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1208 SECTION 15: Toxicology followed meticulously during the hospitalization. All patients should be instructed to avoid contraindicated foods and medications for a minimum of 2 weeks after MAOI drug exposure. Patients who require transfer to hospitals with intensive care units should be transferred as soon as possible to avoid the problems anticipated with delayed onset of toxicity. All patients being transferred should be accompanied by medical personnel capable of performing advanced life support and airway management. Even a single MAOI tablet may produce life-threatening drug interactions under the right circumstances. TYRAMINE REACTION Tyramine is an exogenous dietary amine that is normally metabolized by intestinal and hepatic MAO. 11,26,27 Tyramine can be found in small amounts in many foods but is present at much higher levels in aged, cured, smoked, pickled, or fermented dietary products. The body nor mally has multiple levels of protection to prevent tyramine and other similar exogenous amines from entering the systemic circulation, but this protection is lost once the normal activity of MAO-A is inhibited by >80%. Therefore, all nonselective inhibitors predispose to tyramine reactions; however, tranylcypromine is associated more frequently with tyramine reactions than either phenelzine or isocarboxazid. Selective MAO-B inhibitors and reversible inhibitors are associated with a much lower incidence of tyramine reactions because they leave intestinal and hepatic MAO-A unaffected to metabolize tyramine. Selegiline (MAO-B selective) is unlikely to produce a tyramine reaction if taken in oral form at therapeutic doses, but at elevated doses, its selectivity is lost and it functions the same as the nonselective inhibitors. Dietary restrictions are unnecessary with rasagiline because of its greater selectivity for MAO-B at therapeutic dosages and transdermal preparations of MAOIs. Tyramine is structurally similar to amphetamine and is classified as an indirect sympathomimetic. Like most indirect sympathomimetics, tyramine enters the presynaptic neuron through amine uptake pumps. Once inside the neuron, indirect sympathomimetics are capable of releasing presynaptic stores of norepinephrine and, to a lesser degree, serotonin and dopamine. Tyramine also can displace epinephrine from the adrenal gland. A similar effect occurs with ingestion of foods that contain large amounts of dopamine, such as broad (fava) beans. It has been reported that <30% of patients taking MAOIs adhere to the recommended tyramine-restricted diet. In addition, approximately 4% to 8% of adherent patients experience a tyramine reaction during their course of therapy. Many of the previously restricted food sources are no longer considered dangerous, and newer guidelines call for avoiding only a few high-risk food groups such as meats or fish that are not fresh, sau erkraut, aged meats and cheeses, alcohol (tap or unpasteurized beers), pickled fish (herring), concentrated yeast extracts, banana peels, soy sauce, tofu, and broad beans. 11,26,27  CLINICAL FEATURES The tyramine reaction is typically of rapid onset, occurring within 15 to 90 minutes of ingestion of the dietary amine. The severity of this reaction is highly variable and is partially related to the total amount of tyramine ingested. The hallmark symptom of the tyramine reaction is a severe occipital or temporal headache.

