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1194 SECTION 15: Toxicology A toxin must possess a number of properties to be effectively removed by an extracorporeal technique in a clinically meaningful time frame: low volume of distribution (<1.0 L/kg), low molecular weight (<500 Da), relatively low protein binding, and low endogenous clearance. 37 In general, extracorporeal removal must improve endogenous clearance rate by >30% to be clinically beneficial. Hemoperfusion uses a charcoal (or other adsorbent) filter, which comes into direct contact with blood, partially overcoming molecular weight and protein-binding limitations. Continuous renal replacement therapies (including venovenous hemofiltration and venovenous hemodiafiltration) are widely avail able and easily instituted in most hospitals. However, there is sparse evidence demonstrating any benefit in poisoning, primarily due to slow clearance rates. 37 A patient who requires extracorporeal removal should undergo hemodialysis or hemoperfusion, if available. Continuous renal replacement therapy can be used if hemodialysis or hemoperfusion is unavailable or will not be tolerated (e.g., due to hypotension). 37 Extracorporeal removal techniques including high-flux hemodialysis are constantly evolving, so discussion with an intensivist or nephrologist may be beneficial when this approach is considered. Expert consensus advice regarding optimum extracorporeal elimination techniques for individual toxins have been published by the Extracorporeal Treatments in Poisoning group. DISPOSITION Planning for patient disposition from the ED should be part of initial risk assessment. Admission is indicated if the patient has persistent and/or severe toxic effects or will require a prolonged course of treat ment. In most cases, a 6-hour observation period is sufficient to exclude the development of serious toxicity. Onset of clinical toxicity can be delayed after a number of exposures, including (but not limited to) modified-release preparations of calcium channel blockers, selective norepinephrine reuptake inhibitors (tramadol, venlafaxine), and newer antipsychotics (amisulpride); hence, a period of extended observation is indicated. In the developed world, toxicity will resolve within 24 hours in most poisoned patients requiring noncritical care inpatient management, and so these patients can be efficiently and safely managed in a toxicology or short-stay ward, if available. Patients who have deliber ately self-poisoned require appropriate mental health assessment before disposition. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Cyclic Antidepressants Frank LoVecchio INTRODUCTION Cyclic antidepressants were the first generation of drugs developed to treat depression. Their use for treating depression has declined greatly as safer agents have been developed. Cyclic antidepressants are now occasionally used to treat obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, panic and phobia disorders, and anxiety disorders. Cyclic antidepressants have the highest ratio of deaths to exposures for antidepressants reported to U.S. Poison Control Centers. 1 Roughly half of all cyclic antidepressant exposures involve other drugs as well, and most co-ingestants increase the incidence and severity of cyclic antidepressant overdose toxicity. Eight cyclic antidepressants are currently available in the United States (Table 177-1), with more agents available in other countries.

