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1262 SECTION 15: Toxicology Whole-bowel irrigation can be considered for severe overdose with enteric-coated formulations.67 Hemodialysis, hemofiltration, and char coal hemoperfusion are not effective in enhancing elimination because NSAIDs are highly protein bound. Likewise, manipulation of serum and urine pH through IV alkalinization is not beneficial in enhancing renal elimination. Hemodialysis may be needed for severe metabolic derangements or renal failure not responsive to conservative therapies. Patients with symptomatic NSAID overdoses should have a serum chemistry panel, hepatic profile, CBC, and coagulation profile. Serum NSAID levels do not correlate with observed toxicity or outcomes, so serum levels for specific NSAIDs are not indicated. DISPOSITION AND FOLLOW-UP Most patients with asymptomatic NSAID ingestions can be safely discharged after a 4-hour period of observation. Patients with a symp tomatic overdose (altered mental status, abnormal vital signs, electrolyte abnormalities, or acute renal failure) should be admitted for observation and supportive care. All overdoses should be reported to the regional poison control center both for management assistance and for statistical tracking. The majority of NSAID overdoses will not cause significant sequelae, and even patients with major symptoms have a good prognosis if they overcome the initial insult. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Report of NSAID Overdose 1. Definitive airway management required? 2. Hypotensive • Fluid bolus • Vasopressor if refractory 3. Seizures • IV benzodiazepines Admit: symptomatic management Psychiatric consultation Medically cleared for discharge Symptomatic? (altered mental status, seizure, abnormal vital signs, renal failure, acidosis, hepatic toxicity) History Quantity and type of NSAID ingested? Activated charcoal 1 gram/kg PO or via nasogastric tube Check electrolytes, ECG, acetaminophen and salicylate levels Observe for 4 h Symptomatic? (altered mental status, seizure, abnormal vital signs) sN o YesN o FIGURE 191-1. Approach to treatment of acute NSAID overdose. Methylxanthines and Nicotine Chip Gresham Daniel E. Brooks INTRODUCTION Methylxanthines include caffeine, theophylline, theobromine, and nicotine. These agents are plant-derived alkaloids with ubiquitous use in beverages (caffeine in coffee and soda), foods (theobromine in choco late), tobacco products (nicotine), and medications (theophylline and caffeine). Newer methylxanthine derivatives include pentoxifylline (improves peripheral blood flow) and doxofylline (a bronchodilator). 1,2 All methylxanthines have shared pharmacologic properties and very similar pharmacodynamic effects. METHYLXANTHINES  EPIDEMIOLOGY Caffeine (1,3,7-trimethylxanthine), a structural analog of adenosine, is found with varying amounts in beverages and “energy-enhanced” foods, such as candy bars, potato chips, and oatmeal ( Table 192-1). Many “energy drinks” contain guarana, a plant whose seeds contain CHAPTER Tintinalli_Sec15_p1187-1332.indd 1262 8/2/19 8:39 PM

1,3,7-trimethylxanthine), a structural analog of adenosine, is found with varying amounts in beverages and “energy-enhanced” foods, such as candy bars, potato chips, and oatmeal ( Table 192-1). Many “energy drinks” contain guarana, a plant whose seeds contain CHAPTER Tintinalli_Sec15_p1187-1332.indd 1262 8/2/19 8:39 PM CHAPTER 192: Methylxanthines and Nicotine 1263 and vary according to drug level, age extremes, smoking, organ system dysfunction (e.g., cirrhosis), infection, and cytochrome P450 inhibition (Table 192-3). Methylxanthines exhibit Michaelis-Menten kinetics; that is, metabo lism changes from first-order to zero-order kinetics at increased concentrations such that a fixed amount, not percentage, of drug is eliminated per unit of time, making accurate half-life predictions impossible fol lowing an overdose. This also explains why patients who chronically use theophylline may develop a large increase in serum theophylline concentration with only a small increase in dose. Methylxanthines are metabolized in the liver by the cytochrome P450 1A2 pathway. Theophylline undergoes significant enterohepatic recirculation, so toxic serum levels can be maintained longer than anticipated.  