chapter 151 · chapter 151 toxicology ... in any patient with an abnormal neurologic examination....

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Chapter

151ToxicologyKarolina Paziana and andrew Stolbach

InTroducTIon

“What is there that is not poison? All things are poison and nothing [is] without poison. Solely, the dose determines that a thing is not a poison” (1). This observation of the dose–response relationship made by Paracelsus in the 16th century holds today. One need not look farther than basic elements of oxygen or water to see that all substances can act as a poison at a specified dose. Medical toxicology, the care of poisoned patients, was recognized as a medical subspecialty in 1992 and today all 50 states are served by poison control centers; pioneered by the first in Chicago in 1953 (2). The American Association of Poison Control Centers (AAPCC) maintains the National Poisoning and Exposure Database (NPED) and includes comprehensive data from every case reported to poi-son centers throughout the United States. In 2013, the AAPCC received over 2 million reports of human exposures, including 20,749 major effects, as defined by life-threatening exposures or those causing significant disability, and 2,477 deaths (3).

The key principle in managing the poisoned patient is summarized by the phrase “treat the patient, not the poi-son.” Patient stabilization is a priority, starting with address-ing airway compromise, breathing difficulty, and circulatory problems. Significant vital sign abnormalities or oxygen desaturation should be addressed immediately, and a bed-side serum glucose concentration should be rapidly obtained in any patient with an abnormal neurologic examination. Hypoglycemia, while common and easy to correct, can be life threatening if diagnosis is delayed or missed (see section on antidiabetic medications). Additionally, an electrocardiogram (ECG) should be obtained in most cases of suspected poison-ing, as several well-defined exposures may produce character-istic ECG changes (tricyclic antidepressants), life-threatening dysrhythmias via direct myocardial effect (cocaine or lido-caine) or by electrolyte abnormality (hydrofluoric acid [HF]).

A thorough physical examination will help identify the presence of a toxic syndrome, or “toxidrome.” The classic toxic syndromes (Table 151.1) can be differentiated based on vital signs, mental status, pupil size, presence (or absence) of peristalsis, diaphoresis, and urinary retention. The physician should keep in mind that toxic syndromes are archetypes that may be affected by coexisting exposures or disease processes, muddying the clinical picture. For example, the practice of “speedballing” (concurrent heroin and cocaine abuse) might result in small, normal, or large pupils. Though identification of a toxic syndrome will not specifically identify the exact poi-son responsible, it will somewhat guide therapy. For instance, the presence of a sedative–hypnotic toxic syndrome (overdose) warrants support of the airway, whether the condition is a result of ethanol or diazepam abuse.

A comprehensive history should attempt to identify the specific xenobiotic exposure, the amount, the time and reason

for exposure, and general medical history. At times, a specific antidote may be warranted (Table 151.2). When the history is limited, laboratory studies and physical examination alone may be helpful in guiding appropriate therapy. Electrolyte abnormalities complicate many severe poisonings, and as a result, serum chemistries are warranted for all critically ill patients. Arterial blood gas analysis and aminotransferases should be judiciously used as well. A routine urine toxicologic screen, however, rarely aids in management as it focuses on select drugs of abuse and has a high rate of false positives and negatives. Even a true-positive result is not necessarily helpful; the cocaine assay, while remarkably specific, will remain posi-tive for days after the clinical effects have subsided. By way of contrast, the acetaminophen concentration should be obtained following all overdoses where self-harm was intended. In one series, 1 in 365 individuals with suicidal ingestion had a poten-tially hepatotoxic acetaminophen concentration despite a his-tory negative for acetaminophen ingestion (4).

The classification of the severity of the exposure (minor, moderate, major) is based on outcome and is closely tied to the nature of the poisoning, not necessarily the initial appearance of the patient. The need for ICU monitoring is determined by three general factors: (a) hemodynamic stability and clinical presenta-tion, (b) characteristics of the specific xenobiotic, the substance introduced to the body, and (c) hospital unit capabilities (5).

All patients with significant laboratory abnormalities, hemodynamic or neurologic compromise, dysrhythmias, or conduction abnormalities should be admitted to the ICU. Pre-existing medical conditions such as severe liver or renal insufficiency, congestive heart failure, or pregnancy may also influence disposition. Sustained-release products, potentially lethal doses, or xenobiotics that may cause dysrhythmias or require a therapy that has the potential for adverse effects (i.e., high-dose atropine for organophosphate poisoning) have the potential to cause rapid clinical deterioration, and for this rea-son, require ICU admission for even asymptomatic patients. Finally, the capabilities of the hospital as a whole influence the disposition of the patient. Time-consuming nursing activities, such as hourly glucose checks or continuous drug infusions, may not be possible on general inpatient floors.

Throughout this chapter, a number of exposures (whether dermal, oral, ophthalmic, or inhalation) and their pathophysi-ology, clinical presentation, and management will be discussed. For the purpose of consistency, a toxin will be defined as a xeno-biotic produced by a plant, animal, or fungi, while a drug or pharmaceutical refers to a commercially produced xenobiotic.

nonopIoId AnAlgesIcs

In 2013, the American Association of Poison Centers NPED received 298,633 reports of exposures involving analgesics (3).

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e456 SeCtion 18 Pharmacology, nutrition, toxicology, and the environment

TABLE 151.1 Toxidromes

Group BP P R T Mental Status Pupil Size Peristalsis Diaphoresis Primary Treatment

anticholinergic −/↑ ↑ +/− ↑ delirium ↑ ↓ ↓ benzodiazepines

cholinergic +/− +/− −/↑ − normal/depressed +/− ↑ ↑ atropine, oximes

ethanol, sedative–hypnotic ↓ ↓ ↓ −/↓ depressed +/− ↓ − airway support

opioid ↓ ↓ ↓ ↓ depressed ↓ ↓ − naloxone

Sympathomimetic ↑ ↑ ↑ ↑ agitated ↑ −/↑ ↑ benzodiazepines

withdrawal from ethanol or sedative–hypnotic

↑ ↑ ↑ ↑ agitated, disoriented

↑ ↑ ↑ benzodiazepines

withdrawal from opioids ↑ ↑ − − normal, anxious ↑ ↑ ↑ opioids

bP, blood pressure; P, pulse; r, respirations; t, temperature.adapted from Flomenbaum ne, goldfrank lr, hoffman rS, et al. initial evaluations of the patient: vital signs and toxic syndromes. in: Flomenbaum ne, goldfrank lr, hoffman rS,

et al., eds. Goldfrank’s Toxicologic Emergencies. 8th ed. new york: mcgraw-hill; 2006:37–41.