Roughly half of all cyclic antidepressant exposures involve other drugs as well, and most co-ingestants increase the incidence and severity of cyclic antidepressant overdose toxicity. Eight cyclic antidepressants are currently available in the United States (Table 177-1), with more agents available in other countries. Two related CHAPTER antidepressants, amoxapine and maprotiline, have structural differences from traditional cyclic antidepressants but have similar toxicity in overdose. Cyclobenzaprine is a muscle relaxant that is almost structurally identical to amitriptyline but lacks antidepressant activity, and serious toxicity from overdose is rare. Cyclic antidepressants possess a narrow therapeutic index, and toxicity can occur at therapeutic dosages (Table 177-2). PHARMACOLOGY The cyclic antidepressants are named after their chemical struc ture, which consists of a three-ring central structure plus a side chain—thus the common term tricyclic antidepressants . Maprotiline is a tetracyclic (also termed a heterocyclic ), with a four-ring central structure plus a side chain. Cyclic antidepressants are subdivided into two categories: tertiary and secondary amines. Tertiary amines have two methyl groups at the end of the side chain. The five tertiary amines—amitriptyline, clomipramine, doxepin, imipramine, and trimipramine—are generally more potent in blocking reuptake of serotonin compared to blocking reuptake of norepinephrine. Tertiary tricyclics also cause more anticholinergic side effects (e.g., constipa tion or blurred vision) and are also highly sedating because of their central effects on histamine receptors. Secondary amines—desipramine, nortriptyline, and protriptyline— have one methyl group at the end of the side chain and are more potent in blocking reuptake of norepinephrine. The tetracyclic maprotiline has a side chain identical to that of the secondary amines; thus, it is more potent in blocking reuptake of norepinephrine. Amoxapine has a three-ring central structure and a side chain that differs from the other tricyclics. It is a potent norepinephrine reuptake inhibitor and also blocks postsynaptic dopamine receptors. Thus, it is the only antidepressant that has antipsychotic effects and can produce seizures with minimal warning and normal QRS complex. Cyclic antidepressants are nonselective agents with multiple pharmacologic effects (Table 177-3) with considerable variation in potency at therapeutic dosages. 3-5 However, these differences become less impor tant at the higher plasma levels typically seen in overdose. Inhibition of amine reuptake (norepinephrine, serotonin) and antagonism of postsynaptic serotonin receptors are believed to produce the therapeu tic effects of these agents. The remaining pharmacologic actions are seemingly without therapeutic benefit in treating major depression, but significantly contribute to cyclic antidepressant–related adverse effects and overdose toxicity. Cyclic antidepressant–induced cardiotoxicity is the most important factor contributing to patient mortality. 6 Cardiac conduction abnormalities occur during cyclic antidepressant poisoning because inhibition of the fast sodium channels in the His-Purkinje system and myocardium decreases conduction velocity, increases the duration of repolarization, and prolongs absolute refractory periods. Fast sodium channel blockade produces changes in the QRS complex. Severe sodium channel blockade culminates in depressed myocardial contractility, hypotension, various types of heart blocks, cardiac ectopy, bradycardia, widening of the QRS complex, and/or the Brugada pattern. Cyclic antidepressants also block myocardial potassium channels and inhibit the efflux of potassium during repolarization.

channel blockade culminates in depressed myocardial contractility, hypotension, various types of heart blocks, cardiac ectopy, bradycardia, widening of the QRS complex, and/or the Brugada pattern. Cyclic antidepressants also block myocardial potassium channels and inhibit the efflux of potassium during repolarization. 6 This effect is seen on the ECG as QT interval prolongation, which is more pronounced at slower heart rates.7,8  PHARMACOKINETICS All cyclic antidepressants share similar pharmacokinetic properties. 3 They are highly lipophilic, readily cross the blood–brain barrier, and achieve peak plasma levels between 2 and 6 hours after ingestion at therapeutic doses. In overdose, GI absorption can be prolonged because of the antimuscarinic effect on gut motility. Bioavailability is only 30% to 70% because of extensive first-pass hepatic metabolism. Cyclic antidepressants are highly protein bound to α 1-acid glycoproteins, with a large apparent volume of distribution, ranging from 10 to 50 L/kg. Tissue cyclic antidepressant levels are commonly 10 to 100 times greater than plasma levels, and only 1% to 2% of the total body burden of cyclic antidepressants is found in the blood. These pharmacokinetic properties explain why it is Tintinalli_Sec15_p1187-1332.indd 1194 8/2/19 8:39 PM