CLINICAL FEATURES OF TOXICITY Theophylline has the most potential for significant toxicity, followed by caffeine and then theobromine. The underlying pathophysiology involves adenosine antagonism, increased endogenous adren ergic stimulation, and, at toxic levels, phosphodiesterase inhibition (Table 192-4). The main organ systems involved in methylxanthine toxicity are GI, neurologic, cardiovascular, and metabolic (Table 192-5). GI Toxic Effects Nausea and vomiting are reported in >70% of acute overdoses.6 Theophylline can also induce esophageal reflux by decreas ing lower esophageal sphincter pressure. Neurologic Toxic Effects Methylxanthine-induced seizures can be severe and refractory to treatment. First-time seizures in the setting of heavy caffeinated “energy drink” consumption have been reported. 7,8 In theophylline toxicity, incidence of seizures is approximately 50% when serum levels are >40 micrograms/mL (>200 micromole/L) during chronic therapy and >120 micrograms/mL (>600 micromole/L) after an acute ingestion. 6 Seizures during chronic therapy are seen with lower serum concentrations due to relatively higher tissue levels. In chronic toxicity, seizures can occur without prior neurologic symptoms of tremor or agitation. Cardiovascular Toxic Effects Methylxanthines induce the release of endogenous catecholamines, stimulating β-adrenergic receptors and resulting in increased inotropy and chronotropy, vasodilation, hypo tension, and reflex tachycardia. Sinus tachycardia is the most common cardiac manifestation of both caffeine and theophylline use and toxicity. Both atrial and ventricular tachydysrhythmias are described with excessive caffeine intake. 9,10 Theophylline toxicity may result in atrial dysrhythmias such as multifocal tachycardia and fibrillation or flut ter. Ventricular ectopy is more common with chronic toxicity and in patients with advanced age or underlying cardiac dysfunction. 11 Ventricular fibrillation and tachycardia are rare.

ve caffeine intake. 9,10 Theophylline toxicity may result in atrial dysrhythmias such as multifocal tachycardia and fibrillation or flut ter. Ventricular ectopy is more common with chronic toxicity and in patients with advanced age or underlying cardiac dysfunction. 11 Ventricular fibrillation and tachycardia are rare. TABLE 192-1 Caffeine Content of Various Products Source Caffeine Content (milligrams) Coffee (8 oz or 240 mL, brewed) 60–120 Tea (8 oz or 240 mL, brewed) 20–90 Colas, caffeinated (8 oz or 240 mL) 20–40 Dark chocolate (1 oz or 30 mL) 5–35 “Higher caffeine energy drinks” (8–24 oz) 70–505 Acetaminophen-aspirin-caffeine tablet 65 Nonprescription antidrowsiness tablet 200 Caffeine powder (via online sources) Varies; up to 1700 per 5 mL TABLE 192-2 Pharmacokinetics of Methylxanthines Parameter Caffeine Theophylline Therapeutic serum concentration 5–20 micrograms/mL (25–100 micromole/L) 8–20 micrograms/mL (44–110 micromole/L) Bioavailability (oral) ∼100% ∼100% Oral peak absorption (h) (delayed in overdose) 0.5–1.0 1–2 (up to 8 h with sustainedrelease preparations) Volume of distribution (L/kg) ∼0.6 ∼0.5 Protein binding ∼35% ∼60% Major active metabolites Paraxanthine Theobromine Theophylline Caffeine (only if <6 mo old) Clearance Hepatic <1 y old: 50% hepatic and 50% renal >1 y old: 90% hepatic and 10% renal Half-life (accurate only at therapeutic concentrations) Neonates: >50 h Neonates: 20–30 h <1 y old: 20 h Children and adults: 5 h >1 y old: 5 h >60 y old: 10 h TABLE 192-3 Factors Affecting Theophylline Clearance