TABLE 151.2 Selected Antidotes with Common Doses

Xenobiotic Antidote and Dose

acetaminophen N-acetylcysteine, IV: 150 mg/kg infused over 60 min, followed by 50 mg/kg over 4 hr, then 100 mg/kg over 16 hrOral: 140 mg/kg, followed by 70 mg/kg every 4 hr for 17 doses

β-adrenergic antagonists

Atropine (for bradycardia): 0.5–1 mg ivGlucagon: 3–5 mg iv (50 μg/kg in children) up to 10 mg/hCalcium: 13–25 meq of ca2+ iv bolus (10–20 ml of 10% calcium chloride or 30–60 ml of 10% calcium gluconate)Hyperinsulinemia/euglycemia: insulin 0.5–1 u/kg/hr accompanied by 0.5 g/kg/hr dextrose, titrated to maintain

euglycemia

calcium channel blockers

Atropine (for bradycardia): 0.5–1 mg ivCalcium: 13–25 meq of ca2+ iv bolus (10–20 ml of 10% calcium chloride or 30–60 ml of 10% calcium gluconate)Glucagon: 3–5 mg iv (50 μg/kg in children) up to 10 mg/hrHyperinsulinemia/euglycemia: insulin 0.5–1 u/kg/hr accompanied by 0.5 g/kg/hr dextrose, titrated to maintain

euglycemia

cholinergic compounds

Atropine: 1 mg iv (0.05 mg/kg in children) doubled every 2 min until muscarinic symptoms are controlledPralidoxime: adults: 1–2 g iv over 30 min followed by 500 mg/g infusion for sickest patients. children: 20–50 mg/kg

(max 1–2 g) infused iv over 30–60 min and then 10–20 mg/kg/hr (max 500 mg/hr)

cyanide Adults:1. Sodium nitrite: 300 mg (10 ml of a 3% conc.) infused iv over 2–5 min2. Sodium thiosulfate: 12.5 g (50 ml of a 25% conc.) infused iv over 10–20 min or as a bolus3. hydroxocobalamin iv 70 mg/kg (up to 5 g)Children:1. Sodium nitrite: 6–8 ml/m2 (0.2 ml/kg of a 3% conc., up to adult dose) infused iv over 2–5 min2. Sodium thiosulfate: 7 g/m2 (0.5 g/kg, up to adult dose) infused over 10–30 min or as a bolus

cyclic antidepressants Sodium bicarbonate: 1 meq/kg iv bolus, followed by infusion of 150 meq in 1 l of d5w, infused at twice maintenance rate

digoxin Digoxin-specific Fab: Known level: # of vials = [wt (kg) × level (ng/ml)/100] rounded up to nearest vial. empiric dosing: acute: 10–20 vials. chronic: adults 3–6 vials; children: 1–2 vials. usually given as iv infusion over 30 min (administer as iv bolus for asystole)

ethylene glycol, methanol

Fomepizole: 15 mg/kg infused iv over 30 min; next 4 doses at 10 mg/kg every 12 hr; additional doses at 15 mg/kg every 12 hr if needed

Ethanol (when fomepizole not available): 0.8 g/kg infused iv over 20–60 min, followed by initial infusion of 100 mg/kg/h

methemoglobin Methylene blue: 1–2 mg/kg iv over 5 min followed by a 30-ml fluid flush

Salicylates Sodium bicarbonate: 150 meq in 1 l of d5w, infused at twice maintenance rate. activated charcoal, 1g/kg every 4 hr

Sulfonylurea-related hypoglycemia

Octreotide: 50 μg SQ every 6 hr. children: 1.25 μg/kg (up to adult dose) SQ every 6 hr

data from Flomenbaum ne, goldfrank lr, hoffman rS, et al., eds. Goldfrank’s Toxicologic Emergencies. 8th ed. new york: mcgraw-hill; 2006.

The extensive availability of these drugs contributes to their prevalence in both suicidal ingestions and unintentional pedi-atric ingestions. Although they are generally safe when used correctly, the widely held misconception that these pharma-ceuticals are harmless undoubtedly contribute to their poten-tial for causing harm.

Acetaminophen Poisoning

Acetaminophen is estimated to be responsible for 51% of all cases of acute liver failure in the United States (6). Acetamino-phen ingestions require ICU admission when hepatotoxicity is

established. The analgesic effects of acetaminophen are medi-ated by central cyclo-oxygenase (COX)-2 and prostaglandin synthase inhibition (7). The metabolism of acetaminophen occurs principally in the liver and less than 5% of acetamino-phen is eliminated unchanged in the urine. Ninety percent of absorbed acetaminophen undergoes hepatic conjugation with either glucuronide or sulfate to produce inactive metabolites. The remainder (5% to 15%) is oxidized by the cytochrome P450, forming N-acetyl-p-benzoquinoneimine (NAPQI), a toxic oxidant (8). Thiol-containing compounds, such as reduced glutathione, are used as electron donors to detoxify NAPQI.

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Chapter 151 toxicology e457

The single dose of acetaminophen generally thought to pro-duce toxicity is at least 150 mg/kg (8). In overdose, absorption of acetaminophen may be delayed, although peak absorption generally occurs at 2 hours, and rarely after 4 hours (9,10). Absorption may be expected to be further delayed in the pres-ence of peristalsis-decreasing opioid or anticholinergic co-ingestants, or if the acetaminophen is formulated for extended release. In overdose, metabolism by sulfation becomes satu-rated, and the formation of NAPQI exceeds that which can be detoxified by available glutathione (11). Because the toxic metabolite is formed in the liver, hepatic toxicity is the key clinical feature. N-acetylcysteine (NAC), the key to manage-ment of acetaminophen poisoning, acts as a precursor to glu-tathione synthesis, a substrate for sulfation; it directly binds to NAPQI itself; and enhances the reduction of NAPQI to acet-aminophen (12).

Clinical Manifestations

Acute acetaminophen toxicity has been divided into four clinical stages (13). Not every untreated patient will advance through each of these stages. Spontaneous improvement is possible at any point, but the stages of toxicity serve as a use-ful guide to the progression of symptoms. During stage I, the patient is either asymptomatic or has nonspecific clinical find-ings (nausea, vomiting, malaise), and no laboratory abnor-malities are recognized. Stage II begins with the onset of liver injury, generally within 24 hours but always within 36 hours of ingestion (14). Initial laboratory findings include elevated aminotransferases (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]), but progress to signs of hepatic dys-function, including prolonged prothrombin time (PT), meta-bolic acidosis, and hypoglycemia. Stage III represents the time of peak hepatotoxicity, usually 72 to 96 hours from ingestion. While AST and ALT may ultimately exceed 10,000 IU/L, cre-atinine, lactate, phosphate, and PT are better indicators of prognosis. Fatalities usually occur within 3 to 5 days of inges-tion. When death does not occur, hepatic recovery is referred to as stage IV. Hepatic regeneration will be histologically and functionally complete in survivors.

Management

Decontamination with activated charcoal should be consid-ered if significant co-ingestants are suspected. N-acetylcysteine is the key to managing acetaminophen poisoning and is avail-able for both oral and intravenous (IV) administration. The oral protocol for acute ingestions is a 140 mg/kg loading dose, followed by 17 doses of 70 mg/kg every 4 hours for a total of 72 hours. The IV regimen is 150 mg/kg over 45 minutes, followed by 50 mg/kg over 4 hours, and then 100 mg/kg over 16 hours. Both regimens have equal efficacy for simple acute ingestion, but the IV regimen has the advantage of a shorter course, and is the only route that has been studied adequately in patients with hepatic failure. Unlike oral NAC, however, parenteral NAC carries the risk of anaphylactoid reactions. The duration and route of treatment should be determined by the patient presentation.