on, ranging from 10 to 50 L/kg. Tissue cyclic antidepressant levels are commonly 10 to 100 times greater than plasma levels, and only 1% to 2% of the total body burden of cyclic antidepressants is found in the blood. These pharmacokinetic properties explain why it is Tintinalli_Sec15_p1187-1332.indd 1194 8/2/19 8:39 PM CHAPTER 177: Cyclic Antidepressants 1195 unproductive to attempt removal of cyclic antidepressants by hemodialysis, hemoperfusion, peritoneal dialysis, or forced diuresis.9 Cyclic antidepressants are eliminated almost entirely by hepatic oxidation, which consists of N-demethylation of the amine sidechain groups and hydroxylation of ring structures. The removal of a methyl group from the tertiary amine side chain usually produces an active metabolite designated by the desmethyl prefix (Table 177-1). Clinical toxicity from cyclic antidepressants usually lasts longer than explained by the activity of the parent drug because of the production of active metabolites. TOXICITY Ingestions of <1 milligram/kg are generally nontoxic. 10 Life-threatening symptoms usually occur with ingestions of >10 milligrams/kg in adults, and fatalities are commonly associated with ingestions of >1 gram. Children are particularly susceptible to antimuscarinic effects and show clinical toxicity at lower dosages. 4 The majority of adult intentional ingestions and pediatric accidental exposures of >2.5 milligrams/kg are expected to result in some clinical toxicity based on the low therapeutic index of cyclic antidepressants. 10 In addition, patients at higher risk for cyclic antidepressant toxicity include patients who have co-ingested cardiotoxic or sedative-hypnotic medications, geriatric patients, and patients with underlying heart or neurologic disease. Desipramine is the most potent sodium channel blocker among the cyclic antidepressants and is able to precipitate severe cardiotoxicity (e.g., wide QRS complex, hypotension) without producing significant TABLE 177-1 Cyclic Antidepressants and Related Drugs Generic Name Typical Adult Outpatient Daily Dose (milligrams) Recommended Maximum Adult Outpatient Daily Dose (milligrams) Elimination Half-Life (h) Active Metabolites Amitriptyline 75–150 300 10–26 (amitriptyline) 18–44 (nortriptyline) Nortriptyline Amoxapine * 50–300 400 8 (amoxapine) 30 (8-hydroxyamoxapine) 7-Hydroxyamoxapine (minor) 8-Hydroxyamoxapine (major) Clomipramine 25–50 250 32 (clomipramine) 69 (desmethylclomipramine) Desmethylclomipramine Cyclobenzaprine * 15–30 30 18 None Desipramine 75–200 300 12–27 None Doxepin 75–300 300 15 (doxepin) 31 (desmethyldoxepin) Desmethyldoxepin Imipramine 75–200 300 11–25 Desipramine Maprotiline * 75–150 225 43 (maprotiline) 60–90 (desmethylmaprotiline) Desmethylmaprotiline Nortriptyline 75–150 150 18–44 None Protriptyline 15–60 60 67–89 None Trimipramine 75–200 300 9–11 Desmethyltrimipramine *See text for clarification.

31 (desmethyldoxepin) Desmethyldoxepin Imipramine 75–200 300 11–25 Desipramine Maprotiline * 75–150 225 43 (maprotiline) 60–90 (desmethylmaprotiline) Desmethylmaprotiline Nortriptyline 75–150 150 18–44 None Protriptyline 15–60 60 67–89 None Trimipramine 75–200 300 9–11 Desmethyltrimipramine *See text for clarification. TABLE 177-2 Mechanisms for Cyclic Antidepressant Drug Toxicity at Therapeutic Dosages •   Administration of high therapeutic dosages to naive individuals •   Drug interactions with medications sharing similar pharmacologic actions •   Elevated levels of cyclic antidepressants due to genetically slow hepatic metabolism •   Drug interactions with other medications that inhibit hepatic metabolism (cytochrome P450 system) •   Additional toxicity from other active ingredients (e.g., antipsychotics) contained in some combination cyclic antidepressant formulations •   Preexisting cardiovascular or CNS disease that predisposes patients to toxicity •   Development of serotonin syndrome, usually in combination with serotoninergic medications TABLE 177-3 Pharmacologic Profile of Cyclic Antidepressants Pharmacologic Activity Clinical Presentation Antagonism of postsynaptic histamine receptors Sedation, depressed consciousness Antagonism of postsynaptic muscarinic receptors (both central and peripheral) Central antimuscarinic: agitation to delirium, confusion, amnesia, hallucinations, slurred