yramine reaction is typically of rapid onset, occurring within 15 to 90 minutes of ingestion of the dietary amine. The severity of this reaction is highly variable and is partially related to the total amount of tyramine ingested. The hallmark symptom of the tyramine reaction is a severe occipital or temporal headache. Other associated symptoms include hypertension, diaphoresis, mydriasis, neck stiffness, pallor, neuromuscular excitation, palpitations, and chest pain. Most symptoms resolve gradually over 6 hours without specific therapy, but fatalities have been reported in rare cases, usually due to intracranial hemorrhage or myocardial infarction.  TREATMENT An ECG should be obtained for all patients with tyramine-associated chest pain. Focal neurologic findings or a persistent, severe headache warrants investigation with a CT scan. In cases of severe hypertension, the recommended drug is phentol amine, given as 2.5- to 5.0-milligram IV doses every 5 to 15 minutes until the blood pressure is controlled. The half-life of phentolamine is approximately 20 minutes, and its duration of action is <1 hour. Nitroprusside is another rapidly acting direct vasodilator that is administered as a continuous IV infusion (1 to 4 micrograms/kg per minute). In cases of moderate hypertension, nifedipine and prazosin have been reported to be effective. β-Adrenergic blockers are contraindicated because of unopposed α-receptor stimulation.  DISPOSITION Hospital admission should be strongly considered for patients whose symptoms do not resolve completely within 6 hours of onset. Patients who are asymptomatic after 4 hours of observation can safely be dis charged home. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Antipsychotics Michael Levine Frank LoVecchio  ANTIPSYCHOTICS INTRODUCTION The first-generation (typical) antipsychotics, introduced in the 1950s, were effective against the positive features of psychosis (e.g., delusions, hallucinations, disorganized thought) but provided no treatment for the negative features (e.g., avolition, alogia, social withdrawal). In addition, numerous adverse side effects associated with these agents led to poor patient compliance. The second-generation (atypical) antipsychotics were introduced in the 1990s, and the third generation followed in the 2000s. These second- and third-generation drugs work on both the positive and negative symptoms and, when taken at therapeutic doses, are associated with fewer extrapyramidal effects than the first-generation antipsychotics (Table 180-1). Antipsychotics were historically referred to as major tranquilizers or neuroleptics. With the advent of the atypical antipsychotics, it became clear that antipsychotic properties do not necessarily parallel neuroleptic properties. For this reason, the preferred term is antipsychotics. These drugs are sometimes administered to treat other conditions, such as agitation, nausea and vomiting, and headache conditions; to suppress hiccups; and to control involuntary motor disorders, such as Tourette’s syndrome, Huntington’s chorea, and basal ganglia disorders. PATHOPHYSIOLOGY More than 50 different antipsychotics are available worldwide. Their pharmacologic effect is mediated by binding to CNS dopaminergic, α-adrenergic, muscarinic, histaminergic, and serotoninergic receptors. In overdose, the clinical toxicity is primarily an exaggerated effect of the pharmacologic activity. Virtually all antipsychotics bind to (and inhibit) presynaptic and postsynaptic dopamine-2 (D 2) receptors in the CNS. 2 Blockade of dopamine receptors in different regions of the brain produces varying effects.

eptors. In overdose, the clinical toxicity is primarily an exaggerated effect of the pharmacologic activity. Virtually all antipsychotics bind to (and inhibit) presynaptic and postsynaptic dopamine-2 (D 2) receptors in the CNS. 2 Blockade of dopamine receptors in different regions of the brain produces varying effects. Blockade of D 2 receptors in the mesocortical and mesolimbic system is associated with antipsychotic efficacy, whereas D 2 receptor blockade in the area postrema (chemotactic trigger zone) is responsible for antiemetic activity. The third-generation agents, such as aripiprazole, are also partial 2-agonists, with effects dependent on the concentration of dopamine. At low levels of dopamine, they will stimulate the D 2 receptors, and at high levels of dopamine, they will inhibit the D 2 receptors. CHAPTER Tintinalli_Sec15_p1187-1332.indd 1208 8/2/19 8:39 PM