For simple, acute ingestions, the serum acetaminophen concentration should be plotted against the number of hours following ingestion on the Rumack–Matthew nomogram to determine whether treatment with NAC is necessary (15). The

treatment line is a sensitive, but not specific, predictor of hepa-totoxicity. The currently recommended line intersects 150 μg/mL at 4 hours, incorporating a 25% safety margin over the origi-nal nomogram line, which was itself nearly 100% sensitive for predicting hepatotoxicity. When the concentration at a specific time is plotted above the line, treatment is required. When treatment is initiated within 8 hours of ingestion, NAC has complete efficacy in preventing hepatotoxicity (16), and so should be started immediately when the laboratory result for the acetaminophen concentration is not expected to be available within 8 hours of the initial ingestion. Once the serum acetaminophen concentration is available, the deci-sion whether to continue NAC can be reassessed based on the nomogram (Fig. 151.1). When there is uncertainty with regard to the exact time of ingestion, the physician should use the most conservative estimate (i.e., the earliest possible time) when using the nomogram. The risk of inadvertently failing to treat because of an incorrect history is mitigated by the safety margin associated with the nomogram.

The literature is less clear on the indications for the use of NAC for hepatotoxicity following suspected chronic acet-aminophen use. The vast majority of people who take acet-aminophen have no adverse clinical manifestations. Clinical trials involving daily dosing of 4 g of acetaminophen in both alcoholics and nonalcoholics showed that patients either have normal aminotransferase concentrations or very minor increases (17,18). Despite its safety, hepatotoxicity from chronic use occurs. Because chronic acetaminophen use often occurs in the setting of comorbid conditions, the diagnosis can be difficult to establish with certainty. NAC should be admin-istered to all patients with suspected acetaminophen hepato-toxicity until the diagnosis has been excluded.

The nomogram cannot be used for patients who present more than 24 hours after ingestion. In such cases, NAC should be started immediately upon presentation. If the patient has both an undetectable acetaminophen concentration and nor-mal aminotransferases, acetaminophen overdose is highly

300200

1007050

3020

10

Ace

tam

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hen

conc

entr

atio

n µg

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Acetaminophen Nomogram

75

32

4 8 12

Hours postingestion

16 20 24

Treatment line

FIgure 151.1 acetaminophen nomogram. (adapted from hendrickson rg, bizovi Ke. acetaminophen. in: Flomenbaum ne, goldfrank lr, hoff-man rS, et al., eds. Goldfrank’s Toxicologic Emergencies. 8th ed. new york: mcgraw-hill; 2006:523–543.)

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unlikely, and NAC need not be continued. If either acetamino-phen or aminotransferase concentrations are elevated (even minimally so), the patient should be administered 20 hours of IV NAC. Following the treatment period, aminotransferase and acetaminophen concentrations should be obtained again; at this point, if the aminotransferase concentrations are only minimally elevated, the patient was either minimally poisoned or acetaminophen was not the cause of the liver damage.

When acetaminophen-induced hepatotoxicity is encoun-tered, IV NAC should be administered as described above, but the maintenance dose should be continued until clinical improvement, liver transplantation, or death occurs. Even in the presence of fulminant hepatic failure, IV NAC has been shown to decrease mortality, cerebral edema, and the need for vasopressors (19).

Hepatic Transplantation

The long-term complications of a transplant are significant, and those who survive acetaminophen poisoning without transplant will make a complete recovery. Under ideal con-ditions, the clinician could immediately determine which patients would survive without transplant and which would not, so that the appropriate patients could be candidates for a liver transplant before irreversible clinical deterioration; in practice, it is not always clear. Several prognostic criteria are available. The King’s College Hospital Criteria suggest that pH less than 7.3 after resuscitation or the combination of PT more than 100, creatinine more than 3.3 mg/dL, and grade III or IV encephalopathy are predictive of death in the absence of a transplant (20). Alternatively, a 48-hour serum phosphate concentration more than 1.2 mmol/L has also been shown to be sensitive and specific for predicting the need for transplant and the probability of death from acetaminophen hepatotox-icity (21). Presumably, a low or normal phosphate concen-tration is an evidence that the phosphate is being utilized by hepatocytes for adenosine triphosphate (ATP) generation.

sAlIcylATes And oTher nonsTeroIdAl AnTI-InFlAmmATory drugs

The nonsteroidal anti-inflammatory drugs (NSAIDs) are widely available both with and without prescription for relief of inflammation, pain, and fever. Salicylates are a subgroup of NSAIDs that have unique features of toxicity and require dis-tinct management. In this chapter, we will use the term NSAID to refer to nonsalicylate NSAIDs.

The therapeutic effects of salicylates and NSAIDs result from the inhibition of COX, a mediator of prostaglandin syn-thesis. In general, they are renally eliminated. Because they are designed to promote fast relief, therapeutic doses of the imme-diate-release drugs produce significant concentrations within an hour. However, when taken in overdose or as enteric-coated or sustained-release formulations, absorption may be delayed and maximal serum concentrations may not be observed for hours after the ingestion.

In addition to these effects, salicylates also uncouple oxi-dative phosphorylation, meaning that some of the proton gradient across the mitochondrial matrix is dissipated in the

formation of heat, rather than ATP, forcing the production of lactate. As a result, ICU admission is required when patients present with metabolic acidosis and hemodynamic instability, or if they require bicarbonate infusion or frequent measure-ments of salicylate concentration.

Salicylate Poisoning


Acute salicylate poisoning may cause epigastric pain, nausea, and vomiting. Salicylates induce hyperventilation (both tachy-pnea and hyperpnea) by direct stimulation of the brainstem respiratory center (22). Neurologic signs and symptoms of salicylate poisoning range from mild to severe, and include tinnitus, delirium, coma, and seizure. The initial feature of toxicity is primary respiratory alkalosis. A primary metabolic acidosis is characterized by the presence of lactic acid, keto-acids, and salicylic acids (23); the net result is an increased anion gap metabolic acidosis. The simultaneous presence of a respiratory alkalosis and metabolic acidosis can be difficult to interpret. Because the respiratory alkalosis initially predomi-nates in adults, the presence of an acidemia or even normal pH indicates advanced poisoning.

Chronic salicylate poisoning presents with the same signs and symptoms as acute poisoning, but typically occurs in elderly patients taking supratherapeutic amounts of salicy-late to treat a chronic condition. Chronic poisoning can be a challenging diagnosis to establish because it is often not sus-pected. Elderly salicylate-poisoned patients presenting with metabolic acidosis and an altered sensorium may be initially misdiagnosed with sepsis, dehydration, or cerebrovascular accident (CVA) if a salicylate concentration is not obtained.

Serum salicylate concentrations only correlate loosely with toxicity because the principal site of poisoning is the central nervous system (CNS). The threshold for toxicity is usually considered to be 30 mg/dL when tinnitus develops. Chroni-cally poisoned patients have a lower salicylate concentration for the same degree of illness because much of their total body burden has redistributed into the CNS. The degree of poison-ing is determined by evaluating the serum concentration in the context of the patient’s clinical appearance, laboratory results, and acuity of the ingestion.