speech, ataxia, sedation, and coma Peripheral antimuscarinic: dilated pupils, blurred vision, tachycardia, hyperthermia, hypertension, decreased oral and bronchial secretions, dry skin, ileus, urinary retention, increased muscle tone, and tremor Antagonism of postsynaptic α-adrenergic receptors (α 1-adrenergic > α2-adrenergic receptors) α 1-Adrenergic receptor: sedation, miosis, orthostatic hypotension, reflex tachycardia α 2-Adrenergic receptor: mild hypertension Inhibition of norepinephrine reuptake Agitation, mydriasis, diaphoresis, tachycardia, early hypertension Inhibition of serotonin reuptake Sedation, mydriasis, myoclonus, hyperreflexia (see Chapter 178, “Atypical and Serotonergic Antidepressants”) Inhibition of voltage-gated sodium channels Impaired conduction, wide QRS complex, other conduction abnormalities; impaired cardiac contractility; wide-complex tachycardia, Brugada pattern, ventricular ectopy Hypotension Inhibition of voltage-gated rectifier potassium channels Prolongation of QT interval, ventricular ectopy, torsades de pointes antimuscarinic symptoms. It is associated with a higher case-fatality rate than the other cyclic antidepressants. 11 Amoxapine and maprotiline have historically been associated with greater toxicity than other cyclic antidepressants, especially in regard to causing seizures. Quantitative measurement of plasma levels of cyclic antidepressants (parent and metabolite) is helpful in monitoring long-term drug therapy, with therapeutic levels of 75 to 300 nanograms/mL (300 to 1000 nmol/L) for most agents. Patients with a combined plasma level of parent cyclic antidepressant and metabolite of >1000 nanograms/mL (>3500 nmol/L) are at greater risk for developing seizures and cardiotoxicity, but the severity of clinical toxicity does not always correlate with plasma cyclic antidepressant level. Tintinalli_Sec15_p1187-1332.indd 1195 8/2/19 8:39 PM

d plasma level of parent cyclic antidepressant and metabolite of >1000 nanograms/mL (>3500 nmol/L) are at greater risk for developing seizures and cardiotoxicity, but the severity of clinical toxicity does not always correlate with plasma cyclic antidepressant level. Tintinalli_Sec15_p1187-1332.indd 1195 8/2/19 8:39 PM 1196 SECTION 15: Toxicology CLINICAL FEATURES The clinical presentation of cyclic antidepressant toxicity varies from mild antimuscarinic symptoms to severe cardiotoxicity secondary to sodium channel blockade. Antimuscarinic symptoms commonly serve as markers for cyclic antidepressant toxicity (e.g., dry mouth and axillae, sinus tachycardia), but they alone are rarely responsible for fatali ties. Moreover, antimuscarinic symptoms are not uniformly present in cyclic antidepressant toxicity. Altered mental status is the most common symptom reported after cyclic antidepressant exposure. 4,12-14 A Glasgow Coma Scale score of <8 in the ED is a strong predictor of serious com plications such as seizures and cardiac dysrhythmia.5,6 Sinus tachycardia is the most frequent dysrhythmia noted in cyclic antidepressant toxicity, occurring in up to 70% of symptomatic patients. 6,12-14 Mild to moderate cyclic antidepressant toxicity presents as drowsi ness, confusion, slurred speech, ataxia, dry mucous membranes and axillae, sinus tachycardia, urinary retention, myoclonus, and hyper reflexia. Antimuscarinic syndrome is classically associated with decreased bowel sounds and ileus, but bowel function is fairly resis tant to inhibition, so the presence of active bowel sounds does not exclude antimuscarinic syndrome. Mild hypertension is occasionally present and rarely requires treatment. Overflow urinary incontinence may be mistaken for normal micturition in diaper-dependent chil dren or older adults. Most cyclic antidepressant overdose fatalities occur within the initial hours after ingestion, often before the patient reaches the hospital. If serious toxicity is going to occur, it almost always is seen within 6 hours of ingestion and consists of the following features: coma, cardiac conduction delays, supraventricular tachycardia, hypotension, respiratory depression, ventricular tachycardia, and seizures. Secondary complications from serious toxicity include aspiration pneumonia, pulmonary edema, anoxic encephalopathy, hyperthermia, and rhabdomyolysis. Seizures are more commonly reported in maprotiline and trimipramine overdoses. 15 Seizures are usually generalized, are of brief duration, and occur with other signs of serious toxicity. 