Toxidromes and Their Treatment

Chapter

106

VII

Toxidromes and Their Treatment Ashley N. Webb and Prashant Joshi

PEARLS • W  hen given for a benzodiazepine overdose, flumazenil may precipitate acute withdrawal in the patient who habitually uses benzodiazepines or may unmask seizures caused by a coingested substance. • A  lthough rare, pulmonary edema may be a serious complication of reversal of opioids with naloxone. • β  -Adrenergic antagonists, when used to lower blood pressure in a sympathomimetic overdose, may lead to unopposed α-receptor stimulation and therefore paradoxic worsening of hypertension. • P hysostigmine should be reserved for severe, life-threatening manifestations of anticholinergic toxicity because of the risk of asystole or seizures. It is absolutely contraindicated in the reversal of the anticholinergic toxidrome produced by tricyclic antidepressant ingestion. • P ulse oximetry is unreliable in methemoglobinemia and may show falsely increased or falsely decreased values depending on the methemoglobin concentration. • M  ethylene blue should not be administered to individuals with known glucose-6-phosphate dehydrogenase deficiency because they lack adequate concentrations of reduced nicotinamide adenine dinucleotide phosphate to produce reductase activity and because methylene blue can trigger hemolysis or methemoglobinemia in those individuals. • T he skin is a distinguishing factor between sympathomimetic (pale, cool, and diaphoretic) and anticholinergic (flushed, warm, and dry) toxidromes. • T he toxic differential diagnosis of hyperthermia should include malignant hyperthermia, serotonin syndrome, neuroleptic malignant syndrome, sympathomimetic poisoning, and anticholinergic poisoning. • A  n elevated osmolar gap suggests ingestion of a toxic alcohol, whereas a normal result does not exclude it. Levels in the blood are the gold standard for diagnosis and prognosis. • S uccinylcholine is generally contraindicated in cholinesterase inhibitor toxicity, and its duration of effect will be significantly prolonged. • N  itrites should be used with extreme caution in patients with cyanide poisoning and concomitant carbon monoxide poisoning because of the risk of further decreasing oxygen-carrying capacity. • T otal iron-binding capacity may be falsely elevated in patients with acute iron overdose and is not a reliable marker in iron toxicity. • In the United States, the local Regional Poison Center may be reached by calling 800-222-1222.

Every year almost 2.5 million human exposures to toxic substances are reported to poison centers in the United States.1 Of these, approximately 60% involve children younger than 12 years, and this age group accounts for approximately 4% of the reported fatalities. Although 75% of calls are managed without referral to a health care facility, of the 25% of patients who are seen in a health care facility, one in eight is admitted to a critical care unit. In most cases of poisoning, the agents involved are known, or at least circumstantial evidence points to a specific toxin or toxins. However, even in cases in which the toxic exposure is unknown or the clinical presentation is inconsistent with the history, the intensivise care physician can find physical and analytical clues of the inciting agent and provide targeted therapy. The term toxidrome, a contraction of toxic syndrome, refers to a constellation of signs associated with certain substances or groups of substances. Several toxidromes have been described; although their expression may not be complete in every case, they can provide valuable information to guide investigation and treatment. A list of toxidromes appears in Chapter 105. The patient should be examined carefully and thoroughly, paying particular attention to vital signs, mental status, pupil size and reactivity, skin characteristics (color, temperature, moisture), and bowel sounds. Other important aspects of the physical examination include muscle tone, respiratory effort, presence of tremor, and characteristics of the mucous membranes. Laboratory investigations may help narrow the differential diagnosis and determine the need for additional examination while guiding therapy. However, diagnostic laboratory tests should be reviewed with caution. Some assays may further cloud the clinical picture because of false-positive results from cross-reactivity and may lead to an inaccurate diagnosis, inappropriate therapy, or withholding of a specific antidote.2 Utility of a specific test should be based on its probability of indicating or guiding therapy and prognosis of endorgan toxicity. This chapter addresses some common presentations of toxic ingestions and their treatment. For more in-depth information, the reader is referred to several comprehensive textbooks of medical toxicology.

Opiates The classic triad of respiratory depression, coma, and miosis is seen with both naturally occurring opiates and synthetic opioids. Additional features include bradycardia, hypotension, 1451

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and decreased gastrointestinal (GI) motility. A similar clinical picture may be encountered with ingestion of clonidine, other imidazoline derivatives found in over-the-counter eye drops or nasal sprays, or tizanidine, all of which are centrally acting α2-adrenergic agonists that decrease sympathetic tone.3-5 Not all patients exposed to an opiate present with the classic toxidrome. Respiration becomes shallow with increasing central nervous system (CNS) depression, so hypercarbia may occur before overt respiratory depression.6-9 In addition, several opiates and opioids, including morphine, meperidine, pentazocine, diphenoxylate/atropine, and propoxyphene, may result in mid-position or mydriatic pupils either from their pharmacologic activity or from brain anoxia.3,10,11 Effects on respiration are likely a result of action at the μ-receptors. Analgesic effect is exerted through action at both μ- and κ-receptors.6 Several opioids have been designed to function as agonist-antagonists. In general, they provide spinal analgesia through agonist effects at the κ-receptors and simultaneously antagonize μ-receptors. This allows them to provide pain relief at higher doses while reaching a ceiling effect on respiratory depression.7 However, in overdose, receptor selectivity may be lost, and decreased respiratory drive can occur with these medications. Naloxone is an opiate receptor antagonist that reverses the toxic effects of opioids. A starting dose of 0.1 mg/kg intravenously is recommended to prevent the need for artificial ventilation in life-threatening opiate-induced respiratory depression. If no intravenous access is available, it can be administered subcutaneously, intramuscularly, or via endotracheal tube. However, the intramuscular route exhibits variable pharmacokinetics with an unpredictable duration of action and may therefore allow recurrent sedation after a period during which the patient is thought to be free of further toxicity. Naloxone may precipitate acute withdrawal in opioid-dependent individuals; in such patients a lower starting dose, titrated upward to effect, may be warranted. Because of the different receptor affinities of each opioid, some individuals may not respond to lower doses of naloxone. The titration should proceed upward to 10 mg, at which point if no response has been illicited, naloxone should be discontinued and an etiology other than opioids should be considered for the cause of respiratory depression.12 In patients with apnea, artificial ventilation should be promptly provided before the administration of naloxone. Because the duration of action of naloxone is shorter than that of most opioids, repeated doses or a continuous intravenous infusion may be necessary. The accepted infusion rate is two thirds of the initial reversal dose per hour.12 Reversal of opioid toxicity has been associated with pulmonary edema, although this has also been described in the setting of opiate toxicity itself.13-16 Naloxone has been reported anecdotally to reverse clonidine overdose, although failure of naloxone to reverse clonidine has also been described.17 Naloxone administration has occasionally been associated with significant hypertension.18,19 This is usually short lived and does not require treatment. If hypertension persists, treatment should consist of a short-acting antihypertensive such as nitroprusside so that the drug and its effects can be quickly stopped. This will prevent the development of hypotension as the hypertensive crisis resolves. Nalmefene is a newer, long-acting opiate receptor antagonist. It is available as a parenteral product with a potency

equivalent to naloxone on a milligram-per-milligram basis but with a duration of action nearly five times longer.20-22 Its half-life can range from 2 to 8 hours. Before it is administered, a test dose of naloxone should be used to exclude the possibility of acute withdrawal. In at least one prospective, controlled trial, it offered no advantage over naloxone.21 It has a similar side effect profile, including cases of short-lived noncardiogenic pulmonary edema, and may provide false security in a patient who has ingested a long-acting opioid in which symptoms may recur after the antagonist has worn off.