neration agents, such as aripiprazole, are also partial 2-agonists, with effects dependent on the concentration of dopamine. At low levels of dopamine, they will stimulate the D 2 receptors, and at high levels of dopamine, they will inhibit the D 2 receptors. CHAPTER Tintinalli_Sec15_p1187-1332.indd 1208 8/2/19 8:39 PM CHAPTER 180: Antipsychotics 1209 anterior hypothalamus (preoptic area) can produce alterations in body temperature. In addition to blocking dopamine receptors, many antipsychotics have activities at the α-adrenergic, muscarinic, histaminergic, and sero toninergic receptors. Antagonism of the α 1-adrenergic receptors leads to orthostatic hypotension and reflex tachycardia. Antagonism of the muscarinic receptors can produce hyperthermia, tachycardia, mydriasis, dry mucosal membranes, and urinary retention. Blockade of the histaminergic receptors primarily results in sedation. A consistent feature of the second- and third-generation antipsychotics is their potent blockade TABLE 180-1 Common Antipsychotics Generic Name Brand Name in the United States Typical Adult Maintenance Dose (milligrams) Maximum Adult Daily Dose for Psychosis (milligrams) Elimination Half-Life (oral dosing) First-generation or typical antipsychotics Chlorpromazine Thorazine ®* 50–100 orally 3 or 4 times day 1000 23–37 h (parent drug) 10–40 h (active metabolite) Fluphenazine Prolixin®* 1–2.5 orally 3 or 4 times a day 40 15 h Haloperidol Haldol®* 0.5–2 orally 2 to 3 times a day 100 21–24 h Loxapine Loxitane® 15–25 orally 2 to 4 times a day 250 3–4 h Perphenazine Trilafon®* 8–16 orally 2 to 4 times a day 64 9–12 h Pimozide Orap® 2–10 orally once or twice a day 10 55 h Prochlorperazine# Compazine®* 5–10 orally 3 or 4 times a day 150 3–5 h Promethazine# Phenergan® 6.25–25 orally 3 to 4 times a day 100 7–14 h Thioridazine Mellaril®* 50–100 orally 3 to 4 times a day 800 24 h Thiothixene Navane®* 2–5 orally 2 to 3 times a day 60 34 h Trifluoperazine Stelazine®* 2–5 orally twice a day 40 18 h Second-generation or atypical antipsychotics Amisulpride† Solian® 200 orally twice a day 1200 12 h Asenapine Saphris® 5–10 SL twice a day 20 24 h Brexpiprazole Rexulti® 2–4 orally once a day 4 91 h Cariprazine Vraylar® 1.5–6 orally once a day 6 2–4 d (parent drug) 1–3 wk (active metabolite) Clozapine Clozaril® 150–300 orally twice a day 900 8 h (single dose) 12 h (steady state) Iloperidone Fanapt ® 6–12 orally twice a day 24 18 h (extensive metabolizers) 33 h (poor metabolizers) Lurasidone Latuda ® 4–160 orally once a day 160 18 h Olanzapine Zyprexa® 10 orally once a day 20 21–54 h Paliperidone Invega® 6 orally once a day in the morning 12 23 h Pimavanserin Nuplazid® 34 orally once a day 34 57 h (parent drug) 200 h (active metabolite) Quetiapine Seroquel ® 50–100 orally 2 or 3 times a day 800 6–7 h Risperidone Resperidal® 1–2 orally once or twice a day 16 20 h Sulpiride† Dogmatil® 200–400 orally twice a day 1200 11 h Ziprasidone Geodone® 20 orally twice a day 160 7 h Third-generation antipsychotics Aripiprazole Abilify® 10–15 orally once a day 30 75 h (extensive metabolizers) 146 h (slow metabolizers) Brexpiprazole Rexulti® 2–4 orally once a day 4 91 h Cariprazine Vraylar® 1.5–6 orally once a day 6 2–4 d (parent drug) 1–3 wk (active metabolite) Note: Several of these drugs are used for other conditions, such as nausea/vomiting, allergic disorders, and hiccups. Abbreviation: SL = sublingual. *Brand name formulation has been discontinued in the United States. †Not available in the United States. #Promethazine and prochlorperazine have low antipsychotic potency. Blockade of the D 2 receptors in other regions of the brain produces many of the adverse effects associated with antipsychotics.