nly if <6 mo old) Clearance Hepatic <1 y old: 50% hepatic and 50% renal >1 y old: 90% hepatic and 10% renal Half-life (accurate only at therapeutic concentrations) Neonates: >50 h Neonates: 20–30 h <1 y old: 20 h Children and adults: 5 h >1 y old: 5 h >60 y old: 10 h TABLE 192-3 Factors Affecting Theophylline Clearance Increase Theophylline Clearance Decrease Theophylline Clearance Medications Barbiturates Benzodiazepines (suspected) Carbamazepine Phenytoin St. John’s wort Cimetidine Ethanol (coingested) Erythromycin (all macrolides suspected) Oral contraceptives Propranolol (metoprolol suspected) Fluoroquinolones (most) Verapamil Medical conditions   Cirrhosis Heart failure Pneumonia (other infections suspected) Other Hyperthyroidism Tobacco Marijuana (cannabis) Pregnancy Obesity Fever (suspected) high concentrations of caffeine and other methylxanthines. Drinks with guarana may not list caffeine as an ingredient. 4 Other uses for caffeine include apnea of prematurity, analgesic adjuncts, postdural puncture headache, appetite suppression for weight loss, sleep prevention, and diuresis. Theophylline (1,3-dimethylxanthine) and its water-soluble salt, aminophylline, were used extensively in the past for the treatment of asthma and chronic obstructive pulmonary disease. However, theophylline’s use has declined due to its narrow therapeutic window and the development of safer agents. Theophylline is still used in patients with debilitating bronchospastic disease, particularly outside the United States. Theobromine (3,7-dimethylxanthine) is found in the seeds of Theobroma cacao, from which chocolate and cocoa are derived, and Camellia thea, from which teas are steeped, and is an ingredient in numerous “energy drinks” in addition to caffeine. There are very few cases of human toxicity, but theobromine has been associated with atrial fibrillation.  PHARMACOLOGY Caffeine is most commonly consumed orally; however, it can be administered rectally or parenterally. Theophylline is usually taken orally as an elixir or as an extended-release or controlled-release tablet, although its absorption may be affected by food. Controlled-release tablets can result in erratic or delayed absorption. Theophylline can also be administered IV as aminophylline. All methylxanthines are rapidly absorbed with early peak levels, cross the blood–brain barrier and placenta, and are excreted in breast milk (Table 192-2). Half-lives are only accurate at therapeutic concentrations Tintinalli_Sec15_p1187-1332.indd 1263 8/2/19 8:39 PM

ylline can also be administered IV as aminophylline. All methylxanthines are rapidly absorbed with early peak levels, cross the blood–brain barrier and placenta, and are excreted in breast milk (Table 192-2). Half-lives are only accurate at therapeutic concentrations Tintinalli_Sec15_p1187-1332.indd 1263 8/2/19 8:39 PM 1264 SECTION 15: Toxicology Metabolic Toxic Effects Methylxanthine toxicity is associated with hypokalemia, hyperglycemia, and metabolic acidosis. Hypokalemia is most common in acute overdose, due to increased catecholamines. 12 Rhabdomyolysis has been reported in caffeine and theophylline over doses, presumably due to the hypermetabolic state, agitation, and seizures. 13,14 Tolerance and Withdrawal Chronic use of methylxanthines, particularly caffeine, can lead to tolerance, dependence, or withdrawal. Caffeine withdrawal syndrome has a varied course depending on use. With drawal symptoms typically start at 6 to 24 hours after the last dose, peak at about 36 hours, and can last for several days. Headache and fatigue are the most common symptoms and are seen after either chronic use or short-term, high-dose exposures. Caffeine withdrawal headaches can be debilitating and should be included in the differential diagnosis of ED patients with headache.  DIAGNOSIS OF TOXICITY Caffeine Toxicity There is no clearly defined toxic dose or level of caffeine. Following a single ingestion of 120 milligrams of caffeine, an average peak serum concentration of 3 micrograms/mL (15 micromole/L) results at 1 hour. Caffeine doses around 120 milligrams enhance arousal and performance of both cognitive and psychomotor skills. Ingestions of 100 to 150 milligrams/kg or serum levels >100 micro grams/mL (>500 micromole/L) are likely to cause life-threatening toxicity, and an acute ingestion of >200 milligrams/kg can be lethal. 