Management

The key principles for management of salicylate poisoning are to minimize absorption, speed elimination, and mini-mize redistribution to tissues. Gastric emptying should only be attempted if a significant amount of drug is expected to be present in the stomach. Activated charcoal, 1 g/kg, should be administered every 4 hours if it can be given safely. Salicylates cause pylorospasm and may form concretions in overdose, leading to delayed absorption. Multiple-dose activated char-coal (MDAC) not only prevents delayed absorption, but also may speed up the elimination of salicylates by disrupting the enteroenteric circulation of the drug (24). Serum chemistry, venous or arterial blood gas analysis, and salicylate concen-tration should be obtained every 2 hours until the salicylate concentration demonstrates an interval decrease.

Moderately poisoned patients (increased anion gap or a salicylate concentration >40 mg/dL) should also have blood and urine alkalinized with sodium bicarbonate. As a weak acid

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(pKa 3.5), salicylates will be ionized in an alkaline environ-ment and “trapped” (i.e., unable to passively move through lipid membranes). Ionization prevents salicylate in the proxi-mal tubule from diffusing into the plasma and salicylate in the plasma from diffusing into tissues, such as the brain (25). Alka-linization can be achieved with an infusion of sodium bicar-bonate of 150 mEq in 1 L of D5W at twice the maintenance rate. The urine pH should be maintained from 7.5 to 8.0 and systemic arterial pH between 7.45 and 7.55. Close attention should be paid to potassium repletion, as low serum potassium will cause preferential reabsorption of potassium over hydro-gen ions in the proximal tubule and compromise attempts to alkalinize the urine (26). Endotracheal intubation and seda-tion should be avoided whenever possible. The tachypnea and hyperpnea of salicylate poisoning do not necessarily represent “tiring,” and produces a helpful alkalosis. When intubation is unavoidable, patients should be administered 1 to 2 mEq/kg of bicarbonate prior to the procedure, intubated quickly, and hyperventilated afterward to avoid respiratory acidosis (27).

Early consultation with a nephrologist is recommended for seriously ill patients. Extracorporeal elimination is reserved for patients who are very ill, those who cannot tolerate alka-linization, or those with serum concentrations so elevated that their clinical status is expected to deteriorate. We recommend hemodialysis for severe acid–base disturbances, mental status changes, inability to tolerate alkalinization (renal failure or congestive heart failure), and serum salicylate concentrations of 100 mg/dL after acute poisoning and 60 mg/dL in chronic poisoning (Table 151.3).

NSAID Poisoning


NSAIDs are considered safer than salicylates in therapeutic dosing. While chronic NSAID use is associated with interstitial nephritis, nephritic syndrome, or analgesic nephropathy, acute overdose can cause gastric injury and is sometimes accompa-nied by a reversible azotemia caused by vasoconstriction from decreased prostaglandin production (28). In severe overdose, the most consequential effects are elevated anion gap meta-bolic acidosis, coma, and hypotension (29).

Management

Activated charcoal should be administered if the patient pres-ents within several hours of overdose. Good supportive care is the mainstay of therapy after NSAID overdose. NSAID

elimination is not increased with alkalinization and NSAIDs’ high degree of protein binding precludes removal with hemo-dialysis. Hemodialysis has, however, been used to correct acidemia and electrolyte abnormalities in patients with mul-tiorgan system failure.

psychIATrIc medIcATIons

Psychiatric medications represent a disproportionate number of poisonings in the United States. Antidepressants, antipsy-chotics, and sedative–hypnotics accounted for more than 20% of all deaths reported to poison control centers in 2013, while accounting for only 5.9% of total exposures (3).

Antipsychotic Poisoning

The antipsychotics are categorized as either typical or atypical. The typical antipsychotics, which include haloperidol, chlor-promazine, and thioridazine, antagonize dopamine primarily at the D2 receptor. The newer, atypical, medications are exem-plified by clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, which have less dopaminergic antagonism and more serotonergic effects than the typical antipsychotics. When antipsychotic medications produce coma, conduction abnor-malities, or hyperthermia, these patients require ICU admission.


All antipsychotics produce sedation in overdose, though respi-ratory depression is usually not consequential. The drugs have varying degrees of muscarinic and α-adrenergic antagonism, often resulting in tachycardia and moderate hypotension (30). Many of the typical antipsychotics have type-IA antidysrhyth-mic properties; most of the typical and a few of the atypical drugs (notably ziprasidone) can cause QTc prolongation and torsades de pointes (31,32). Management of overdose of the antipsychotics generally only requires supportive care.

Neuroleptic Malignant Syndrome

The dopamine antagonism required for control of psychosis can cause a group of distinct movement disorders that range in severity from mild to life threatening. These conditions—dystonia, akathisia, parkinsonism, tardive dyskinesia, and neuroleptic malignant syndrome (NMS)—are more likely to occur in the presence of the typical antipsychotics, although the atypical antipsychotics can cause them as well. The first four conditions mentioned above are of less concern to the intensivist than NMS, and will not be discussed.

NMS is characterized by the presence of altered mental status, muscular rigidity, hyperthermia, and autonomic dys-function (33). While symptoms usually begin within weeks of starting treatment, they do occur in individuals that are tak-ing the drug on a chronic basis. Risk factors include young age, male gender, extracellular fluid volume contraction, use of high-potency antipsychotics, depot drug preparations, concomitant lithium use, rapid increase in dose, or simul-taneous use of multiple drugs (32). Diagnosis is not always clear because there is no reference standard. Other diagnoses to consider include infection, environmental hyperthermia, hyperthyroidism, serotonin syndrome, ethanol and sedative–hypnotic withdrawal, sympathomimetic intoxication, and anticholinergic intoxication.

TABLE 151.3 Indications for Hemodialysis in Salicylate Poisoning

•renal failure•congestive heart failure (relative)•acute lung injury•Persistent central nervous system disturbances•Progressive deterioration in vital signs•Severe acid-base or electrolyte imbalance, despite appropriate

treatment•hepatic compromise with coagulopathy•Salicylate concentration (acute) >100 mg/dl or (chronic)

>60 mg/dl

adapted from Flomenbaum ne. Salicylates. in: Flomenbaum ne, goldfrank lr, hoffman rS, et al, eds. Goldfrank’s Toxicologic Emergencies. 8th ed. new york, ny: mcgraw-hill; 2006:550–564.

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Management of NMS begins with immediate treatment of life-threatening hyperthermia. Ice–water immersion and paralysis by neuromuscular blockade should not be delayed if temperature is more than 106°F (41.1°C). In instances of environmental hyperthermia, a delay of cooling longer than 30 minutes has been associated with significant morbidity and mortality (34). Benzodiazepines should be titrated to seda-tion and muscle relaxation. When present, rhabdomyolysis, electrolyte disorders, and hypotension should be aggressively treated.

Bromocriptine, a centrally acting dopamine agonist given at 2.5 to 10 mg three to four times a day, may be of theoretical benefit even though it is not well studied and may take days to control symptoms. After evidence of clinical improvement, bromocriptine should be decreased by no more than 10% a day since decreasing the dose too rapidly may precipitate a relapse of NMS. We do not recommend dantrolene, the drug of choice for malignant hyperthermia, in the management of NMS.

Benzodiazepine Poisoning

Benzodiazepines are widely used for their sedative, anxiolytic, and anticonvulsant properties, which are moderated by the frequency of opening of γ-aminobutyric acid (GABA)-medi-ated chloride channels in the CNS (35). In overdose, these drugs produce somnolence, coma, and minimal decreases in blood pressure, heart rate, and respiratory rate.