n: SL = sublingual. *Brand name formulation has been discontinued in the United States. †Not available in the United States. #Promethazine and prochlorperazine have low antipsychotic potency. Blockade of the D 2 receptors in other regions of the brain produces many of the adverse effects associated with antipsychotics. Antagonism of the D 2 receptors in the tuberoinfundibular region is associated with hyperprolactinemia, which can cause galactorrhea, gynecomastia, and sexual dysfunction. Blockade of the D 2 receptors in the nigrostriatal region is associated with the development of extrapyramidal symptoms. Agents with greater D 2 receptor affinity (e.g., haloperidol or fluphenazine) have higher likelihood of inducing extrapyramidal symptoms, whereas agents with less receptor affinity (e.g., clozapine) are less likely to cause extrapyramidal symptoms. Blockade of the D 2 receptors in the Tintinalli_Sec15_p1187-1332.indd 1209 8/2/19 8:39 PM

r D 2 receptor affinity (e.g., haloperidol or fluphenazine) have higher likelihood of inducing extrapyramidal symptoms, whereas agents with less receptor affinity (e.g., clozapine) are less likely to cause extrapyramidal symptoms. Blockade of the D 2 receptors in the Tintinalli_Sec15_p1187-1332.indd 1209 8/2/19 8:39 PM 1210 SECTION 15: Toxicology of serotonin subtype 2A, which is greater than D 2 receptor inhibition. This intense antagonism of serotonin subtype 2A actually increases dopaminergic transmission in the nigrostriatal pathway, reducing the risk of extrapyramidal symptoms, and enhances the ability to treat negative features of psychosis. 3,4 PHARMACOKINETICS Most antipsychotics have similar pharmacokinetic profiles. After oral administration, absorption occurs rapidly, the drugs undergo significant first-pass metabolism, and peak plasma concentrations typically occur within 1 to 6 hours. Following intramuscular injection, peak plasma concentrations typically occur within 60 minutes for immediate-release products but can be delayed up to 1 day with depot preparations. Nearly all antipsychotics have high protein binding and a large volume of distribution. Metabolism is primarily through the cytochrome P450 enzyme system. Because of the near-complete hepatic metabolism of these drugs, renal impairment rarely requires dosage adjustments. CLINICAL FEATURES Isolated overdose of antipsychotics is rarely fatal, and most patients develop only mild to moderate symptoms. 5-7 Toxicity is largely a func tion of the dose ingested, habituation, comorbid conditions, and age. Following overdose, CNS depression is frequent but is less severe in patients receiving long-term therapy, because tolerance to the sedative effects develops after days to weeks of regular use. CNS effects range from lethargy, ataxia, dysarthria, and confusion to coma with respira tory depression in cases of severe overdose. 6,7 The ingestion of a single pill of some antipsychotics can cause significant CNS and respiratory depression in young children. Respiratory depression in adults is more common in multidrug overdoses. Paradoxical agitation and delirium may occur in mixed overdoses, especially those involving agents with antimuscarinic properties. Seizures occur in approximately 1% of individuals after overdose, with the incidence higher for loxapine and clozapine. Gastric pharmacobe zoars have been reported with quetiapine extended-release overdose. Many of the antipsychotics have antimuscarinic properties, especially clozapine, olanzapine, quetiapine, and thioridazine. Thus, patients can manifest signs or symptoms that are consistent with antimuscarinic toxicity, including tachycardia, dry mucous membranes, dry skin, decreased bowel sounds, urinary retention, agitation, delirium, and hyperthermia. However, due to the concurrent α-adrenergic antagonism of many of these agents, miosis, rather than mydriasis, is frequently observed. The most common cardiovascular manifestations of antipsychotic overdose are sinus tachycardia and orthostatic hypotension . ECG changes also include QT prolongation (highest rate with amisulpride and thioridazine), QRS widening (usually with large ingestions), and nonspecific T-wave abnormalities. 9,10 Ventricular dysrhythmias are rare,11 with the exception of amisulpride overdoses.12 DIAGNOSIS Routine laboratory analysis should include basic chemistry tests and a pregnancy test for women of childbearing age. Test for co-ingestants, including acetaminophen and salicylate levels, in all intentional over doses. Perform an ECG to assess the conduction intervals. Obtain complete blood counts for patients who develop a fever while taking clozapine or chlorpromazine.