4,16 Serum caffeine concentrations are not readily available in most clinical settings and offer little in terms of clinical decision making, so management of caffeine toxicity is guided by clinical findings. Theophylline Toxicity Although there is an established therapeutic serum concentration for theophylline, clinical effects are determined by the amount of free drug in tissue, not the serum. The best predictor of major theophylline toxicity after an acute overdose—seizures, hypotension, or cardiac dysrhythmias—is the peak serum concentra tion. In chronic toxicity, although serum levels are elevated, the level itself does not necessarily predict major toxicity. In an acute ingestion, monitor serial theophylline levels to establish a trend in absorption and document a declining concentration to assist in the medical clearance of patients, because peak levels may be delayed many hours following a massive, acute overdose (Table 192-6). Management decisions should be based on symptoms and the patient’s clinical condition, not on drug levels alone.  TREATMENT The three main components to caring for a patient with methylxanthine toxicity are resuscitation (stabilizing cardiovascular and pulmonary function), GI decontamination to interrupt continued absorption (when appropriate), and minimizing end-organ effects. Supportive care and an appropriate observation period are required to prevent secondary sequelae. Monitor patients in a high-acuity setting. Treatments specific to methylxanthines, particularly theophylline, include use of acti vated charcoal, treatment of dysrhythmias and seizures, and enhanced elimination. Initial ancillary studies should include ECG, serum electrolytes, cre atinine, urea, glucose, and total creatine kinase. Other laboratory tests may be required based on patient presentation, available medications, and comorbidities.

acti vated charcoal, treatment of dysrhythmias and seizures, and enhanced elimination. Initial ancillary studies should include ECG, serum electrolytes, cre atinine, urea, glucose, and total creatine kinase. Other laboratory tests may be required based on patient presentation, available medications, and comorbidities. After an intentional ingestion, consider comorbid poisonings, such as with acetaminophen (paracetamol) or salicylate. Consult with a medical toxicologist or a regional poison control center to discuss case-specific treatment. GI Decontamination Consider GI decontamination with a potentially life-threatening theophylline poisoning provided there are no contraindications, such as an unprotected airway, intractable nausea or vomiting, ileus, bowel obstruction, or need for emergent endoscopy (Table 192-7). 17 In caffeine ingestion, there is little benefit to GI decontamination because of the rapid absorption and associated nausea. Ondansetron is the preferred antiemetic to control associated nausea or vomiting. Do not use phenothiazines (i.e., promethazine) because these agents lower the seizure threshold. Ranitidine can be used to decrease gastric acid hypersecretion. Do not give cimetidine as it can prolong methylxanthine half-life. Multidose activated charcoal can enhance theophylline elimination by interrupting enterohepatic recirculation. 18 Consult with a toxicolo gist or poison center regarding the use of whole-bowel irrigation for the ingestion of sustained-release preparations. 19 Endoscopic removal of a slow-release, theophylline-containing bezoar may be necessary. Ipecac syrup, cathartics, and gastric lavage after theophylline ingestion are without proven benefit, have potential adverse effects, and are not recommended. 20-22 Seizures Due to adenosine antagonism, seizures may be difficult to control, particularly with theophylline toxicity. Benzodiazepines, such as lorazepam 2 to 4 milligrams IV or diazepam 5 to 10 milligrams IV in adults, are first-line agents. Repeated, larger doses may be necessary. TABLE 192-4 Methylxanthine Mechanisms of Action and Toxicity Adenosine Antagonism Increased Catecholamines Inhibition of Phosphodiesterase Mechanism Inhibition of adenosine-1 and adenosine-2 > adenosine-3 receptors Increased circulating catecholamines (epinephrine and norepinephrine) Phosphodiesterase inhibition (at toxic levels) Effect Decreased adenosine activity Increased excitatory neurotransmitters activity Stimulation of β 1 and β 2 receptors Increased concentration of cyclic adenosine monophosphate and catecholamine effects Therapeutic effect Bronchodilation Bronchodilation No role at therapeutic doses Clinical toxicity Vasoconstriction Dysrhythmias Seizures Tachycardia Vasodilation Hypotension Enhanced β-adrenergic effects TABLE 192-5 Clinical Manifestations of Methylxanthine Toxicity Organ System Manifestation GI Nausea Vomiting Gastritis Neurologic Headache Tremor Agitation Seizure Cardiovascular Tachycardia Hypotension Atrial dysrhythmias Ventricular ectopy Metabolic Hypokalemia Hyperglycemia Metabolic acidosis Hyperthermia Rhabdomyolysis Tintinalli_Sec15_p1187-1332.indd 1264 8/2/19 8:39 PM