Sympathomimetic Agents Symptoms and signs of sympathetic excess may be seen with a number of therapeutic and illicit agents that either mimic endogenous excitatory neurotransmitters or act on receptors to increase their release.23 Drugs that produce the sympathomimetic toxidrome are listed in Box 106-1. Any or all of the manifestations in Box 106-2 may be observed depending on the agent involved. Agents with predominantly β-adrenergic activity are more likely to produce tachycardia and hypotension from peripheral vasodilation compared with agents with predominantly α-adrenergic effects that may produce severe hypertension with reflex bradycardia. Hyperthermia, rhabdomyolysis, and myoglobinuria may result from increased metabolic activity. Additional morbidity, including ischemic or hemorrhagic stroke, have been documented. With cocaine use, for example, cases of myocardial ischemia and infarction have been reported23,24 Thrombolytics should not be used unless the patient has confirmed myocardial infarction and is at low risk for intracranial bleeding.25 The methylxanthines, caffeine and theophylline, are not sympathomimetics per se, but they may produce many of the same clinical features as a result of their β-adrenergic activity and effect on adenosine receptors.26-28 Patients with acute overdose of methylxanthines may initially present with severe GI symptoms and quickly progress to hypotension, tachydysrhythmias, and status epilepticus.27,29,30 Designer amphetamines, such as methylenedioxyamphetamine (MDMA) and its derivatives, additionally cause a release of serotonin and may precipitate hallucinations in addition to the sympathomimetic effects listed above. These patients are at risk for seizures, dysrhythmias, hyperthermia, rhabdomyolysis, the syndrome of inappropriate secretion of antidiuretic hormone resulting in hyponatramia, and disseminated intravascular coagulation.28,31 Benzodiazepines are the first-line agent to reduce CNS catecholamine release, thereby eliminating severe hypertension, tachycardia, agitation, and muscle overactivity. Large doses may be required. Caution should be exercised when adrenergic antagonists are used to treat tachycardia and hypertension; β-adrenergic antagonist use may result in unopposed α-adrenergic receptor stimulation and cause a paradoxic worsening of hypertension. Although labetalol is a β-antagonist with weak α-blocking activity, it has not been shown to be effective in this scenario. Concomitant administration of a vasodilator in refractory hypertension is recommended.23,24,32 Agents such as cocaine may deplete norepinephrine, leading to cardiovascular collapse. Therefore short-acting agents are the only advisable treatment for hypertension if benzodiazepines administration has failed. Seizures should also be managed with benzodiazepines. In patients refractory to this therapy, a barbitruate such as phenobarbital should be considered.

Chapter 106 — Toxidromes and Their Treatment

Box 106–1  Agents that Cause Sympathomimetic Syndrome Albuterol Amphetamines Caffeine Catecholamines Cocaine Ephedrine Ketamine Phencyclidine (PCP) Phenylephrine Phenylpropanolamine Pseudoephedrine Terbutaline Theophylline

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Box 106–3  Anticholinergic Agents Antihistamines (e.g., diphenhydramine, hydroxyzine) Atropine Benztropine mesylate Carbamazepine Cyclic antidepressants Cyclobenzaprine Hyoscyamine Jimsonweed Oxybutynin Phenothiazines Scopolamine Trihexyphenidyl

Box 106–4  Anticholinergic Toxidrome Features Box 106–2  Sympathomimetic Toxidrome Features Agitation Seizures Mydriasis Tachycardia Hypertension Diaphoresis Pallor Cool skin Fever

Phenytoin does not play a role in seizures resulting from toxicity and, in the case of methylxanthines, may actually worsen patient outcome by lowering the seizure threshold.28 Confirmation by urinary drug screening is of little use in the emergency setting. While a positive test result for cocaine is likely confirmatory for its use, a positive result for amphetamines is not. Several medications cross-react to produce a falsepositive amphetamine presence, including buproprion2 and pseudoephedrine.23

Anticholinergic Agents The anticholinergic toxidrome, more appropriately referred to as an antimuscarinic toxidrome, is produced by a number of agents that possess antimuscarinic properties as their primary effect or as a side effect. Examples of such toxins are provided in Box 106-3. Muscarinic receptors are located in the CNS, in the target organs of the parasympathetic nervous system (PNS), and in the sweat glands (sympathetic nervous system).33 The syndrome may have features that are similar to those of the sympathomimetic toxidrome (Box 106-4). Examination of the skin usually provides clues to differentiate between the two; the patient will be dry in this scenario versus increased diaphoresis with sympathomimetic toxicity. Hypertension and tachycardia are typically less severe than when seen with sympathomimetics. Also, the dilated pupils in the anticholinergic syndrome are nonreactive because there is associated cycloplegia.33,34 Because sweating is inhibited in intoxicated patients, treatment of agitation is important to prevent hyperthermia. Benzodiazepines are the drug of choice. Physostigmine is a cholinesterase inhibitor that may be used to reverse the central

Agitation Delirium Coma Mydriasis Dry mouth Warm, dry, flushed skin Tachycardia Hypertension Fever Urinary retention Decreased bowel sounds

and peripheral manifestations of anticholinergic toxicity.33 Because of case reports of convulsions35 or asystole36 associated with administration of physostigmine, it should not be used to treat the anticholinergic manifestations of tricyclic antidepressant overdose. Diphenhydramine overdose can present with anticholinergic toxicity and also manifest electrocardiographic (ECG) changes, including sodium channel blockade. Therefore the use of physostigmine to reverse toxicity in this patient population should be approached with caution. In general, physostigmine has a short duration of action compared with the anticholinergic agent ingested; because of its severe side effects, it has fallen out of favor as an antidote for most previously indicated ingestions.

Cholinergic Agents Cholinergic agents are best divided into the following three categories: muscarinic agents, nicotinic agents, and cholinesterase inhibitors. The muscarinic agents act in the CNS, at postganglionic parasympathetic nerve endings, and in the sweat glands. Nicotinic agents act in the CNS, in the autonomic ganglia (both sympathetic and parasympathetic), and at the neuromuscular junction. Cholinesterase inhibitors increase the available acetylcholine in the cholinergic synapse and present with a combination of symptoms that result from action at both the nicotinic and muscarinic receptors.37,38 Agents with cholinergic activity are listed in Box 106-5. Signs and symptoms of cholinergic excess are listed in Box 106-6. Direct-acting muscarinic agents produce typical features of excessive parasympathetic activity. Nicotine produces salivation, nausea, and vomiting.37,38 Hypotension, bradycardia,

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Box 106–5  Drugs Causing Cholinergic Excess

Box 106–6  Cholinergic Toxidrome Features

Inhibitors of Acetylcholinesterase Organophosphate insecticides (malathion, parathion, diazinon) Carbamate insecticides (aldicarb, carbaryl, propoxur) Nerve agents (soman, sarin, tabun, Vx, cyclosarin) Drugs used for myasthenia gravis or reversal of neuromuscular blockade (e.g., physostigmine, pyridostigmine, neostigmine, edrophonium)