istry tests and a pregnancy test for women of childbearing age. Test for co-ingestants, including acetaminophen and salicylate levels, in all intentional over doses. Perform an ECG to assess the conduction intervals. Obtain complete blood counts for patients who develop a fever while taking clozapine or chlorpromazine. TREATMENT Treatment for patients with antipsychotic poisoning is largely supportive.5-7 For patients who are known to have ingested or are suspected of having ingested a significant amount, establish IV access and monitor cardiac rhythm. Ventilatory support should be provided to patients with respi ratory depression. Patients with depressed consciousness should receive oxygen supplementation, continuous pulse oximetry, assessment of blood glucose, and consideration for administration of naloxone and thiamine. Seizures should be treated with a benzodiazepine such as lorazepam. Treat hypotension with IV fluid resuscitation; adults without previ ously known or suspected cardiac disease should receive at least 1 to 2 L of crystalloid and children should receive 20 to 40 mL/kg. If hypotension persists, direct-acting α-adrenergic agonists, such as phenylephrine or norepinephrine, are the preferred vasopressors for treatment. Dopa mine, an indirect-acting vasopressor, is not recommended as a first-line agent for treatment of hypotension following an antipsychotic overdose. Patients with a QT c interval of >500 milliseconds are at increased risk for torsades de pointes.13,14 Assuming there are no contraindications to magnesium supplementation and regardless of the serum magnesium level, adults with a QT c interval of >500 milliseconds should receive magnesium sulfate, 2 grams IV over 10 minutes.6 Patients with torsades de pointes should receive 2 grams of magnesium sulfate as a bolus, fol lowed by an infusion of 2 to 4 milligrams/min, regardless of the magnesium concentration. Overdrive pacing can also be useful, especially in cases that prove refractory to magnesium. Patients with an intraventricular conduction delay (e.g., prolonged QRS complex) and ventricular dysrhythmias should be treated with sodium bicarbonate, 1 to 2 mEq/kg IV bolus, followed by intermittent boluses or a continuous infusion. Lidocaine is an acceptable alternative or second-line agent for ventricular dysrhythmias. Avoid using class Ia (e.g., quinidine, procainamide), Ic (e.g., propafenone), III (e.g., amio darone), and IV antiarrhythmics in patients with cardiac conduction disturbances or ventricular dysrhythmias who are concurrently taking an antipsychotic because these antiarrhythmics may potentiate such cardiotoxicity. DISPOSITION AND FOLLOW-UP Following ingestion, observe the patient for at least 6 hours. Obtain orthostatic pulse and blood pressures and observe successful ambulation prior to discharge. The patient can be judged to be free of toxicity if there are no mental status changes, pulse and blood pressure abnormalities, orthostatic hypotension, and QT c interval prolongation after 6 hours of observation from the time of ingestion. 16,17 Patients with evidence of toxicity (e.g., sinus tachycardia or QT interval prolongation) should be admitted to a monitored bed for observation. Patients who develop severe symptoms (e.g., seizure, respiratory depression, hypotension, acidosis) during the observation period in the ED should be admitted to an intensive care unit.  ADVERSE EFFECTS OF THERAPEUTIC DOSING CARDIOVASCULAR Antipsychotics can affect myocardial conduction and repolarization. At therapeutic dosages, this is usually evidenced by prolongation of the QT interval. Of the typical agents, thioridazine, pimozide, and IV haloperi dol cause the greatest degree of QT prolongation.