icity Organ System Manifestation GI Nausea Vomiting Gastritis Neurologic Headache Tremor Agitation Seizure Cardiovascular Tachycardia Hypotension Atrial dysrhythmias Ventricular ectopy Metabolic Hypokalemia Hyperglycemia Metabolic acidosis Hyperthermia Rhabdomyolysis Tintinalli_Sec15_p1187-1332.indd 1264 8/2/19 8:39 PM CHAPTER 192: Methylxanthines and Nicotine 1265 Barbiturates, such as phenobarbital 10 to 20 milligrams/kg IV in adults, should be used if escalating doses of benzodiazepines are ineffective. At high doses, benzodiazepines and barbiturates can compromise the airway or lead to respiratory depression, so maintain a low threshold for endotracheal intubation. Phenytoin is not useful or recommended. Patients who fail to respond to anticonvulsant therapy should be sedated, intubated, and paralyzed with a neuromuscular blocking agent; general anesthesia may be required. Paralyzed patients should have an electroencephalogram to monitor for continued seizure activity. Due to the severity of theophylline-induced seizures, some toxicologists recommend prophylactic use of a γ-aminobutyric acid agonist (e.g., lorazepam) to raise seizure threshold in patients presenting with mark edly elevated theophylline levels, although this approach has not been validated in human studies. Cardiovascular Support Manage hypotension initially with IV fluids. The most commonly reported methylxanthine-induced tachydysrhythmias are atrial fibrillation and supraventricular tachycardia, managed using cardioselective β-blockers (esmolol or metoprolol). Ventricular dysrhythmias are uncommon. Enhanced Elimination Enhanced elimination techniques can prevent or help treat significant toxicity following methylxanthine poisonings. Multidose activated charcoal is recommended for toxic or potentially toxic theophylline ingestions. Hemodialysis is safe and is as efficacious as hemoperfusion for the treatment of theophylline toxicity. 25 Hemodialysis is also effective for massive caffeine ingestions and pentoxifylline toxicity.26,27 Hemodialysis enhances methylxanthine clearance and provides fluid and electrolyte correction. Most experts suggest that a methylxanthineinduced life-threatening event, such as seizures or intractable dysrhythmias, is an indication for hemodialysis. In addition, we suggest that dialysis should be considered if (1) after an acute ingestion, a symp tomatic patient has a serum theophylline level >100 micrograms/mL (>555 micromole/L) or (2) a chronic toxicity patient has a serum theophylline level >60 micrograms/mL (>333 micromole/L) with significant symptoms or comorbidities.28 Published experience suggests that most patients who receive hemodialysis after a methylxanthineinduced life-threatening event, such as a seizure or dysrhythmia, will continue to have them, whereas as few as 5% of patients who received hemodialysis before manifesting severe toxicity will go on to develop a life-threatening event. Supportive Care Treat vomiting with antiemetics, and correct volume depletion with isotonic fluids. Hypokalemia may not require treatment unless there are clinical findings such as ECG changes, cardiac ectopy, or muscle weakness because potassium is shifted intracellularly and totalbody potassium is only mildly depleted. Provide continuous cardiac monitoring until toxicity has resolved. Assess for hyperthermia, rhabdomyolysis, and compartment syndrome, and provide specific treatment. Patients who are sedated and paralyzed should undergo continuous electroencephalographic monitoring to evaluate for occult sustained or recurrent seizures.