Muscarinic Effects (DUMBBELS) Diarrhea Urinary incontinence Miosis Bradycardia Bronchorrhea Emesis Lacrimation Salivation

Direct Muscarinic Agonists Bethanechol Carbachol Methacholine Pilocarpine Muscarinic mushrooms (e.g., Clitocybe spp., Inocybe spp.) Nicotinic agents Nicotine Water hemlock

and respiratory depression can be preceded by tachycardia, hypertension, and tachypnea. Central features include initial stimulation followed by seizures, lethargy, and coma. Neuromuscular blockade may occur. Management of nicotine poisoning, which can be severe, is entirely supportive.39-41 Children are at increased risk of nicotine poisoning from ingestion of cigarettes or chewing tobacco as well as from exposure to smoking cessation products, including gums, lozenges, patches, and inhalers. Cholinesterase inhibitors, such as organophosphate pesticides and nerve agents, produce a mixed picture of toxicity. Parasympathetic manifestations tend to dominate the autonomic component of toxicity. Organophosphates bind to and inactivate acetylcholinesterase, preventing the normal termination of cholinergic stimulation at the postsynaptic receptors. The end result is excessive nicotinic and muscarinic activity in the PNS and CNS. At the neuromuscular junction, the result is depolarizing neuromuscular blockade. Over time the enzyme becomes phosphorylated, a process referred to as aging. Not all organophosphorous agents age at the same rate. Some nerve agents may age in as quickly as a few minutes, whereas some pesticides can take as long as 72 hours to permanently inactivate the cholinesteraseses.42 Cholinesterase activity is only restored by synthesis of a new enzyme.38 Carbamates bind reversibly to acetylcholinesterase, and the enzyme/chemical complex undergoes spontaneous hydrolysis, generally restoring cholinesterase function within hours. Carbamates do not penetrate the CNS well, so central manifestations are less severe. Because these agents cause bronchorrhea, bronchospasm, decreased respiratory drive, and paralysis of the muscles involved in breathing, death results from respiratory failure. The order of appearance of signs and symptoms depends on the route of administration. With dermal exposure, the first manifestation may be local hyperhidrosis, followed by systemic manifestations once the agent is absorbed through the skin. Inhalational exposure results in initial upper airway manifestations and respiratory distress. Ingestion presents with drooling and vomiting as the earliest expression of toxicity. Treatment of cholinergic toxicity involves atropine to reverse the muscarinic effects, an oxime to reverse neuromuscular

Nicotinic Effects Fasciculations Weakness Paralysis Tachycardia Hypertension Agitation Central Effects Lethargy Coma Agitation Seizures

blockade, and benzodiazepines to treat seizures. Extremely large doses of atropine may be necessary, and the end point of therapy is the drying of secretions, not heart rate or pupil size. Organophosphate-poisoned patients may manifest tachycardia as a result of their exposure, and atropine is not contraindicated in these patients. Tachycardia during therapy is limited and not life-threatening.42,43 Depending on the agent involved, repeated doses or a constant infusion may be necessary. Pralidoxime is the oxime available and indicated for organophosphate poisoning in North America. It works by preventing aging of the cholinesterase and reactivating the enzyme. Pralidoxime is generally not indicated in carbamate overdose because of the reversible binding of toxin to acetylcholinesterase, which limits the duration of toxicity.38 Pralidoxime does not readily cross the blood-brain barrier, and benzodiazepines should initially be provided for the prevention of seizures.43 Cholinesterase levels can be obtained in poisoned patients and may confirm exposure and indicate the severity of toxicity. However, they are usually not available in real time and should not be used to guide therapy because this will likely delay treatment of the severely poisoned patient.

Methemoglobinemia Methemoglobinemia results from the oxidization of iron in hemoglobin from the ferrous (2+) form to the ferric (3+) form. It results in the inability to carry oxygen; by shifting the oxygen saturation curve to the left, it decreases off-loading of any bound oxygen at the tissues.44 Methemoglobinemia is associated with drugs and toxins that cause oxidative stress (Box 106-7). Clinically, the patient appears cyanotic, and the cyanosis does not respond to the administration of oxygen. The blood may have a chocolate color, and exposure of the blood sample to oxygen does not restore a normal appearance. The diagnosis is confirmed by multiple-wavelength co-­oximetry. Standard pulse oximetry, which uses only two wavelengths of

Chapter 106 — Toxidromes and Their Treatment

Box 106–7  Toxins that Cause Methemoglobinemia Benzocaine Dapsone Inhaled nitric oxide Lidocaine Naphthalene (found in certain mothballs) Nitrates Nitrites Nitroprusside Phenazopyridine Prilocaine Sulfonamides

light, cannot reliably be used to assess the degree of methemoglobinemia. However, newer models of pulse oximeters that use several different wavelengths of light may be used to measure methemoglobin levels. Standard pulse oximetry may overestimate or underestimate true oxygen saturation depending on the methemoglobin level.45,46 In a patient with cyanosis and a normal partial pressure of oxygen, methemoglobinemia should be suspected. The body produces a small amount of methemoglobin (typically <1%). Under normal physiologic conditions, this is reduced by a methemoglobin reductase dependent on reduced nicotinamide adenine dinucleotide (NADPH). Additional reduction can occurr through a minor pathway requiring the presence of reduced NADPH. Because a large oxidative stress overwhelms the reducing capacity of these pathways, the result is clinically apparent methemoglobinemia. Patients may appear blue with methemoglobin concentrations as low as 15 g/L, treatment may not be required. The appearance of cyanosis depends on the total methemoglobin present. Although anemic patients have less hemoglobin to convert to methemoglobin, this is usually a larger percent of their functioning hemoglobin. So, although they may not manifest cyanosis, they are less tolerant of methemoglobin at a lower percentage and are more likely to express symptoms of hypoxia.44 Therapy should be provided according to the signs of hypoxia and not the methemoglobin level or the presence of cyanosis. If required, treatment begins with the administration of 100% oxygen (to maximize oxygen-carrying capacity with the certainty that unaffected hemoglobin is fully saturated), followed by intravenous methylene blue at a dose of 1 mg/kg. Methylene blue facilitates the reduction of the oxydized heme iron of methemoglobin to its normal state by NADPH-dependent methemoglobin reductase. Response is rapid and occurs within 30 minutes. Depending on the toxin involved, in the case of dapsone, recrudescent methemoglobinemia may be seen and may require repeated doses of methylene blue. The total (cumulative) dose should not exceed 7 mg/kg because methylene blue can itself be an oxidizing agent, cause additional methemoglobinemia, and potentially lead to hemolysis. Methylene blue may be ineffective in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, in whom it may increase the risk of hemolysis or methemoglobinemia. In general, the patient can safely be treated with two doses of methylene blue; if no response is elicited, G6PD deficiency should be suspected. G6PD testing, however, should not be conducted until several months after

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resolution of the methemoglobinemia. When done concommittantly with the insult, patients will have a false-positive result for the deficiency. In nonresponding patients who are severely ill, exchange transfusion should be considered. Although hyperbaric oxygen increases the percent of oxgensaturated blood, this is likely not beneficial for treatment of methemoglobinemia because no functioning hemoglobin has been added and patients will return to their previous state when removed from the chamber.44,47

Hyperthermia Several distinct hyperthermia syndromes may result from xenobiotics. In addition to the following syndromes described, the sympathomimetic and anticholinergic syndromes may also cause hyperpyrexia and are detailed separately. Distinction of malignant hyperthermia, serotonin syndrome, and neuroleptic malignant syndrome are provided in Table 106-1. While differences exist, there is also potential for overlap, and diagnosis may be difficult when there is no previous patient history available.