5 The exception to this rule is amoxapine overdoses; this agent can cause status epilepticus without warning or QRS complex widening. Cyclobenzaprine overdoses are usually characterized by prolonged CNS sedation and antimuscarinic toxicity with minimal cardiotoxicity compared to amitriptyline. DIAGNOSIS Cyclic antidepressant toxicity is diagnosed using a combination of four criteria: history of exposure, clinical symptomatology, characteristic ECG findings, and positive cyclic antidepressant urine drug screen results. Other toxic exposures may produce similar symptoms, signs, and ECG changes; the essential point is that the initial treatment for toxicity due to any of these medications is identical and should not be delayed until definitive drug test results become available. At least half of all cyclic antidepressant exposures involve co-ingestion of other substances, which can significantly increase or alter toxic manifestations. False-positive results on qualitative cyclic antidepressant urine drug screens occur with carbamazepine, cetirizine, cyclobenzaprine, cyproheptadine, diphenhydramine, hydroxyzine, quetiapine, and phe nothiazines (e.g., thioridazine).

n of other substances, which can significantly increase or alter toxic manifestations. False-positive results on qualitative cyclic antidepressant urine drug screens occur with carbamazepine, cetirizine, cyclobenzaprine, cyproheptadine, diphenhydramine, hydroxyzine, quetiapine, and phe nothiazines (e.g., thioridazine). 16 The false-positive cyclic antidepressant screen result is generally dose dependent and is more common following a supratherapeutic dose of these medications. Most of these medications are structurally similar to cyclic antidepressants, producing the same ECG abnormalities and clinical toxicity in overdose as cyclic antidepressants. Conversely, false-negative results on cyclic antidepressant drug tests are extremely unusual with clinical toxicity. ECG abnormalities are common with cyclic antidepressant toxicity and are useful in identifying patients at increased risk for seizures and ventricular dysrhythmias. 17 The classic ECG with cyclic antidepressant toxicity shows sinus tachycardia, right axis deviation of the terminal 40 milliseconds, and prolongation of the PR, QRS, and QT intervals (Figure 177-1). Right axis deviation is demonstrated as a positive terminal R wave in lead aVR and a negative S wave in lead I (Figure 177-1). This classic ECG pattern is seen frequently in moderate to severe cyclic antidepressant toxicity, but its absence does not eliminate the possibility of toxicity, and life-threatening complications can occur in the absence of significant ECG abnormalities, especially follow ing amoxapine ingestion. Less common ECG abnormalities include right bundle branch block and high-degree atrioventricular blocks. The Brugada pattern is seen in roughly 10% to 15% of patients with cyclic antidepressant poisoning who require intensive care unit admission but is rarely seen in other overdoses. 18,19 Torsades de pointes is rarely seen in cyclic antidepressant overdoses in the presence of sinus tachycardia, which is partially protective against severe QT interval prolongation and afterpotential generation. The risk of seizures increases if the QRS complex is >100 milliseconds, and ventricular dysrhythmias are more common if the QRS duration is >160 milliseconds. 6,17 Widening of the QRS complex from baseline and positive deflection of the terminal QRS complex in lead aVR are usually seen together but can occur independently of each other. The develop ment of right axis deviation of the terminal 40 milliseconds and/or QRS complex widening appear to be less predictive of cyclic antidepressant– induced cardiotoxicity in young children because pediatric ECGs tend to have a wider range of acceptable variant features, and this complicates the identification of cyclic antidepressant toxicity on the ECG. ECG abnormalities develop within 6 hours of ingestion and typi cally resolve over 36 to 48 hours. 6 Although these ECG abnormalities in isolation are not 100% specific for cyclic antidepressant toxicity, they should be assumed to be attributable to cyclic antidepressant exposure and managed accordingly in appropriate clinical circumstances. TREATMENT Evaluate patients for alterations of consciousness, hemodynamic insta bility, and respiratory impairment. Establish an IV line, initiate con tinuous cardiac rhythm monitoring, and obtain serial ECGs. Suggested laboratory studies include serum electrolytes, creatinine, and glucose. To identify co-ingestants, obtain serum acetaminophen and salicylate levels. Blood gas measurement is recommended for symptomatic patients. In patients with antimuscarinic symptoms, urinary catheterization may be required to prevent urinary retention, and a nasogastric tube may be needed if ileus is present.