rovide continuous cardiac monitoring until toxicity has resolved. Assess for hyperthermia, rhabdomyolysis, and compartment syndrome, and provide specific treatment. Patients who are sedated and paralyzed should undergo continuous electroencephalographic monitoring to evaluate for occult sustained or recurrent seizures.  DISPOSITION AND FOLLOW-UP Following an intentional or accidental methylxanthine ingestion, patients are judged nontoxic when they are asymptomatic, have a normal physical examination and vital signs, and, if available, have normal or decreasing serum concentrations. Patients who remain asymptomatic for at least 6 hours after an acute ingestion of immediaterelease tablets can be considered nontoxic. Patients with an ingestion of sustained-release medication should be monitored for 12 hours or longer. Patients with intentional ingestions should receive a behavioral health or psychiatric evaluation to assist with appropriate disposition and follow-up. NICOTINE  EPIDEMIOLOGY Nicotine is the primary alkaloid in tobacco, a product produced from the dried leaves of plants in the genus Nicotiana. Tobacco is consumed as smoke (i.e., cigarettes) or smokeless (i.e., chewing tobacco) products. A typical cigarette contains approximately 20 milligrams of nicotine, but only about 1 milligram is absorbed during smoking. Nicotine gums usually contain 2 or 4 milligrams per piece; formulation and mastication assist in higher absorption compared to smoking a cigarette. Liquid nicotine used in electronic (E)-cigarettes contains up to 36 milligrams/mL of nicotine. Calls to poison centers for pediatric ingestion of liquid nicotine are increasing, 31,32 with more serious toxicity seen with liquid nicotine exposure compared to cigarettes, 31 and deaths have been reported.33,34 Other nicotine sources include smoking cessation products (gums, patches, nasal inhalers), pesticides, traditional remedies, and plants, including dermal exposures during tobacco harvest causing “greentobacco sickness. ”  PHARMACOLOGY Nicotine is rapidly absorbed in the lungs, as well as across mucous membranes, the intestinal tract, and intact skin.