ADVERSE EFFECTS OF THERAPEUTIC DOSING CARDIOVASCULAR Antipsychotics can affect myocardial conduction and repolarization. At therapeutic dosages, this is usually evidenced by prolongation of the QT interval. Of the typical agents, thioridazine, pimozide, and IV haloperi dol cause the greatest degree of QT prolongation. 13,18 Among the atypical antipsychotics, ziprasidone, sertindole, and amisulpride are associated with the greatest degree of QT prolongation in therapeutic dosing. 13,18 EXTRAPYRAMIDAL SYMPTOMS Although high-potency typical agents cause the highest rate of extra pyramidal symptoms, all antipsychotic agents are capable of producing these symptoms. 2 The four extrapyramidal syndromes include acute dystonia, akathisia, drug-induced parkinsonism, and tardive dyskinesia. Acute dystonias manifest as hyperkinetic movements characterized by intermittent, uncoordinated, involuntary contractions of the muscles of the face, tongue, neck, trunk, or extremities. Although distressing to patients, these effects are not life threatening. Akathisias are a subjective sensation of motor restlessness. Occasionally, akathisia can be misinterpreted as increasing agitation related to an underlying psychiatric con dition and can thereby prompt additional medication administration. Tintinalli_Sec15_p1187-1332.indd 1210 8/2/19 8:39 PM

s are not life threatening. Akathisias are a subjective sensation of motor restlessness. Occasionally, akathisia can be misinterpreted as increasing agitation related to an underlying psychiatric con dition and can thereby prompt additional medication administration. Tintinalli_Sec15_p1187-1332.indd 1210 8/2/19 8:39 PM CHAPTER 180: Antipsychotics 1211 Acute dystonic reactions and akathisia are typically encountered early after starting therapy (or increasing the dose of a drug) and can be reversed with diphenhydramine (25 to 50 milligrams IV) or benztropine (1 to 2 milligrams IV). Diphenhydramine, 25 to 50 milligrams PO three or four times a day, or benztropine, 1 to 2 milligrams PO twice a day, should be continued for 2 to 3 days after parenteral treatment because of the prolonged effects of the dystonia-inducing agent. Tardive dyskinesia and drug-induced parkinsonism typically develop after prolonged therapeutic use and are unlikely to be reversible. OTHER ADVERSE EFFECTS Therapeutic use of atypical antipsychotics is linked with the develop ment of type 2 diabetes mellitus and diabetic ketoacidosis. 2,19-21 There is some suggestion that the risk is greatest with olanzapine. 22 Phenothiazines are associated with leukopenia in up to 0.8% and agranulocytosis in 0.05% of patients. 23 Several atypical antipsychotics have also been associated with agranulocytosis, with the highest incidence in patients taking clozapine, in whom leukopenia occurs in 3% and agranulocytosis in 0.8%. Due to these adverse effects, clozapine can only be prescribed within a strictly monitored program. Seizures have been associated with several antipsychotics, primarily chlorpromazine, loxapine, and clozapine. 24-26 The risk of seizure appears to be dose dependent. If they occur, seizures, should be treated with benzodiazepines (e.g., lorazepam, 1 to 2 milligrams IV bolus).  NEUROLEPTIC MALIGNANT SYNDROME Neuroleptic malignant syndrome is a rare but potentially fatal idiosyn cratic complication of antipsychotic drug therapy and not the result of an overdose. 27-29 Neuroleptic malignant syndrome most often occurs shortly after the start of therapy or after a dosage adjustment, and the antipsychotic serum concentration is usually within the therapeutic range. Neuroleptic malignant syndrome is associated with all the typical antipsychotics and most of the commonly available atypical antipsy chotics, including aripiprazole, clozapine, olanzapine, risperidone, and ziprasidone. 30,31 Neuroleptic malignant syndrome patients are more commonly adult males, with peak incidence in the 20- to 25-year age range. 32 The incidence is about 1 to 2 cases per 10,000 patients treated.28 CLINICAL FEATURES Neuroleptic malignant syndrome typically develops over a period of 1 to 3 days and is characterized by the tetrad of altered mental status, muscular rigidity, fever, and sympathetic nervous system lability. The rigidity is typically described as lead pipe and cogwheel rigidity, similar to that observed with parkinsonism. The majority of patients present first with altered mental status, followed by rigidity, then fever, and lastly sympathetic nervous system lability. Fever can be delayed for more than 24 hours after the first symptom. In addition to the tetrad, two other features embody important con cepts about this syndrome: recent dopamine antagonist exposure or dopamine agonist withdrawal and negative evaluation for other causes (Table 180-2). 33,34 Common laboratory abnormalities include elevated creatine kinase level, leukocytosis, elevated levels of hepatic transaminases, hypernatremia or hyponatremia, metabolic acidosis, myoglobinuria, elevated BUN and creatinine levels, and decreased serum iron level.