Management

Management of benzodiazepine overdose is supportive. Care of the comatose patient should focus on supporting the airway and blood pressure while waiting for the drug to be elimi-nated. There is a limited role for flumazenil, a competitive benzodiazepine antagonist; flumazenil can precipitate with-drawal in individuals who are tolerant to benzodiazepines and induce seizures in those with seizure disorders (36,37). Flumazenil may be indicated in patients without tolerance to benzodiazepines, such as children, who suffer from benzodi-azepine overdose. When indicated, flumazenil should be given intravenously, 0.1 mg/min, up to 1 mg and can be repeated if the clinical response is inadequate. Because the duration of the effect of flumazenil is shorter than the effect of the benzodiaz-epine, recurrence of symptoms should be expected.

If there is any doubt as to whether the patient has toler-ance to benzodiazepines, flumazenil should not be adminis-tered. Benzodiazepine poisoning can be managed effectively and safely with supportive care only, but benzodiazepine with-drawal precipitated by flumazenil can be life threatening.

Cyclic Antidepressant Poisoning

Until the introduction of the selective serotonin reuptake inhibitors (SSRIs), the cyclic antidepressants (CAs) were the principal pharmacologic treatment available for depression. In 2013, 13,037 CA exposures were reported to the AAPCC, with tricyclic antidepressants accounting for 2.27% of total fatalities (3). While the CAs differ slightly from each other in their receptor affinities, they can be treated as a group.

The CAs are usually absorbed within hours of ingestion, although the antimuscarinic effects may delay absorption in overdose. The drugs also exhibit α-adrenergic antagonism, inhibition of reuptake of norepinephrine, and anticholinergic

properties. Acting as type-IA antidysrhythmics, CAs block sodium entry into myocytes during phase 0 of depolarization. Acute ingestions of 10 to 20 mg/kg of most CAs can cause significant poisoning (38).


Important CNS effects include lethargy, delirium, coma, and seizures. Tachycardia and hypotension develop early in tox-icity. The IA antidysrhythmic properties cause prolongation of the QRS interval. CAs also produce a characteristic right-ward shift of the axis in the terminal portion of the QRS, best seen as an R wave in the terminal 40 milliseconds of lead aVR (Fig. 151.2) (39). Serum drug concentrations may be obtained but do not correlate well with toxicity (40).

Management

Gastrointestinal decontamination should be considered in every patient. If the history suggests a recent large ingestion, activated charcoal should be administered and gastric lavage may be attempted. The ECG is the most important diagnostic test when managing CA overdose. A terminal 40-millisecond QRS axis of 130 to 270 degrees discriminated patients with CA toxicity from those without toxicity in one study (41). While the terminal 40-millisecond QRS axis is a good indica-tor of exposure, QRS duration is a better indicator of sever-ity of poisoning. In another series, no patients with QRS less than 160 milliseconds had ventricular dysrhythmias and no patients with a QRS duration less than 100 milliseconds had seizures (40).

Sodium bicarbonate should be administered if the QRS duration is 100 milliseconds or more. Both the high sodium concentration and alkaline pH of sodium bicarbonate solu-tion are responsible for its salutary effects. The sodium load increases the sodium gradient across the poisoned myocardial sodium channel, resulting in a narrowing of the QRS com-plex. The bicarbonate raises the pH, reducing CA binding to the sodium channel. Sodium bicarbonate should be admin-istered as a 1- to 2-mEq/kg bolus during continuous ECG monitoring. If the complex narrows, sodium bicarbonate can be administered as an infusion. If the complex remains unchanged, the diagnosis of CA poisoning should be reconsid-ered. The sodium bicarbonate infusion may be performed by adding 150 mEq of bicarbonate to 1 L of D5W and infusing at twice the maintenance rate, with an arterial pH target of 7.50 to 7.55. Occasional repeat boluses of 1 to 2 mEq/kg may

aVR

aVL

I

II

FIgure 151.2 terminal elevation of avr and QrS prolongation. (From clancy c. electrocardiographic principles. in: Flomenbaum ne, gold-frank lr, hoffman rS, et al., eds. Goldfrank’s Toxicologic Emergencies. 8th ed. new york: mcgraw-hill; 2006:51–62.)

LWBK1580-CH151E_p455-479.indd 460 02/08/17 7:45 PM


be necessary. Hypertonic sodium chloride (3% NaCl) may be indicated when the QRS complex widens and the serum pH precludes further alkalinization. Hyperventilation may be used to induce alkalemia in intubated CA-poisoned patients and in those who cannot tolerate the fluid or sodium load from sodium bicarbonate. Although hyperventilation did not have an effect in one experimental model, it has been used clinically with success (42,43).

Seizures should be rapidly controlled as they will cause a metabolic acidosis, which will lead to even more avid bind-ing of the CA to the cardiac sodium channels and potentially worsen cardiotoxicity. Benzodiazepines can be safely adminis-tered or, alternatively, propofol or barbiturates are also appro-priate. Phenytoin, a type-IA antidysrhythmic, may worsen cardiac toxicity and is therefore not indicated (44).

If hypotension persists despite fluid resuscitation and vaso-pressors become necessary, norepinephrine may be superior to dopamine because intracellular catecholamines may be depleted. Therapy should continue until vital signs and ECG improve. In most instances, CA poisoning results in a rapid deterioration within hours of overdose. Unless there has been a significant secondary injury (such as from shock), those who survive to 24 hours are expected to make a complete recovery. Because of avid CA protein binding, hemodialysis is deemed ineffective.

Lithium Poisoning

Lithium is used in the treatment of bipolar affective disorders. Of 6,610 exposures reported to the AAPCC, 2.3% were clas-sified as major or fatal (3). Patients will require ICU admission when they have signs of CNS toxicity, do not tolerate fluid therapy, or have serum concentrations more than 2 mmol/L, which may result in rapid deterioration.

Lithium is thought to increase serotonin release and increase receptor sensitivity to serotonin, as well as modulate the effects of norepinephrine on its second-messenger sys-tem (45). Lithium is freely filtered by the glomerulus, 80% of which is reabsorbed, with 60% occurring in the proximal tubule (46). Immediate-release preparations produce peak serum concentrations within hours, but sustained-release lith-ium may not peak for 6 to 12 hours. Acute toxicity occurs when an individual without a body burden of lithium takes a supratherapeutic dose of the drug. Chronic toxicity is usually the result of decreased elimination of the drug in a patient who is receiving a fixed dose (e.g., after developing renal insuffi-ciency). Acute-on-chronic toxicity occurs when a patient with a pre-existent total body drug takes a supratherapeutic dose. The generally accepted therapeutic range of lithium is 0.6 to 1.2 mmol/L, although in both overdose and therapeutic dos-ing, clinical signs and symptoms may serve as a better guide than the serum concentration.

Diagnosis

In acute toxicity, a large ingestion of lithium—a gastrointes-tinal irritant—will initially cause gastrointestinal symptoms, such as vomiting and diarrhea. Neurotoxicity—which is clini-cally more significant—will be delayed until the drug has been absorbed and is redistributed into the CNS. In chronic tox-icity, gastrointestinal symptoms may be completely absent. Neurotoxicity manifests itself as disorders of movement and alterations in mental status. In very mild toxicity, only a fine

tremor will be present, but in more advanced poisoning, fas-ciculations, hyperreflexia, dysarthria, and nystagmus may be seen as well (46). Mental status changes range from confusion to coma and seizures (47).