Malignant Hyperthermia Malignant hyperthermia is a genetically determined condition that is triggered by exposure to depolarizing neuromuscular blocking agents (succinylcholine) or inhalational anesthetic agents. It is a life-threatening condition that results from dysfunction of the ryanodine receptors. This elevates the intracellular calcium in somatic muscle cells, resulting in rigidity and muscle damage. This syndrome requires prompt intervention with aggressive cooling and treatment with dantrolene, which allows muscle relaxation through blockade of calcium release from the sarcoplasmic reticulum.48 Malignant hyperthermia is discussed in more detail in Chapter 124.

Serotonin Syndrome Serotonin syndrome is a constellation of features resulting from excessive serotonergic activity in the CNS. It is most commonly associated with therapeutic regimens that include two or more drugs that increase CNS serotonin transmission, often by different mechanisms (Box 106-8). Serotonin syndrome has also been described with single agents in overdose, with the most commonly mentioned being clomipramine, a potent tricyclic antidepressant. Hallmark features include altered mental status, excessive muscle activity, and autonomic instability. Diagnostic criteria have been suggested by Sternbach.49 This diagnosis requires history of exposure to a serotonergic agent(s) and the presence of three of the following: mental status change, agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and/or fever. A distinguishing feature from the other hyperthermic syndromes is the presence of rigidity and hyperreflexia more pronounced in the lower limbs than in the upper limbs and the rigidity described more as “clasp knife” than “lead pipe.”48,50 Symptoms typically start within hours of exposure to the offending agent and resolve within 24 hours, providing a quickon, quick-off effect. Most cases are mild and self-limiting; however, patients with severe toxicity may develop extreme hyperthermia and rhabdomyolysis with renal failure and cardiovascular collapse. Treatment is supportive: withdrawal of all serotonergic agents, benzodiazepines for muscle overactivity,

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Table 106–1  Differences Between Drug-Induced Hyperthermia Syndromes Timing of Onset

Treatment

Depolarizing neuromuscular blockers or Inhalational anesthetics

Minutes

Dantrolene

Serotonin syndrome

Coadministration of two or more serotonergic agents

Hours

Supportive care, cyproheptadine

NMS

Antipsychotic drugs

Days

Supportive care, bromocriptine

Syndrome

Causative Agent

Malignant hyperthermia

Box 106–8  Drugs Associated with Serotonin Syndrome

Box 106–9  Agents that Cause Anion Gap Metabolic Acidosis

Amphetamines Bupropion Cocaine Dextromethorphan Fenfluramine Lithium Lysergic acid diethylamide (LSD) l-tryptophan Meperidine Monoamine oxidase inhibitors Selective serotonin reuptake inhibitors Trazodone TCAs Venlafaxine

Carbon monoxide Cyanide Ethylene glycol Iron Isoniazid Metformin Methanol Paraldehyde Phenformin Salicylates

and aggressive cooling. Cyproheptadine, a serotonin blocker, has been proposed for the treatment of serotonin syndrome. Doses range from 16 to 32 mg in divided doses up to four times daily. Although it might be considered to prevent further progression of the syndrome early in its course, its utility has not been established.51-53 In cases of severe hyperthermia, cyproheptadine will do little to prevent further symptoms and should be abandoned for more aggressive therapy with cooling and paralysis with a nondepolarizing paralytic.

Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS) is a constellation of features triggered by exposure to neuroleptic drugs (phenothiazines, butyrophenones, atypical antipsychotics). It is most commonly associated with initiation of therapy or with a dose escalation; it can also be triggered by the addition of a serotoninergic agent to an established antidopaminergic agent or the withdrawal of dopaminergic agents used to treat ­Parkinson disease.54,58 The onset is insidious, occurring over several days. The diagnosis requires exposure to a neuroleptic drug, fever, muscular rigidity, and at least two of the following: mental status change, mutism, tachycardia, labile blood pressure, diaphoresis, dysphagia, tremor, incontinence, leukocytosis, or elevated creatine kinase level.55 Muscle rigidity in this syndrome is often described as “lead pipe” and greater in the upper extremities than in the lower extremities. Distinguishing NMS from lethal catatonia may be difficult. NMS is thought to represent the extreme end of the spectrum of extrapyramidal (antidopaminergic) side effects of these medications. Unlike its milder counterparts, however, it is unresponsive to centrally acting anticholinergic agents; therefore diphenhydramine or

benztropine have no role in the treatment of this syndrome. The recommended treatment is supportive, including sedation, neuromuscular blockade with a nondepolarizing paralytic, and active cooling if required. Hyperthermia does not respond to antipyretics. Myoglobinuria and renal failure may complicate the course. Bromocriptine, a dopamine receptor agonist, and dantrolene have been advocated in the treatment of NMS, but their value is debated.56 Because it is a syndrome that results from CNS activation, dantrolene’s action at the muscle end plate is likely not effective, and its nonselective activity on skeletal muscle could theoretically weaken the diaphragm and increase respiratory dysfunction.57

Metabolic Acidosis with Increased Anion Gap Metabolic acidosis is a laboratory toxidrome that presents a substantial differential diagnosis. Common nontoxicologic causes of this disorder in children include diabetic ketoacidosis, uremia, lactic acidosis, and inborn errors of metabolism. The agents most commonly associated with metabolic acidosis are listed in Box 106-9 (also see Chapter 68). In addition, any agent causing shock will increase lactate and cause metabolic acidosis with an increased anion gap. Note that although metabolic acidosis from toxic agents is generally associated with an increase in the anion gap, nonanion gap acidosis may be seen with the therapeutic use of carbonic anhydrase inhibitors such as acetazolamide or topiramate, or with toxins that cause renal tubulopathy with chronic use such as toluene (an agent seen commonly with inhalant abuse).

Methanol and Ethylene Glycol Methanol and ethylene glycol are toxic alcohols found in various automotive antifreeze products and as chemical reagents. Ethylene glycol has a sweet taste that may be masked by the