negative evaluation for other causes (Table 180-2). 33,34 Common laboratory abnormalities include elevated creatine kinase level, leukocytosis, elevated levels of hepatic transaminases, hypernatremia or hyponatremia, metabolic acidosis, myoglobinuria, elevated BUN and creatinine levels, and decreased serum iron level. All antipsychotics have been associated with neuroleptic malignant syndrome, but the clinical features of reported cases associated with second- and third-generation agents differ somewhat from the classic presentation induced by the first-generation drugs. Fever and sympa thetic liability are less common in neuroleptic malignant syndrome induced by second- and third-generation antipsychotics. The differential diagnosis of neuroleptic malignant syndrome includes infectious, endocrine, toxicologic, and metabolic disorders. The most common disorder creating diagnostic confusion is serotonin syndrome (see Chapter 178, “ Atypical and Serotonergic Antidepressants”). Clinical features more indicative of serotonin syndrome include a more rapid onset (2 to 24 hours), shivering, hyperreflexia, myoclonus, nausea, vomiting, diarrhea, and less intense muscle rigidity and fever. TREATMENT Treatment is primarily supportive ( Table 180-3).27,28,37,38 Withdraw any antipsychotics and potentiating drugs. Consider and evaluate for other medical conditions that can present in a similar manner, including CNS infection, other drug-induced hyperthermic syndromes, serotonin syndrome, anticholinergic poisoning, and sympathomimetic toxicity. 37,38 Reduce the patient’s temperature with external cooling measures; pharmacologic antipyretics such as acetaminophen are not beneficial in lowering the temperature associated with this syndrome. Sedation is very important to decrease agitation and sympathetic activity; a benzodiazepine, such as lorazepam, is recommended. 27,37,38 Airway and breathing difficulties should be anticipated, and patients with excessive secretions, dysphagia, decreased airway reflexes, acidosis, or hypoxia should be intubated. In addition, strongly consider intubat ing patients with fever and rigidity, because neuromuscular paralysis reduces the muscle contraction and thereby reduces the fever. When patients with neuroleptic malignant syndrome are intubated, nondepolarizing agents (e.g., rocuronium) are preferred over depolarizing agents (e.g., succinylcholine). TABLE 180-2 Diagnostic Criteria for Neuroleptic Malignant Syndrome Major features

lysis reduces the muscle contraction and thereby reduces the fever. When patients with neuroleptic malignant syndrome are intubated, nondepolarizing agents (e.g., rocuronium) are preferred over depolarizing agents (e.g., succinylcholine). TABLE 180-2 Diagnostic Criteria for Neuroleptic Malignant Syndrome Major features Fever >38°C (100.4°F), measured orally on at least two occasions Lead-pipe muscle rigidity Psychomotor slowing and altered mental status Sympathetic nervous system lability (2 or more features) •   Elevated blood pressure •   Blood pressure fluctuation •   Diaphoresis •   Urinary incontinence Recent dopamine antagonist exposure or dopamine agonist withdrawal Minor features Increased creatine kinase level (> 4 × upper limit) or myoglobinuria Tachycardia Tachypnea Hypersalivation (more prominent with clozapine or amisulpride) Tremor Muscle cramps Exclusionary criteria No other infectious, toxic, metabolic, or neurologic cause identified TABLE 180-3 Treatment of Neuroleptic Malignant Syndrome •   Withdraw any antipsychotics and potentiating drugs, such as anticholinergics, antihistamines, or lithium •   IV hydration to restore circulating volume and maintain urine output •   Reduce the patient’s temperature with external cooling measures •   Sedation with a benzodiazepine, such as lorazepam, 1–2 milligrams IV every 2–4 h as needed •   Airway protection: consider early intubation, especially if hypersalivation is present •   Nondepolarizing neuromuscular blocking agents •   Consider agents to reduce severe muscle rigidity •   Dantrolene, 1.0–2.5 milligrams/kg IV load, followed by 1 milligram/kg IV every 6 h •   Bromocriptine, starting with 2.5 milligrams PO 3 to 4 times a day •   Amantadine, 100 milligrams PO 3 times a day Tintinalli_Sec15_p1187-1332.indd 1211 8/2/19 8:39 PM