d glucose. To identify co-ingestants, obtain serum acetaminophen and salicylate levels. Blood gas measurement is recommended for symptomatic patients. In patients with antimuscarinic symptoms, urinary catheterization may be required to prevent urinary retention, and a nasogastric tube may be needed if ileus is present. Patients who are initially asymptomatic may deteriorate rapidly and therefore should be monitored closely for 6 hours. Treatment recommendations (Table 177-4) are based primarily on cohort or case-control studies resulting in only moderate strength of evidence for those measures discussed in the following sections.  GI DECONTAMINATION Do not use ipecac syrup or gastric lavage. 9,21-23 Give a single 1 gram/kg dose of activated charcoal PO if patients are awake, have a patent airway, and arrive within 1 hour of ingestion. 9,24 Activated charcoal effectively binds cyclic antidepressants and decreases absorption. Neither multidose activated charcoal nor whole-bowel irrigation is warranted. 21,25 Asymptomatic patients with reliable histories of minimal cyclic antidepressant ingestion can be treated with activated charcoal alone and observed for toxicity.  SODIUM BICARBONATE Sodium bicarbonate is used to treat cardiac conduction abnormalities, ventricular dysrhythmias, or hypotension refractory to IV fluid. 20,26 Administer sodium bicarbonate as an initial IV bolus of 1 to 2 mEq/kg, and repeat until patient improvement is noted or until blood pH is between 7.50 and 7.55 (Figure 177-2). Additional alkalization beyond this point can be deleterious to oxygen extraction and serum electrolytes. As an alternative of repeat boluses, continuous infusions of sodium bicarbonate can be administered as 150 mEq added to 1 L of 5% dex trose in water (or 100 mEq added to 5% dextrose in 0.45% saline, creat ing a slightly hypertonic solution with the sodium bicarbonate added) and infused IV at a rate of 2 to 3 mL/kg per hour. Adjustments in the IV rate are made based on blood pH measurements and clinical response Tintinalli_Sec15_p1187-1332.indd 1196 8/2/19 8:39 PM

r (or 100 mEq added to 5% dextrose in 0.45% saline, creat ing a slightly hypertonic solution with the sodium bicarbonate added) and infused IV at a rate of 2 to 3 mL/kg per hour. Adjustments in the IV rate are made based on blood pH measurements and clinical response Tintinalli_Sec15_p1187-1332.indd 1196 8/2/19 8:39 PM CHAPTER 177: Cyclic Antidepressants 1197 to therapy. Monitor serum electrolytes during the sodium bicarbon ate infusion. Hypernatremia is not of particular concern using this dose of sodium bicarbonate. 13 Serum potassium will decrease during sodium bicarbonate therapy, and IV potassium supplementation may be required.  ALTERED LEVEL OF CONSCIOUSNESS Antagonism of postsynaptic muscarinic, histaminic, and α-adrenergic receptors contributes to the development of depressed mentation in cyclic antidepressant overdose. Coma from cyclic antidepressant toxicity typically is rapid in onset and is a predictive factor for cardiotoxicity and/ or seizures. 5 Pulmonary aspiration is common among comatose cyclic antidepressant overdose patients. Agitation is observed commonly prior to the onset of coma, as well as during awakening. Agitation is best controlled with reassurance, decreased environmental stimulation, and benzodiazepines. Do not give flumazenil or physostigmine for mixed cyclic antidepressant–benzodiazepine or cyclic antidepressant– anticholinergic overdoses, respectively.  SEIZURES Most seizures occur within the first 3 hours following ingestion and are typically generalized and of brief duration. 