Chapter 106 — Toxidromes and Their Treatment

addition of bittering agents to many antifreeze products. Ethylene glycol–containing radiator antifreeze products contain fluorescein, and examination of the urine under a Wood’s lamp has been advocated to screen for ingestion.59 In one study, even in the absence of ingestions, urinary fluorescence was shown in most hospitalized pediatric patients60; in addition, several types of hospital tubing and plastic containers may provide their own fluorescence under a Wood’s lamp, calling into question the usefulness of this simple test. Both compounds produce CNS depression, with intoxication seen more substantially with ethylene glycol than with methanol. Beyond that, they have little toxic effect in their parent form. Both substances are metabolized by alcohol dehydrogenase to highly toxic metabolites. The end product of methanol metabolism is formic acid, which causes severe metabolic acidosis and retinal toxicity described as “snowstorm blindness.” Ethylene glycol is converted to a number of intermediate toxic products and ultimately to oxalate. This conversion results in severe metabolic acidosis, renal failure, and hypocalcemia through binding of oxylate to calcium to form crystals.61 Ingestions greater than 0.5 mL/kg of either agent are potentially toxic, and ingestions of more than 1 mL/kg are potentially fatal. Because both substances are osmotically active, they will increase serum osmolality and therefore raise the osmolar gap, the difference between calculated serum osmolarity and actual osmolality as determined by freezing point depression. Caution should be exercised in interpreting this gap. Because the normal range is −8 to +12, significant levels of toxic alcohols may be present with a “normal” osmolar gap. In short, an elevated gap suggests toxic alcohol poisoning, but a normal result does not exclude it.62 As the parent compound is metabolized and the anion gap increases from the development of acid metabolites, the osmolar gap will fall and therefore may be normal in patients presenting with symptoms of toxicity. Measured levels of ethylene glycol and methanol are the gold standard for diagnosis and treatment guidance. Hemodialysis is indicated in severely toxic patients, even when the parent compound is no longer detectable, to eliminate toxic metabolites and correct metabolic abnormalities. Once the diagnosis of toxic alcohol poisoning is made and life-sustaining measures have been undertaken, initial therapy is targeted at blocking alcohol dehydrogenase to limit further generation of toxic metabolites. This may be achieved either with ethanol or with fomepizole. Ethanol infusion is difficult to titrate; requires frequent measurements; and carries the risks of inebriation, CNS depression, hypoglycemia, and hypotension. Fomepizole, a drug with known kinetics and approval by the Food and Drug Administration (FDA) for the treatment of toxic alcohol poisoning, is the agent of choice. A loading dose of 15 mg/kg followed by 10 mg/kg every 12 hours is sufficient. The dose must be increased to 15 mg/kg after 48 hours because of induction of its own metabolism. In addition, the dosing regimen requires adjustment during hemodilayisis to maintain suffucient concentrations to continue to block alcohol dehydrogenase because fomepizole is itself dialyzable.63 Once alcohol dehydrogenase is blocked, the parent alcohol is excreted through the kidneys with a half-life of 19.7 hours for ethylene glycol64 and 54 hours for methanol.63 Hemodialysis is recommended in the presence of high levels of methanol or ethylene glycol, in the presence of significant acidosis or electrolyte disturbance, or if there is renal or visual impairment.

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Table 106–2  Half-Life of COHb Oxygen Concentration 21% (room air)

Half-Life 4–5 hours

100% (mask or endotracheal)

60–90 minutes

100% (hyperbaric molecular oxygen)

20–30 minutes

Carbon Monoxide Carbon monoxide (CO) is the product of incomplete combustion of carbonaceous fuels. These include natural gas, fuel oil, gasoline, propane, and charcoal. CO causes tissue hypoxia through several mechanisms: it binds with high affinity to oxygen-binding sites of hemoglobin; it binds to myoglobin and disrupts the transfer of oxygen from erythrocytes to mitochondria; it binds to mitochondrial cytochrome oxidase; and it interferes with electron transport and adenosine triphosphate production. CO also displaces nitric oxide from platelets, leading to increased generation of the free radical peroxynitrite. Standard pulse oximetry is unreliable at detecting CO poisoning and overestimates arterial oxygen saturation. The diagnosis is made with multiple-wavelength co-oximetry on a blood sample. Additional CO levels are not required with appropriate oxygen therapy because they will reliably decrease with time. An exception to this rule occurs in the case of inhalation of methylene chloride, found in degreasers and furniture strippers. Its metabolism leads to endogenous production of CO. In this case, serial levels should be obtained, watching for a downward trend during treatment. Correlation between symptoms and carboxyhemoglobin (COHb) level is poor, but a level should be obtained to confirm the diagnosis. At low levels of CO, symptoms are nonspecific and include fatigue, malaise, nausea, and headache. Higher concentrations lead to impaired cognition and finally coma. CO poisoning may also cause hypotension and syncope, explained in part by the effect of CO on nitric oxide. CO poisoning is also associated with delayed or persistent neurologic sequelae, particularly in patients who lose consciousness or demonstrate syncope. Treatment consists of accelerating the removal of CO from hemoglobin by providing as much oxygen as possible. The halflife of COHb under various oxygen concentrations is provided in Table 106-2. Hyperbaric oxygen (HBO), the administration of oxygen at supra-atmospheric pressure, has been advocated in the treatment of severe CO poisoning.65 In addition to increasing the rate of resolution of COHb, it accelerates the removal of CO from cytochrome oxidase. However, because most CO has been eliminated from the blood by the time the patient is placed in the chamber, the benefits are likley seen from the reduction of leukocyte adhesion to endothelium.66 It is through this last mechanism that HBO is proposed to decrease the incidence of delayed neurologic sequelae, although two randomized trials have led to conflicting results.65,67 There are no clinical trials of HBO in children. Although its use remains controversial, it is recommended in children who have a history of loss of consciousness or syncope or who have persistent neurologic findings on examination despite treatment with simple oxygen. A thorough neurologic exam should evaluate the patient for persistant ataxia when attempting to walk as well as other cerebellar signs. Adverse reactions to HBO therapy include

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claustrophobia, barotrauma (pneumothorax, tympanic membrane rupture), and oxygen toxicity (seizures).67 It is recommended that if the patient is to undergo HBO treatment, it should be completed within 24 hours of exposure. Patients who have had a cardiac arrest are not considered candidates for HBO.65 Fetal hemoglobin has a higher affinity for CO than does adult hemoglobin. As a result, neonates may have higher COHb levels than older children with the same exposure. Although the fetus may serve as an additional compartment, or “sink,” for CO, exhibiting higher CO levels, no data on pregnancy and HBO therapy are available.

Cyanide Cyanide is a highly toxic compound that may produce poisoning from a variety of sources. It is widely used as a reagent in industry. A number of plants, including the seeds of several edible fruits (e.g., apples, cherries, peaches, pears), contain cyanogenic glycosides that may be converted to cyanide in the GI tract. The unapproved substance Laetrile, sometimes used to treat cancer, is synthesized from amygdalin, a cyanogenic glycoside. Fires, particularly those in which certain plastics or fabrics are combusted, can generate hydrogen cyanide (HCN). Finally, iatrogenic cyanide poisoning results from administration of nitroprusside, which is metabolized to cyanide and can cause toxicity at high doses, after prolonged therapy without coadministration of sodium thiosulfate, or in the presence of renal failure.68,69 Cyanide produces toxicity rapidly, especially through inhalation of HCN. Cyanide salts (sodium cyanide [NaCN], potassium cyanide [KCN]), when ingested, are converted to HCN in the presence of gastric acid and then absorbed. Cyanide binds to heme iron in the cytochrome complex IV of the electron transport chain (cytochrome C oxidase), resulting in inhibition of oxidative phosphorylation. Consequently, the patient is unable to use oxygen to produce adenosine triphosphate, and the result is energy failure. Signs and symptoms are nonspecific and reflect tissue hypoxia. However, a symptomatic patient with a lactate level of 10 mmol/L or more is highly suspect for cyanide toxicity.70 Death may occur within minutes. Venous oxygen levels are elevated from the impairment of oxygen use at the cellular level. However, because of this, patients do not appear cyanotic. Treatment of cyanide poisoning involves immediate life support measures followed by administration of an antidote. The traditional three-antidote kit contains inhaled amyl nitrite, intravenous sodium nitrite, and intravenous sodium thiosulfate. Amyl nitrite is only used if intravenous access is unavailable. Nitrites are therapeutic by inducing methemoglobinemia. Although the mechanism of action of nitrites in cyanide poisoning is incompletely understood, it is postulated that methemoglobin has a higher affinity for cyanide than cytochrome oxidase and therefore removes cyanide from the affected cytochromes. Nitrites are potent vasodilators and can cause significant hypotension that may be avoided by slow administration. However, the most significant vasodilation occurs in the most hypoxic tissues, and therefore this effect may provide additional therapuetic benefits. Excessive methemoglobinemia is a potential risk. The initial dose in pediatric patients is 0.2 mL/kg of a 3% solution. The dose should be decreased in the presence of anemia. Nitrites should not immediately be administered to fire victims, who may have significant CO poisoning. The induction of methemoglobin in these individuals may reduce