Nephrogenic diabetes insipidus and hypothyroidism occur following chronic therapeutic lithium use, but are not features of overdose. The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) is a chronic neurologic disorder with many of the same features of lithium neurotoxicity. The dis-tinction is that SILENT persists even when the body burden of lithium is eliminated. The mechanism is not completely elucidated but may involve demyelination. SILENT has been reported both as a result of chronic therapeutic use and as a sequela of lithium intoxication (48).

Management

Since lithium does not bind to activated charcoal, it should only be considered when a mixed overdose is suspected (49). When sustained-release preparations are ingested, whole bowel irriga-tion has been shown to decrease serum lithium concentration (50); whole bowel irrigation can be performed by administer-ing 2 L of polyethylene glycol orally every hour (25 mL/kg/hr in children) until the rectal effluent is clear. After both acute and chronic toxicities, IV fluids should be given to optimize intravascular volume, as volume-depleted patients will have a decreased glomerular filtration rate and increased reabsorption of lithium. When fluid deficits are restored, 0.9% saline can be administered at twice the maintenance rate or approximately 200 mL/hr in adults to aid in elimination of lithium.

Lithium can be removed by hemodialysis due to its low volume of distribution and limited protein binding. Although hemodialysis can only remove the lithium residing in the vascular compartment, the elimination of serum lithium will allow the remaining intracellular lithium to redistrib-ute into the plasma. Thus, although lithium concentrations may rebound following dialysis, the tissue burden has actu-ally decreased. The indications for dialysis are not universally agreed upon. Hemodialysis should be performed when there are signs of significant end-organ damage, when lithium can-not be eliminated without dialysis, or when the serum con-centration is elevated such that severe toxicity is highly likely. We recommend dialysis when there is significant CNS toxicity such as clonus, obtundation, coma, or seizures; when a patient with milder toxicity cannot eliminate lithium efficiently (renal insufficiency) or tolerate saline resuscitation (congestive heart failure); or in the presence of a serum lithium concentration more than 4.0 mmol/L following acute poisoning, or more than 2.5 mmol/L following chronic poisoning. Since repeat dialysis may be necessary, the clinician should reapply the above criteria 4 hours after dialysis is completed to determine if dialysis should be repeated.

A common clinical pitfall is to deny dialysis to patients with an elevated lithium concentration and signs of toxic-ity because consecutive lithium concentrations have shown a small decrease. The clinician concludes that the lithium will eventually be eliminated without dialysis, so dialysis should not be helpful. Unfortunately, duration of exposure to the toxic lithium levels may predispose the patient to SILENT. In other words, it is better to be exposed to a neurotoxin for a few hours than a few days. While this area is not adequately studied, it seems prudent to hemodialyze these patients.

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ToxIcologIc BrAdycArdIA

In 2013, the AAPCC NPED reported 101,544 exposures to cardioactive medications including digoxin, β-adrenergic antagonists, and calcium channel blockers (CCBs), and accounted for 10.67% of total exposure fatalities that year (3). These xenobiotics have a narrow therapeutic index, draw-ing a fine line between therapeutic dosing and poisoning. The individuals who take these medications usually have underly-ing cardiovascular disease, making management of overdose even more challenging.

Digoxin Poisoning

Digoxin is a cardioactive steroid derived from the foxglove plant. Though digoxin and digitoxin are the only pharmaceu-ticals in the class, plants such as oleander, yellow oleander,

dogbane, and red squill contain cardioactive steroids with similar toxicity. While some of these plants cause a great deal of morbidity worldwide, this chapter will deal primarily with digoxin, which causes more morbidity than any other cardio-active steroid in North America.

Digoxin has multiple therapeutic and toxic cardiovas-cular effects, all of which result from inhibition of the Na+–K+–ATPase. The Na+–K+–ATPase extrudes sodium from the myocardial cell, creating a sodium gradient that drives Na+–Ca2+–antiporters to move calcium extracellularly. The inhibi-tion of the Na+–K+–ATPase by digoxin increases intracellular Ca2+, which therapeutically triggers Ca2+-mediated Ca2+ release from the sarcoplasmic reticulum (SR); this is commonly called Ca-mediated Ca release (Fig. 151.3).

Digoxin also slows conduction through the sinoatrial (SA) and atrioventricular (AV) nodes, probably through direct and vagally mediated mechanisms (51). In therapeutic use, digoxin decreases heart rate and increases inotropy. In overdose, the

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FIgure 151.3 normal depolarization. (adapted from hack Jb, lewin na. cardioactive steroids. in: Flomenbaum ne, goldfrank lr, hoffman rS, et al., eds. Goldfrank’s Toxicologic Emergencies. 8th ed. new york: mcgraw-hill; 2006:971–982.)

LWBK1580-CH151E_p455-479.indd 462 02/08/17 7:45 PM


increased intracellular Ca2+ brings the cell closer to threshold, resulting in increased automaticity.

Digoxin does not exert its therapeutic and toxic effects until it redistributes from the serum into the myocardium. Digoxin has a large volume of distribution, precluding elimination by hemodialysis, and is mostly eliminated renally, although there is some hepatic metabolism. The maximal effect from a thera-peutic dose of digoxin is seen at 4 to 6 hours when adminis-tered orally and 1.5 to 3 hours when given intravenously.


Digoxin poisoning can be either acute or chronic. Acute toxicity occurs when an individual without a tissue burden of digoxin ingests a supratherapeutic dosage of the drug. Chronic toxic-ity usually occurs when an individual on a fixed dose of the drug loses the ability to excrete it effectively. Both syndromes have similar cardiovascular manifestations, but acute toxicity may feature more prominent gastrointestinal symptoms. Acute poisoning may result in nausea, vomiting, and abdominal pain, whereas chronic poisoning develops more insidiously. In addition to gastrointestinal symptoms, chronic poisoning may present with weakness, confusion, or delirium (52,53).

Bradycardia with a preserved blood pressure typically occurs in digoxin toxicity. The ECG is the most important test in establishing the diagnosis. Because digoxin has mul-tiple cardiac effects, there is no single ECG manifestation that is consistently seen in patients with digoxin toxicity. The most common rhythm disturbance reported is the presence of ventricular ectopy (54). The ECG could potentially exhibit increased automaticity from elevated resting potential, con-duction disturbance from AV and SA nodal block, both, or neither. The ectopy may degrade into ventricular tachycardia or ventricular fibrillation. If conduction disturbance predomi-nates, the ECG may demonstrate sinus bradycardia or varying degrees of AV block.

The laboratory provides clues to toxicity. The therapeutic range for digoxin is usually reported as 0.5 to 2.0 ng/mL. Serum digoxin concentration should be interpreted in the context of the history and ECG. Digoxin is a cardiotoxin, and serum con-centrations do not necessarily reflect the degree of poisoning. Digoxin requires several hours to redistribute from the serum to the tissues. Shortly after an acute ingestion, the serum con-centration may overestimate toxicity, while a mild increase in serum concentration of a patient chronically on digoxin may underestimate the high extent of the increased tissue burden.

