as described in detail earlier. Seizures are often brief and self-limited, but they can be treated with benzodiazepines if necessary. Trazodone-associated hypotension typically responds to fluids, though it can require vasopressors in extreme cases. Because of the potential for delayed seizures, patients who ingest a sustained-release preparation of bupropion should be admitted to a monitored setting for at least 20-24 hr of observation.

Pathophysiology

Methanol is metabolized in the liver by alcohol dehydrogenase to formaldehyde, which is further metabolized to formic acid by aldehyde dehydrogenase. Toxicity is caused primarily by formic acid, which inhibits mitochondrial respiration.

Clinical and Laboratory Manifestations

Drowsiness, mild inebriation, nausea, and vomiting develop early after ingestion. The onset of serious effects, including profound metabolic acidosis and visual disturbances, is often delayed for up to 12-24 hr as the parent methanol is undergoing metabolism to its toxic metabolites. Visual disturbances include blurred or cloudy vision, constricted visual fields, decreased acuity, and the “feeling of being in a snowstorm.” These visual defects may be reversible if treated early, but untreated they can lead to permanent blindness. On exam, dilated pupils, retinal edema, and optic disc hyperemia may be noted. Initially, patients have an elevated osmolar gap and then develop an anion gap metabolic acidosis as the parent compound is metabolized to formic acid.

In young children, determining if a significant exposure has occurred is usually difficult based on history. Methanol blood levels are available at some laboratories and should be sent after a concerning exposure. If methanol blood levels are not readily available, estimation of an osmolar gap may be used as a surrogate marker. Serum osmolarity is measured by the freezing point depression method and compared with a calculated serum osmolarity. The osmolar gap can be used to estimate the serum methanol concentration using the following formula:

Treatment

Treatment is as discussed ethylene glycol toxicity.

Pathophysiology

Ethylene glycol is metabolized by alcohol dehydrogenase in the liver to glycoaldehyde, which is further converted to glycolic acid by aldehyde dehydrogenase. Glycolic acid is metabolized to glyoxylic acid and oxalic acid, which are responsible for most of the observed toxicity. Oxalic acid combines with serum and tissue calcium, causing hypocalcemia and the formation of calcium oxalate crystals.

Clinical and Laboratory Manifestations

Early symptoms include nausea, vomiting, CNS depression, and inebriation. Delayed manifestations include an anion gap metabolic acidosis, hypocalcemia, and kidney failure (secondary to deposition of calcium oxalate crystals in the renal tubules). Even later, patients can develop cranial nerve palsies.

Ethylene glycol blood concentrations are available at some laboratories. In the absence of readily available ethylene glycol concentrations, calculation of the osmolar gap may be used as a surrogate marker. Serum osmolarity is measured by the freezing point depression method and compared with a calculated serum osmolarity. The osmolar gap can be used to estimate the serum ethylene glycol concentration using the following formula:

Examination of the urine with a Wood lamp is neither sensitive nor specific for ethylene glycol ingestion. Calcium oxalate crystals can be seen on urine microscopy but might not be evident early after exposure. Electrolytes (including calcium), acid-base status, kidney function, and ECG should be closely monitored in poisoned patients.

Treatment

Because methanol and ethylene glycol are rapidly absorbed, gastric decontamination is generally not of value. The classic antidote for methanol and ethylene glycol poisoning was ethanol, a preferential substrate for alcohol dehydrogenase, thus preventing the metabolism of parent compounds to toxic metabolites. Fomepizole (see Table 58-8), a potent competitive inhibitor of alcohol dehydrogenase, has almost entirely replaced the use of ethanol owing to its ease of administration, lack of CNS and metabolic effects, and overall excellent patient tolerability profile. Indications for fomepizole include ethylene glycol or methanol level >20 mg/dL, history of potentially toxic ingestion and an elevated osmolar gap, or history of ingestion with evidence of acidosis. There are few disadvantages to giving the initial dose of fomepizole to patients with a concerning history of ingestion or lab findings, and given the dosing schedule of fomepizole (every 12 hr), this strategy buys the clinician time to confirm or exclude the diagnosis before giving a second dose. Adjunctive therapy includes folate (methanol toxicity) and pyridoxine (ethylene glycol toxicity).

Hemodialysis effectively removes ethylene glycol, methanol, and their metabolites and corrects acid-base and electrolyte disturbances. Dialysis also removes fomepizole, so dosing should be changed to every 4 hr during dialysis. Indications for dialysis include a methanol level of >50 mg/dL, acidosis, severe electrolyte disturbances, and renal failure. However, in the absence of acidosis and kidney failure, even massive ethylene glycol ingestions have been managed without dialysis. Methanol is another story, because its elimination in the setting of alcohol dehydrogenase inhibition is very prolonged, thus often warranting dialysis to remove the parent compound. Therapy (fomepizole and/or dialysis) should be continued until ethylene glycol and methanol levels are <20 mg/dL. Consultation with a poison control center, medical toxicologist, and nephrologist may be helpful in managing toxic alcohol ingestions.