oxygen-carrying capacity below critical levels. The third antidote, sodium thiosulfate, reacts with cyanide in the presence of the mitochondrial enzyme rhodanese to produce the nontoxic thiocyanate that is then excreted in the urine. Although part of a three-antidote kit, sodium thiosulfate may be used without nitrites and can be administred early in patients with significant CO levels because it will not affect hemoglobin. It, too, can cause hypotension if administered rapidly. Additional side effects may include nausea and vomiting; however, it has a minimal adverse effect profile. Hydroxocobalamin (HCO) is an alternative antidote that has been used to treat fire victims in France for several years; it is now available in the United States.71,72 It is a cobalt-containing molecule that allows cyanide to replace a hydroxyl group to produce cyanocobalamin (vitamin B12), which is then excreted in the urine.This antidote, although effective, may be limited by its adverse affects, interference with laboratory assays, and expense. Patients may experience hypertension after administration. Both their skin and body fluids will exhibit a reddish hue as a result of the red color of cyanocobalamin. This discoloration interferes with several important assays that may be needed for patient monitoring because many of the analyses performed in the lab are colorimetric. Patients have also reported severe acne 1 to 2 weeks after administration.72 Pediatric administration consists of a 70 mg/kg dose administered over 30 minutes (IV push is acceptable in severe toxicity). A second dose may be administered if necessary over a total administration time of 6 to 8 hours. The onset of action of HCO is more immediate than sodium thiosulfate, which may take up to 20 minutes to exert its effect. However, because HCO must be reconstituted slowly over 20 minutes and still requires intravenous access, its administration time limits its onset of action and therefore likely provides no benefit over thiosulfate in this respect. It is suspected that the two medications will work synergystically but should be administered in separate lines. To date there are no comparative trials to show that hydroxocobalamin alone is superior to the traditional three-antidote kit.

Iron Iron is available alone and in combination with other vitamins. Several salts have different proportions of elemental iron. Iron toxicity is often divided into several phases. The first phase occurs early, usually within 30 minutes, and consists of GI manifestations of vomiting and diarrhea, which may include both hematemesis and hematochezia. Fluid and electrolyte losses may be severe during this period, and aggressive resuscitation may be necessary. The second phase, the socalled latent period, is a quiescent phase in which the initial GI symptoms have ceased but the patient continues to feel unwell. This is not truly a quiescent phase because the patient may remain tachycardic, and an anion gap metabolic acidosis develops. The third phase, which begins after 12 hours, is characterized by cardiovascular collapse and shock; the fourth phase is liver failure. The corrosive effect of iron on the GI tract may also lead to the development of scarring or stricture after recovery from acute toxicity.73 Doses higher than 20 mg/kg of elemental iron reliably produce GI irritation, although systemic toxicity is generally not seen with doses less than 60 mg/ kg. Absence of a prodromal GI phase within 4 hours of ingestion generally precludes the development of serious systemic iron toxicity.74

Chapter 106 — Toxidromes and Their Treatment

Iron is not effectively adsorbed to activated charcoal, and lavage of the stomach or whole-bowel irrigation can be considered if iron tablets are suspected to have remained in the GI tract. Plain radiographs of the abdomen may help visualize the location of pills and guide decontamination decisions, although not all forms of iron can be visualized. Multivitamins, children’s preparations, and liquid preparations will not be visible on radiographs. Serum iron levels should be determined within 6 hours of ingestion; after that time, significant redistribution to tissues may have occurred. Total iron-binding capacity, used in the evaluation of chronic iron overload, may be falsely elevated in acute iron ingestion and should not be used in treatment decisions. Chelation with deferoxamine is indicated for serum levels higher than 500 μg/dL or for signs of circulatory failure.75 The initial dose is 15 mg/kg/h intravenously. If the patient remains symptomatic beyond 24 hours, the deferoxamine dose should be decreased or temporarily discontinued because prolonged use beyond this time is associated with the development of acute respiratory distress syndrome.76 Interestingly, children’s multivitamin preparations do not produce toxicity at the same iron content as adult preparations, and very few children have ever experienced toxicity with large ingestions.73 Prenatal vitamins, on the other hand, except those containing iron carbonyl, have led to extreme toxicity even in minor ingestions.

Isoniazid Isoniazid (INH), a relative of pyridoxine and nicotinic acid, is a hydrazine used in the treatment of tuberculosis. It has a complex set of metabolic actions on several enzyme systems but produces its acute toxicity primarily by interfering with pyridoxine metabolism. INH both inhibits pyridoxine phosphokinase, which is required to activate pyridoxine by conversion to pyridoxal-5-phosphate, and reacts with pyridoxal-5-­phosphate to form an inactive metabolite that interferes with and prevents the conversion of glutamate to γ-aminobutyric acid (GABA). After the acute ingestion of a large quantity of INH, early GI symptoms and drowsiness are followed by seizures, coma, and metabolic acidosis. The seizures result from the depletion of GABA and are difficult to control with usual anticonvulsant therapy. The acidosis results from lactate and is produced by seizure activity and possible interference by INH in the conversion of lactate to pyruvate. Treatment of INH poisoning is with pyridoxine, which should be administered in a dose equal to the ingested dose of INH (by weight). If the dose ingested is unknown, 5 g is a reasonable empiric starting dose. INH is effectively removed by hemodialysis, although the efficacy of pyridoxine should obviate its need in most cases. Benzodiazepines may work synergistically with pyridoxine; phenobarbital may also be considered in refractory cases. Ingestion of mushrooms from the group of hydrazinecontaining mushrooms, including Gyrometra spp., produces a toxicity identical to INH through its interefence with pyridoxal-5-phosphate and depletion of GABA. This mushroom toxicity is treated with an empiric starting dose of 5 g of pyridoxine in the same manner as above.