Serum potassium concentration is a better predictor of illness following acute ingestions. A study of 91 digitoxin- poisoned patients performed in the pre–digoxin-specific anti-body fragment era found no mortality when the potassium concentration was less than 5.0 mEq/L and 50% mortality when the potassium concentration was 5.0 to 5.5 mEq/L (55).

Management

Because acute toxicity can cause vomiting, activated charcoal and gastric lavage may be of limited value. Atropine can be given intravenously in 0.5-mg doses for bradycardia, although it is probably not important to “correct” the heart rate if the blood pressure is preserved. If necessary, potassium should be supplemented. Hypokalemia inhibits the function of the Na+–K+–ATPase, and thereby exacerbates digoxin poisoning. A pitfall in managing digoxin-poisoned patients is the administra-tion of calcium in response to the recognition of hyperkalemia.

When hyperkalemia is the result of an increase in total body burden of potassium, such as in renal failure, calcium is the treatment of choice. However, calcium administration is not recommended in the setting of digoxin poisoning where extra-cellular distribution of potassium is the result of a poisoned Na+–K+–ATPase, not an increase in total body potassium. Under these circumstances, increasing extracellular calcium may accentuate toxicity.

Digoxin-Specific Immune Fragments

Administration of digoxin-specific antibody fragments (Fab) is the most important intervention in digoxin-poisoned patients. Fab are prepared by cleaving the Fc fragment from IgG. The resulting Fab fragments are much less immunoreactive than the whole IgG antibodies. In a large series, digoxin-specific antibody fragments caused allergic reaction in 0.8% of patients (56).

Digoxin-specific Fab should be administered to anyone with digoxin-induced cardiotoxicity, a serum potassium con-centration of 5.0 mEq/L or more after an acute overdose, or a serum digoxin concentration 15 ng/mL or more at any time or 10 ng/mL or more at 6 hours postingestion (57).

Digoxin-specific Fab are given by IV infusion and dosed according to serum concentration (Table 151.4). In the pres-ence of suspected severe toxicity, treatment should not be dependent on nor await serum digoxin concentration results. The first clinical effect of Fab should be seen within 20 minutes and a maximal response within several hours (58). Following immune-specific antibody fragment administration, the serum digoxin concentration determined by most laboratories will be a total digoxin concentration, which will include the anti-body-bound digoxin. The result will be a very elevated value without clinical utility. The determination of free digoxin con-centration, which is available at some institutions, would not be affected.

a-Adrenergic Antagonist and Calcium Channel Blockers

a-Adrenergic Antagonist Overdose

β-Adrenergic receptors are coupled to G-proteins, which acti-vate adenyl cyclase, resulting in increased production of ATP from cyclic adenosine monophosphate (cAMP). The cAMP activates protein kinase A (PKA), which initiates a series of phosphorylations. Phosphorylation of L-type calcium chan-nels on cell membranes increases intracellular calcium, which

TABLE 151.4 Digoxin-Specific Fab Dose Calculation

When serum digoxin concentration (SDC) knownno. of vials = [Sdc (ng/ml) × patient weight (kg)]/100

When SDC unknown, dose knownno. of vials = amount ingested (mg)/0.5 mg/vial

When both SDC and dose unknown (acute poisoning)empiric therapy10–20 vials (adult or pediatric)

When both SDC and dose unknown (chronic poisoning)empiric therapyadult: 3–6 vialsPediatric: 1–2 vials

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allows more activation of the SR and further calcium release, causing muscle contraction. The calcium influx also brings pacemaker cells closer to threshold (59).

Most of the β-adrenergic antagonists are exclusively metabolized or biotransformed in the liver and then renally eliminated. The exception to the rule is atenolol, which is exclusively renally eliminated.


All β-adrenergic antagonists have the potential to produce bra-dycardia and hypotension in a dose-dependent fashion. How-ever, there are subtle differences among the agents in terms of receptor selectivity (α-, β1-, and β2-adrenergic receptors), lipid solubility, membrane-stabilizing activity, and potassium chan-nel blockade that result in varied clinical manifestations.

Drugs with α- and β-adrenergic antagonist effects, such as labetalol and carvedilol, produce more hypotension and afterload reduction. The more β1-selective drugs, including metoprolol and atenolol, have less potential for β2-related adverse effects such as bronchospasm. The more lipid-soluble β-adrenergic antagonists, such as propranolol, penetrate the CNS more readily, causing obtundation or seizures prior to hemodynamic collapse (60). Membrane-stabilizing activity, similar to type-I antidysrhythmic activity, produces lengthen-ing of the QRS interval, tachydysrhythmias, and hypotension. The membrane-stabilizing effect is usually associated with pro-pranolol and other lipid-soluble drugs, although it has been observed after overdose with others (61,62). Sotalol and ace-butolol can produce QTc prolongation due to potassium chan-nel blockade, which may result in torsades de pointes (63).

Calcium Channel Blocker Overdose

The CCBs are formulated as both immediate and sustained release, but in overdose, the effects of either type may be prolonged. The CCBs undergo hepatic metabolism. There are three major classes of CCBs: dihydropyridines (includ-ing amlodipine, nifedipine, and others ending with the suffix “-pine”), phenylalkylamines (verapamil), and benzothiazepine (diltiazem). In practice, it is more clinically useful to divide them into two classes: the dihydropyridines and the nondihy-dropyridines. All of the drugs inhibit the function of L-type calcium channels. The dihydropyridines have greater affinity for calcium channels in vascular smooth muscle than the myo-cardium (64).


The most consequential clinical features of CCB overdose are cardiovascular. All of the CCBs produce hypotension, but effects on heart rate and contractility vary based on the class of the particular drug. As a result, they cause hypoten-sion with a reflex tachycardia. Diltiazem, in contrast, produces little peripheral blockade, but does suppress contractility and conduction through the SA and AV nodes, resulting in brady-cardia and decreased inotropy. These cardiac effects can be much more difficult to treat than the peripheral vasodilation of the dihydropyridines. In severe poisoning, heart block or complete cardiovascular collapse results. Verapamil, which is active in the peripheral vasculature and in the myocardium, produces a combination of the effects of the dihydropyridines and diltiazem. For this reason, verapamil is considered to be the most dangerous of the CCBs, although any of them can cause death in overdose.

CCBs have effects outside the cardiovascular system. The blockade of L-type calcium channels in pancreatic β-islet cells, where they trigger the blockade of insulin release, may result in hyperglycemia (65).

Management

Patients who initially present without symptoms of β-adrenergic antagonists or CCB overdose may rapidly become very ill. Patients with these overdoses should be taken very seriously and treated aggressively. Many antidotes have been investi-gated, with varying degrees of clinical success. Patients with β-adrenergic antagonist and CCB overdose do not benefit from removal with hemodialysis. There is no single antidote for either β-adrenergic antagonists or CCBs. The optimal treatment con-sists of a combination of the treatments described below.

Gastrointestinal decontamination should be considered in all patients. Gastric lavage may be indicated if there are pills still expected to be in the stomach—usually in the first hour or two after ingestion; activated charcoal should be administered. Whole bowel irrigation with polyethylene glycol is indicated for patients with a history of ingesting sustained-release drugs.