5 Multiple seizures are reported FIGURE 177-1. Twelve-lead ECG showing classic cyclic antidepressant ECG abnormalities: sinus tachycardia; prolonged PR, QRS, and QT intervals; and right axis deviation of the terminal 40 milliseconds of the QRS complex. TABLE 177-4 Treatment of Cyclic Antidepressant Overdose Treatment Dose Indication Comments GI decontamination Activated charcoal 1 gram/kg PO Within 1 h of ingestion as long as airway is stable and patient is awake Do not give multidose charcoal; do not perform wholebowel irrigation Initial treatment of hypotension or dysrhythmias Sodium bicarbonate, 1–2 mEq/kg IV bolus; repeat bolus or add 150 mEq to 1 L 5% dextrose in water at 2–3 mL/kg per hour For dysrhythmias, conduction abnormalities (QRS >100 ms), or hypotension refractory to IV fluid Keep blood pH 7.50–7.55 Hypokalemia Replace potassium as needed Serum potassium <3.5 mEq/L Bicarbonate will decrease potassium level Seizures or agitation Benzodiazepines for seizures or agitation Phenobarbital 10–15 milligrams/kg for seizures refractory to benzodiazepines; watch for hypotension; secure airway with intubation Do not give physostigmine, flumazenil, or phenytoin Hypotension Treat hypotension with normal saline, up to 30 mL/kg Use norepinephrine or epinephrine if refractory to IV normal saline Case reports suggest effectiveness of glucagon, 1 milligram IV bolus Torsades de pointes and refractory dysrhythmias Magnesium sulfate 2 grams IV; 3% saline 1–3 mL/kg IV over 10 min; overdrive pacing Consider lipid emulsion for refractory dysrhythmias, but no convincing evidence of effectiveness Do not give class I antiarrhythmics (i.e., procainamide, lidocaine, phenytoin, flecainide), β-blockers, calcium channel blockers, or class III antiarrhythmics (i.e., amio darone, sotalol, ibutilide) Tintinalli_Sec15_p1187-1332.indd 1197 8/2/19 8:39 PM

refractory dysrhythmias, but no convincing evidence of effectiveness Do not give class I antiarrhythmics (i.e., procainamide, lidocaine, phenytoin, flecainide), β-blockers, calcium channel blockers, or class III antiarrhythmics (i.e., amio darone, sotalol, ibutilide) Tintinalli_Sec15_p1187-1332.indd 1197 8/2/19 8:39 PM 1198 SECTION 15: Toxicology ICU_2 ICU_2 <54> _10 <5|4> 10 AUG 93 1851 **SA02 88 RESP 14I PULSE SAO2 88 NBP 138/84-?- AUG9 3 3858 **ABP 76 < 98 II HR 74 ABP 7475|5 (_63) XB5P PULSE 74 SAO2 9910 FIGURE 177-2. ECG before and after bicarbonate treatment. A. Cardiac rhythm strip of a patient with a wide QRS complex recorded 3 hours after ingestion of amitriptyline. B. Narrowing of the QRS complex in the same patient after administration of an IV bolus of sodium bicarbonate. in approximately 10% to 30% of cases of cyclic antidepressant overdose. Focal seizures and status epilepticus are atypical and should prompt further neurologic evaluation. Seizures are especially common with maprotiline and amoxapine ingestions and require aggressive management, because status epilepticus is frequently associated with these two par ticular antidepressants. 11 Benzodiazepines (e.g., diazepam, lorazepam) are the anticonvulsants of choice to stop seizure activity. Barbiturates (e.g., phenobarbital) are indicated to treat seizures resistant to benzodi azepines. The initial IV dose of phenobarbital is 10 to 15 milligrams/kg, but this can be increased in patients with continued seizure activity and adequate blood pressure. Other therapy for refractory seizures includes continuous-infusion midazolam or propofol. Hypotension is a major side effect of IV phenobarbital administration. Endotracheal intubation and respiratory support may be needed. Phenytoin, sodium bicarbonate, and physostigmine do not stop cyclic antidepressant–induced seizures. Neuromuscular blockers will stop the physical manifestations of seizures and their secondary effects, which include metabolic acidosis, hyperthermia, rhabdomyolysis, and renal failure, but they do not stop brain seizure activity. Therefore, following the induction of muscle paralysis, continue anticonvulsant therapy and consider electroencephalographic monitoring.  