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98% methylsalicylate. Other forms include bismuth subsalicylate, sodium salicylate, and magnesium salicylate. Doses up to 100 mg/kg are likely to produce only minimal toxicity, whereas doses above 300 mg/kg may have serious consequences, including death. Early signs of salicylate toxicity include an increase in minute ventilation (primary respiratory alkalosis), tinnitus, nausea, and vomiting. Salicylates also produce metabolic acidosis through several mechanisms including uncoupling of oxidative phosphorylation and inhibition of the tricarboxylic acid cycle. Mixed-picture respiratory alkalosis and metabolic acidosis from an ingestion are nearly pathognomonic for salicylate intoxication and warrant obtaining a salicylate level for evaluation. Uncoupling of oxidative phosphorylation may also lead to hyperpyrexia. Cerebral edema and pulmonary edema are rare but potentially fatal complications of salicylate poisoning and are more common with chronic toxicity than with acute poisoning. Levels greater than 35 mg/dL produce minor symptoms; significant toxicity and acidosis start to manifest at approximately 45 mg/dL in acute ingestion. Patients with chronic ingestion or exposure may show more severe symptoms at much lower levels (approximately 30 mg/dL). Enhancement of the elimination of salicylates may be achieved through alkalinization of the urine. This is accomplished by administration of an infusion of sodium bicarbonate. The urine pH should be frequently monitored (every void in patients without a catheter) and the bicarbonate infusion rate adjusted accordingly to target a urine pH above 7.5. The goal is to maintain a normal urine output and not to perform forced diuresis. Serum pH should be periodically monitored to avoid serious alkalemia. In addition, serial potassium and magnesium levels should be obtained and maintained in the normal range. As the body tries to retain potassium, it will exchange it for protons in the urine, and obtaining an alkaline urine will be nearly impossible. Potassium can be added to the alkalinizing fluid and/or provided as a separate infusion. Patients should also be monitored for glucose. A bolus of dextrose may be warranted77 even if serum glucose levels are normal in salicylate ingestion with depressed sensorium. In a patient with significant CNS alteration and/or salicylate levels greater than 70 mg/dL, hemodialysis is an effective method for salicylate clearance. As levels approach the therapeutic range, the free fraction of salicylate declines and the efficiency of dialysis is diminished. Its use should be considered for very high serum levels; in the presence of renal impairment, volume overload, or pulmonary edema; and in the case of severe electrolyte or acid-base abnormalities.

Bradycardia, Hypotension, and Cardiac Conduction Abnormality The most important cardiovascular agents that cause bradycardia and hypotension are calcium channel antagonists, β-adrenergic antagonists, and digoxin. All these agents may result in severe toxicity that requires specific therapy.

Salicylates

Calcium Channel Antagonists

There are several forms of salicylate, the most common of which is acetylsalicylic acid (ASA), or aspirin. The most potent form is wintergreen oil, which is made up of

Calcium channel blockers exert their action on l-type calcium channels in the heart and vascular smooth muscle. Blockade of calcium channels in the heart results in negative inotropic,

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chronotropic, and dromotropic effects. Blockade of calcium channels in arteriolar smooth muscle causes vasodilation. Dihydropyridine calcium channel antagonists (e.g., nifedipine, amlodipine, felodipine, nicardipine) act primarily on the vascular smooth muscle. Verapamil, in addition to vasodilatory effects, also has potent cardiac calcium channel–blocking activity and may cause bradycardia, heart block, and myocardial depression. Diltiazem has similar effects to verapamil but is a less potent inhibitor of cardiac calcium channels. Calcium channel blockers also impair the release of insulin in overdose and may cause significant hyperglycemia. Treatment depends on the agent involved and the severity of toxicity. Except in extremely large ingestions, dihydropyridines produce hypotension and reflex tachycardia. These patients may respond to volume expansion alone. Intravenous calcium and vasopressors are indicated if the hypotension remains refractory to intravenous fluids. Verapamil and diltiazem overdose is further complicated by pump failure. These patients may benefit from inotropes such as dobutamine. Glucagon, which acts at a receptor other than the β-receptor, increases cyclic adenosine monophosphate (cAMP) and has been reported to reverse refractory hypotension in calcium channel overdose. The reported dose is 0.15 mg/kg intravenous bolus followed by an infusion of 0.05 to 0.1 mg/kg/hr.78 Phosphodiesterase inhibitors (amrinone, milrinone) may provide some efficacy by preventing the destruction of cAMP. However, animal data have not shown these to be of benefit over glucagon.79,80 High-dose insulin/euglycemia therapy has shown efficacy in several successful animal models as well as in several case reports and case series to reverse cardiogenic shock associated with calcium channel antagonist overdose.81,82 The recommended dose is from 0.5 to 1 unit/kg of insulin as a bolus, followed by an infusion titrated to efficacy. Given the risks of hypoglycemia and its profound deleterious effects, serum glucose concentration should be monitored hourly. Patients with overdose of calcium channel antagonists are not usually responsive to transcutaneous pacing because of an inability to capture. If capture is achieved, the patient should be paced at a low rate, near 60, to attempt to maximize filling of the ventircules. However, most patients exhibit a decreased contractility that, even with pacing, prevents achievement of significant cardiac output. Patients who are unresponsive to medical management should be considered for a left ventricular assist device or extracorporeal life support (see Chapters 27 and 53, respectively).

β-Adrenergic Antagonists β-Adrenergic antagonists comprise a fairly extensive list of therapeutic agents that are largely distinguished from each other by their selectivity (or lack thereof) for the β1 receptor. Atenolol, metoprolol, esmolol, and acebutolol are β1-selective agents, whereas agents such as propranolol, nadolol, and pindolol act both at β1 and β2 receptors. Propranolol is unique in that it is highly lipophilic and has sodium channel–blocking activity. Labetalol, in addition to β-blocking activity, possesses α-receptor–blocking activity. β1 Receptors are largely found in the heart, and agonism causes positive inotropic and chronotropic effects. β2 Receptors are found in the airway smooth muscle, where they cause bronchodilation; in the small blood vessels, where they cause vasodilation; and in several other

organs, where they have a number of effects that are not important in the context of poisoning. Acute overdose of β-adrenergic antagonists results in bradycardia, hypotension, and conduction delay. Toxicity is generally much lower than with calcium channel antagonists such as verapamil and diltiazem. Bronchospasm may occur in susceptible individuals. Propranolol, by virtue of its sodium channel–blocking activity, causes QRS widening, exaggerated negative inotropy, chronotropy, and conduction delay. Patients are also risk for coma and seizures because of the drug’s ability to cross into the CNS. Labetalol may cause vasodilation in addition to β-receptor blockade. Hypoglycemia may also be seen with drugs in this class and has been reported in children with usual dosing of propranolol.83,84 Treatment beyond monitoring is not necessary if the only manifestation is asymptomatic bradycardia. Patients with bradycardia and hypotension may respond to atropine, although they are expected to have decreased vagal tone to start with. β-Agonists have variable effects in the presence of β-adrenertgic blockade. In theory, mixed agonists could worsen hypotension by causing β2 receptor–mediated vasodilation. The phosphodiesterase inhibitors amrinone and milrinone have a theoretical benefit of improving contractility by blocking the breakdown of cAMP but have not been shown to be more effective than glucagon.79,80 Glucagon acts by a nonadrenergic receptor to increase intracellular cAMP and improve cardiac contractility. The recommended dose is the same as that previously described for calcium channel blockers. Patients who do not respond to these measures, such as patients with calcium channel blocker overdose, should be considered for extracorporeal life support. Seizures should be treated with benzodiazepines as first-line therapy, and bronchospasm may respond to anticholinergic agents if inhaled β2agonists fail to overcome the β-blockade.