oking cessation products (gums, patches, nasal inhalers), pesticides, traditional remedies, and plants, including dermal exposures during tobacco harvest causing “greentobacco sickness. ”  PHARMACOLOGY Nicotine is rapidly absorbed in the lungs, as well as across mucous membranes, the intestinal tract, and intact skin. Smoking tobacco TABLE 192-6 Methylxanthine Toxicity Classifications Acute Toxicity Acute on Chronic Toxicity Chronic Toxicity Clinical scenario Acute exposure: one-time ingestion of a bottle of theophylline or caffeine tablets Acute exposure in a person chronically using that methylxanthine: an acute ingestion of a bottle of theophylline in a patient taking theophylline An ongoing exposure to a stable amount with bioaccu mulation; typically, due to decreased clearance: a newly prescribed medication inhibits theophylline metabolism, leading to slowly increasing tissue concentrations Risk of clinical effects Variable, depends on amount High, depends on amount ingested and comorbidities High, depends on tissue level of drug, age, and comorbidities Timing of peak serum concentration Often delayed for many hours Usually delayed Often immediately available Correlation of peak serum concentration with clinical effects Moderate correlation Moderate correlation Weak correlation TABLE 192-7 GI Decontamination for Methylxanthine Toxicity GI Decontamination Technique Indication* Dosing Activated charcoal (single dose) Acute ingestion <12 y old: 0.5–1.0 gram/kg PO >12 y old: 25–100 grams PO Multidose activated charcoal (requires close observation) Acute ingestion Normal activated charcoal loading dose, followed by: 0.25–0.5 gram/kg PO every 2–4 h for 12 h (frequency and duration may vary) Whole-bowel irrigation using iso-osmolar polyethylene glycol electrolyte solution Acute ingestion of sustained-release preparations 9 mo–6 y: 25 mL/kg per hour 6–12 y old: 1000 mL/h >12 y old: 1500–2000 mL/h Duration: 4–6 h or until clear rectal effluent *Consider contraindications; for details see http://www.clintox.org/resources/position-statements. Tintinalli_Sec15_p1187-1332.indd 1265 8/2/19 8:39 PM

e ingestion of sustained-release preparations 9 mo–6 y: 25 mL/kg per hour 6–12 y old: 1000 mL/h >12 y old: 1500–2000 mL/h Duration: 4–6 h or until clear rectal effluent *Consider contraindications; for details see http://www.clintox.org/resources/position-statements. Tintinalli_Sec15_p1187-1332.indd 1265 8/2/19 8:39 PM 1266 SECTION 15: Toxicology leads to a peak serum nicotine concentration of 40 nanograms/mL (250 micromole/L), depending on depth of inhalation. Nicotine crosses the blood–brain barrier and affects the CNS within seconds of smoking. Absorption across mucous (oral) membranes is slower than absorption from smoking and is further delayed by gastric acids. Therapeutic use of a 4-milligram piece of nicotine gum leads to a peak nicotine concen tration of about 10 nanograms/mL (60 micromole/L) at 45 minutes. The half-life of nicotine is variable, averaging about 2 hours in adults. Metabolism is by the liver, mainly by cytochrome P450 2A6, with 85% being converted to cotinine. Once absorbed, nicotine binds to nicotinic acetylcholine receptors throughout the body, including the central nervous, autonomic, and neuromuscular systems. Early in toxicity, nicotine acts as an agonist, activating these ion channels and leading to increased neuronal firing with release of neurotransmitters, including acetylcholine, dopamine, glutamate, norepinephrine, and serotonin. At higher concentrations and/or as toxicity persists, the acetylcholine receptors are inhibited by persistent membrane depolarization, ultimately leading to receptor inactivation.  CLINICAL FEATURES In overdose, nicotine mainly affects the GI, cardiovascular, neuro logic, and respiratory systems ( Table 192-8). Nausea and vomiting are the most common effects and can limit absorbed amounts following ingestion. Early effects are due to acetylcholine receptor activation and include tremor, dizziness, tachycardia, and bronchorrhea. Delayed effects, manifesting after larger exposures, occur due to receptor inactivation and include bradycardia, dysrhythmias, hypoventilation, and coma. Seizures are possible and are due to centrally mediated actions. Nicotine poisoning in children usually results from the ingestion of tobacco or nicotine-containing products, such as E-cigarette liquid. There is no consensus on the estimated lethal dose of nicotine, and accidental ingestion of cigarettes or chewing tobacco in children rarely results in serious outcomes. A child who ingests one or more intact cigarettes, or three or more cigarette butts, has a 90% chance of becoming symptomatic, usually within 30 minutes. 38 More severe poisonings, such as ingestion of nicotine-containing pesticides, self-harm attempts with nicotine-containing E-cigarette liquid, or abuse of dermal patches, can result in seizures, respiratory failure, hypotension, dysrhythmias, and death. 33 Because nicotine freely crosses the placenta and is found in small concentrations in breast milk, neonatal withdrawal is possible. Green-tobacco sickness is characterized by nausea, vomiting, weak ness, dizziness, and headaches, due to the dermal absorption of nicotine during tobacco harvesting.35 Onset of symptoms may be delayed for several hours. Patients with significant comorbidities, particularly underlying cardiovascular or seizure disorders, are theoretically at higher risk for morbidity. Chronic nicotine use has been associated with insulin resistance in diabetics, increased cardiovascular risks, dysrhythmias, and the potential for withdrawal. 40 Nicotine withdrawal manifests with irritability, depression, drowsiness, trouble sleeping, increased appetite, and headaches, with symptoms peaking at 2 to 3 days after last use. Withdrawal can occur in smokers as well as smokeless tobacco and nicotine gum users.