HYPOTENSION Hypotension should be treated initially with isotonic crystalloid fluids in IV boluses in increments of 10 mL/kg to a maximum of 30 mL/kg. With impaired cardiac contractility, pulmonary edema can develop if excessive fluids are administered. Hypotension that does not improve with appropriate fluid challenges should be treated with sodium bicar bonate (regardless of QRS complex duration). Vasopressors should be used when hypotension is unresponsive to fluids and sodium bicarbonate therapy, although response may be inconsistent. 27 Norepinephrine and epinephrine are expected to be the most effective vasopressors because they directly compete with the cyclic antidepressants at the α-adrenergic receptors. Start the IV infusion at 1 microgram/min and titrate according to blood pressure. Vasopressin can be tried if there is no response to norepinephrine or epinephrine. 28 Dopamine is less effective than norepinephrine in reversing cyclic antidepressant–induced hypo tension because it has primarily indirect α-adrenergic agonist activity and, at lower dosages, promotes vasodilation through its β-adrenergic and dopaminergic actions. Placement of a pulmonary artery catheter for monitoring in patients whose hypotension is refractory to fluid, sodium bicarbonate, and vasopressor therapy may precipitate life-threatening conduction abnormalities and ventricular dysrhythmias as the catheter passes through the right ventricle.

c and dopaminergic actions. Placement of a pulmonary artery catheter for monitoring in patients whose hypotension is refractory to fluid, sodium bicarbonate, and vasopressor therapy may precipitate life-threatening conduction abnormalities and ventricular dysrhythmias as the catheter passes through the right ventricle. Mechanical support of the circulation with cardiopulmonary bypass, overdrive pacing, or aortic balloon pump assistance may be warranted in patients with refractory hypotension, although no studies document the effectiveness of these measures. There are case reports suggesting that glucagon administered as 1-milligram IV boluses might be effective in patients with refractory cyclic antidepressant–induced hypotension.  CARDIAC CONDUCTION ABNORMALITIES AND DYSRHYTHMIAS Cyclic antidepressants frequently alter cardiac rate, conduction, and contractility. These negative cardiac effects are increased with acidosis, which occurs in patients with respiratory depression or seizures. Asymptomatic patients with sinus tachycardia, isolated PR interval prolongation, or first-degree atrioventricular block do not require specific pharmacologic therapy. Conduction blocks greater than firstdegree atrioventricular block are worrisome because they can progress rapidly to complete heart block secondary to impaired infranodal conduction. The controversial issue is whether asymptomatic or mildly toxic patients with isolated QRS complex prolongation should be treated with sodium bicarbonate therapy. 20 There are no controlled human trials demonstrating benefits in otherwise asymptomatic patients with QRS complex prolongation. Nonetheless, many physicians use sodium bicarbonate therapy in asymptomatic or minimally toxic patients with cyclic antidepressant overdose if the QRS duration is Tintinalli_Sec15_p1187-1332.indd 1198 8/2/19 8:39 PM