Digoxin Digoxin and related digitalis glycosides are used in the management of cardiac failure and tachydysrhythmias. Digoxin blocks the sodium-potassium adenosine triphosphatase (Na/K-ATPase) and ultimately leads to increased intracellular calcium concentration and improved contractility. It also increases vagal tone and causes sinoatrial (SA) and atrioventricular (AV) nodal depression. In overdose, sympathetic tone is increased and may lead to increased automaticity. Overdose of digoxin presents with nausea, vomiting, lethargy or confusion, and cardiac dysrhythmias. Although virtually every rhythm has been described in digoxin toxicity, bidirectional ventricular tachycardia and atrial tachycardia with AV block are characteristic. Blockade of Na/K-ATPase causes hyperkalemia, and levels greater than 5.5 mEq/L have been associated with a significant mortality rate.85 The diagnosis is confirmed with measurement of the serum digoxin level. Because of a long distribution phase, the serum level may not accurately reflect tissue levels until at least 6 hours after ingestion. Sinus bradycardia or heart block may respond to atropine alone. More serious arrhythmias are an indication for treatment with digoxin-specific Fab fragments (e.g. Digibind, DigiFab). Drugs that further depress the SA or AV node should be avoided. Hyperkalemia resolves with Fab fragment therapy because it restores function of the Na-K pump.

Chapter 106 — Toxidromes and Their Treatment

Because digoxin causes intracellular hypercalcemia, calcium is best avoided because it could theoretically increase toxicity.86 Fab fragment therapy in children is indicated with known digoxin ingestion (strong history of ingestion of at least 0.1 mg/kg or digoxin level greater than 5 ng/mL) and signs and symptoms of digoxin toxicity (rapidly progressing signs and symptoms of digoxin toxicity or potentially lifethreatening arrhythmias or serum potassium level greater than 6 mEq/L).87 A clinical picture similar to digoxin poisoning may be seen with the ingestion of certain cardiac glycoside-containing plants such as oleander. Oleander poisoning may cause a falsepositive result on digoxin immunoassay and may respond to Fab fragment therapy.88 An antidote dose cannot be calculated from the level obtained because of the differences between digoxin and the cardiac glycoside found in the ingested plant. Therefore an empiric dose of 10 to 20 vials is recommended in both pediatric patients and adults.

Patients may initially present with nausea and vomiting, but often they have no symptoms or signs. Initial metabolic acidosis may occur with extremely large ingestions. Transaminases begin to be elevate at approximately 24 hours after ingestion and peak between 48 and 72 hours. Patients either progress to fulminant hepatic failure or recover completely (see Chapter 88). Treatment with N-acetylcysteine (NAC) reduces the incidence of hepatotoxicity when administered in a timely fashion after overdose. NAC acts through several mechanisms, including enhancing the synthesis of glutathione and as a possible free radical scavenger.88 It is most efficacious when administered within 10 hours of ingestion but has shown benefit when administered to patients presenting after this window of time.88 In one study, intravenous NAC decreased the risk of death from acetaminophen-induced fulminant hepatic failure even in patients who presented with already established hepatic encephalopathy.89 Decision to treat an acute ingestion is based on plotting a single acetaminophen blood level at least 4 hours after ingestion on the Rumack-Matthew nomogram (Figure 106-1). After 24 hours, the nomogram is of no benefit. An acetaminophen level should be measured and liver function analysed to assess the patient’s risk for development of toxicity or potential prognosis. In addition, the nomogram has not been validated in chronic ingestion or multiple, staggered ingestions. In these cases, the nomogram should not be relied on for an assessment of toxicity. A poison control center should be consulted for specific treatment advice in those scenarios.

Acetaminophen (Paracetamol) Although it does not cause a toxidrome per se, acetaminophen is the most commonly ingested drug in intentional overdose. It may cause fulminant hepatic failure leading to admission to the pediatric intensive care unit. Major routes of elimination of acetaminophen are through conjugation or sulfation and then excretion in the urine. A minor pathway is via CYP2E1 to produce N-acetyl-p-benzoquinone-imine (NAPQI), a toxic metabolite capable of binding to hepatocytes and causing cell death. With therapeutic doses of acetaminophen, NAPQI is rapidly detoxified by glutathione. In overdose, larger amounts are formed and may overwhelm the available glutathione stores, resulting in a centrilobular hepatic necrosis.

Tricyclic Antidepressants Tricyclic antidepressants (TCAs) are a group of drugs with potentially serious toxicity that are used in the treatment of psychiatric disorders, enuresis, and pain syndromes. Although

Acetaminophen plasma concentration

USE OF NOMOGRAM IN MANAGEMENT OF ACUTE ACETAMINOPHEN OVERDOSE An approach to management of acute acetaminophen overdose 1. Draw blood for acetaminophen plasma assay 4 or more hours post-ingestion. 2. PLOT ON NOMOGRAM. 3. If the acetaminophen level, determined at least 4 hours following an overdose, falls above the broken line, administer the entire course of acetylcysteine treatment. 4. If the acetaminophen level, determined at least 4 hours following an overdose, falls below the broken line, acetylcysteine treatment is not necessary or if already initiated may be discontinued. 5. Serum levels drawn before 4 hours may not represent peak levels.

gmol

µmol

300

2,000

200 150

1,300 1,000 900 800 700 600 500

100 90 80 70 60 50 40 30 20

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400 300 250 200

Potential for toxicity Toxicity unlikely

100 90 80 70 60 50 40 30

Recommended treatment if level is above broken line

20

Take level at least 4 hours 0 post-ingestion

4

8

12

16

20

24

28

32

Hours post-ingestion Figure 106–1.  Use of a nomogram in the management of acute acetaminophen overdose.

36

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in the treatment of depression they have largely been supplanted as first-line agents by less toxic compounds, they still represent a significant cause of morbidity and death. TCAs have multiple mechanisms of toxicity and produce a wide spectrum of clinical effects. Their anticholinergic properties may produce the anticholinergic toxidrome (se Box 106-4). α-Adrenergic inhibition may cause sedation and hypotension. Blockade of cardiac sodium channels causes decreased myocardial contractility and is seen on the ECG as widening of the QRS complex. QRS widening correlates with the development of seizures (QRS >100 ms) and arrhythmias (QRS >160 ms).90 Potassium channel blockade leads to a prolonged QT interval. Seizures, which tend to be single and short lived, occur and may be attributable to a combination of TCA effects on GABA and on reuptake of biogenic amines in the CNS. This constellation of anticholinergic syndrome, seizures, hypotension, and widening of the QRS complex should create a high index of suspicion for TCA overdose. A similar picture may be seen with type Ia antiarrhythmics. Severe toxicity tends to occur early in the course of TCA poisoning. Patients who do not manifest QRS widening, conduction abnormalities on ECG, altered mental status, seizures, or hypotension within the first 6 hours can be classified as low risk and no longer need PICU monitoring.91 Anticholinergic

manifestations should be treated supportively only. Seizures, if prolonged, should be treated with benzodiazepines. If benzodiazepines have been coingested by the patient, then flumazenil, a benzodiazepine receptor antagonist, should not be administered because it may unmask TCA-induced seizures. Widening of the QRS complex (>100 ms in adults) or ventricular arrhythmias should be treated with sodium bicarbonate to produce alkalinization of the serum. Bicarbonate should be given in boluses of 1 to 2 mEq/kg until ECG improvement is seen (narrowing of the QRS). Recurrence of QRS widening may be treated in the same manner. Alternatively, a bicarbonate infusion can be started after the initial bolus to maintain alkalemia (with monitoring to prevent overalkalinization [i.e., pH >7.55]). If continuous infusion of bicarbonate is performed, it may be stopped and the ECG monitored after approximately 6 hours of normal ECG tracings. Although drug levels are available for monitoring these medications in therapy, they serve no purpose in acute toxicity, and studies have shown that ECG findings are superior predictors of toxicity on this scenario. References are available online at http://www.expertconsult. com.