isks, dysrhythmias, and the potential for withdrawal. 40 Nicotine withdrawal manifests with irritability, depression, drowsiness, trouble sleeping, increased appetite, and headaches, with symptoms peaking at 2 to 3 days after last use. Withdrawal can occur in smokers as well as smokeless tobacco and nicotine gum users.  DIAGNOSIS The diagnosis of acute nicotine toxicity is based on reliable history and physical examination, with laboratory analysis being of little value. Qualitative toxicologic screening assays can detect nicotine and cotinine in the urine but may only reflect exposure.  TREATMENT The treatment of nicotine toxicity is symptomatic. Fortunately, because nicotine has a short half-life, symptoms typically resolve rapidly. Car diovascular and ventilatory support may be required in severe toxicity (Table 192-9). Benzodiazepines may be used for seizures, and endotra cheal intubation and mechanical ventilation may be required if signifi cant neuromuscular weakness or respiratory depression develops. Ipecac syrup or activated charcoal is not recommended. Decontamination with soap and water should be done following dermal exposures. There is no role for enhanced elimination or urine acidification. Nicotine withdrawal can be distressing but is not life threatening. Treatment options include the use of nicotine replacement therapy and antidepressants.  DISPOSITION AND FOLLOW-UP Monitor patients with known or suspected nicotine toxicity; the length of observation depends on the type of product ingested. Patients who remain asymptomatic with normal vital signs after 3 hours from an acute ingestion of nicotine-containing product (except intact trans dermal patches) can be discharged from medical care. Those who ingest intact transdermal patches should be observed longer, at least 6 hours. Patients with intentional ingestions should receive a behavioral health or psychiatric evaluation to assist with appropriate disposition and follow-up. REFERENCES The complete reference list is available online at www.TintinalliEM.com. TABLE 192-8 Clinical Effects of Nicotine Toxicity Signs and Symptoms of Nicotine Toxicity* Organ System Immediate (<1 h) Delayed (>1 h) GI Hypersalivation Nausea Vomiting Diarrhea Cardiovascular Tachycardia Hypertension Dysrhythmias Bradycardia Hypotension Neurologic Tremor Headache Ataxia Hypotonia Seizure Coma Respiratory Bronchorrhea Hypoventilation Apnea *Onset of toxicity is varied and can be delayed for hours following dermal exposure. TABLE 192-9 Treatment of Nicotine Toxicity Clinical Condition Intervention Considerations Nausea, vomiting, gastritis Antiemetics Proton pump inhibitors Ondansetron, 4 milligrams IV Pantoprazole, 40 milligrams IV Tremor, seizures Benzodiazepines Lorazepam, 1–2 milligrams IV Diazepam, 5–10 milligrams IV Hypotension Fluid resuscitation Monitor and replace serum electrolytes Hypoventilation Intubation and mechanical ventilation — Withdrawal Nicotine replacement therapy Requires outpatient follow-up Tintinalli_Sec15_p1187-1332.indd 1266 8/2/19 8:39 PM