The initial management for hypotension will be IV crystal-loid fluid. Although IV atropine, 0.5 to 1 mg, may be given for bradycardia, studies of atropine efficacy in CCB toxicity are not definitive (66). Calcium has a role not only in CCB tox-icity, but also for β-adrenergic antagonist poisoning (67,68). Increasing extracellular calcium helps to overcome calcium channel blockade and increase intracellular calcium, typically with greater improvement in blood pressure than heart rate. The ideal dosing of calcium is not yet established. An IV bolus of 13 to 25 mEq of Ca2+ (10 to 20 mL of 10% calcium chloride or 30 to 60 mL of 10% calcium gluconate) can be followed by repeat boluses or an infusion of 0.5 mEq/kg/hr of Ca2+ (69); calcium concentration should be closely monitored.

Glucagon, an endogenous polypeptide hormone released by pancreatic α-cells, has significant inotropic effects medi-ated by its ability to activate myocyte adenylate cyclase, effectively bypassing the β-adrenergic receptor (70). Because calcium channel opening occurs “downstream” from adenyl-ate cyclase, glucagon may not be as effective for overcoming calcium channel blockade. Glucagon should be given intrave-nously, at an initial dose of 3 to 5 mg (50 μg/kg in children), up to 10 mg. The total initial dose that produces a response should be given hourly as an infusion (59). Glucagon may cause hyperglycemia or vomiting, but neither complication should limit the therapy if it is effective.

Hyperinsulemia/euglycemia therapy should be instituted early in patients with moderate to severe poisoning. Insulin is a positive inotrope and may independently increase Ca2+ entry into cells (71) and allow the myocardium, which usually relies on fatty acids, to use more carbohydrate for metabolism (72). Although the ideal dose is not known, we recommend an IV bolus of 1 unit/kg, followed by an infusion of 0.5 to 1 unit/kg/hr. The initial bolus should be preceded by a 1-g/kg bolus of dextrose, followed by a 0.5-g/kg/hr infusion of dextrose to maintain euglycemia titrated to subsequent glucose concentra-tions. Although some clinicians are understandably apprehensive about using a dose of insulin that is 10-fold greater than the typi-cal diabetic ketoacidosis regimen, the regimen has been demon-strated to have utility in both clinical and animal testing (73,74).

In severe poisoning, all of the above measures should be performed, as well as institution of inotropes and vasoactive

LWBK1580-CH151E_p455-479.indd 464 02/08/17 7:45 PM


drugs. Intra-aortic balloon counterpulsation should also be considered if cardiac output is severely compromised. These patients may be ideal for this procedure because, unlike with most other causes of cardiogenic shock, their cardiac output can recover in a relatively short period of time.

Controversies

Intravenous lipid emulsion (ILE) therapy, a component of total parenteral nutrition, has been proposed as an adjunctive ther-apy for β-adrenergic antagonist and CCB toxicity in critically ill patients; the exact mechanism is poorly understood. Theo-ries include the induction of an intravascular “lipid sink,” or alternative lipid binding surface for the xenobiotic, effectively inactivating a percentage of the drug; evidence is limited to animal models and case reports. Clinical trials are lacking (75). ILE infusion may be considered after all alternative supportive methods—calcium, glucagon, fluids, insulin, vasopressors—have been attempted.

ToxIc Alcohol poIsonIng

The term toxic alcohols refers in particular to methanol and ethylene glycol, which are the most important chemicals in the class because they are both of high potential toxicity and wide availability. In 2013, the NPED received 6,600 reports of exposure to ethylene glycol, including 2.9% classified as major or fatal, and 1,784 exposures to methanol, with 1.3% major or fatal (3). When suspected, toxic alcohol poisoning requires ICU admission.

Methanol is commonly found in windshield wiper fluid, ethylene glycol in automobile antifreeze, and isopropanol is a ubiquitous topical disinfectant. The toxic alcohols are readily absorbed and have a volume of distribution similar to total body water. Both the parent compounds and the toxic metabo-lites are dialyzable. It is not the toxic alcohols themselves that produce significant toxicity, but their metabolites. Methanol and ethylene glycol are metabolized in a stepwise fashion by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) to the clinically important metabolites: formic acid (methanol) and glycolic, glycoxylic, and oxalic acid (ethylene glycol) (Figs. 151.4 and 151.5). Isopropanol is less clinically consequential, as it is converted by ADH to acetone, which is an end product rather than a substrate of ALDH.

Because ADH preferentially metabolizes ethanol over all other alcohols, no significant metabolism of toxic alcohols will occur while high concentrations of ethanol are present. When ADH is inhibited, the parent compounds are eliminated very slowly without metabolism. In the absence of ADH, ethylene glycol is renally eliminated with a half-life of 8.5 hours while methanol, which is eliminated as a vapor, has a half-life of 30 to 54 hours (76–78).


The initial physical examination may be unremarkable. All of the toxic alcohols can produce significant CNS depression, and a compensatory tachypnea may be present if there is a meta-bolic acidosis. Acetone, generated from ADH metabolism of isopropanol, produces nausea, hypotension, hemorrhagic gas-tritis, and tachycardia, but these are not usually life threatening (79). Formate, a methanol metabolite, can produce blindness

from toxicity to the retina and optic nerve (80). Ethylene gly-col may cause nephrotoxicity in cases where oxalic acid, the primary metabolite, precipitates as calcium oxalate crystals in the renal tubules (81).

H

CH OH

H

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Formaldehyde

CH O

H

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FIgure 151.4 metabolism of methanol. (adapted from wiener Sw. toxic alcohols. in: Flomenbaum ne, goldfrank lr, hoffman rS, et al., eds. Goldfrank’s Toxicologic Emergencies. 8th ed. new york: mcgraw-hill; 2006:1447–1459.)

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FIgure 151.5 metabolism of ethylene glycol. (adapted from wiener Sw. toxic alcohols. in: Flomenbaum ne, goldfrank lr, hoffman rS, et al., eds. Goldfrank’s Toxicologic Emergencies. 8th ed. new york: mcgraw-hill; 2006:1447–1459.)

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Standard laboratory studies can suggest—but not establish or exclude—the diagnosis of toxic alcohol poisoning. Metab-olites of methanol or ethylene glycol may cause an elevated anion gap metabolic acidosis. The hallmark laboratory finding of isopropanol poisoning is ketonemia without acidosis. The osmolar gap, the difference between the measured and unmea-sured osmoles, may be increased when the serum contains toxic alcohol osmoles. A very high osmolar gap does suggest the presence of toxic alcohol, whereas a low or normal gap does not exclude the presence of ethylene glycol or methanol. There is a great population variation in the “normal” osmolar gap, from −10 to 10, such that very high concentrations of toxic alcohols might not be apparent when the gap is calculated (82).

Other tests, such as fluorescence of the urine or the presence of calcium oxalate crystals in the presence of ethylene glycol poisoning, are neither sensitive nor specific (83). Since fluores-cein is added to some brands of ethylene glycol–based anti-freeze in order to facilitate detection of radiator leaks, some authors suggest the use of a Woods lamp to detect urine for fluorescence as a screen for ethylene glycol. However, in one study of a large group of children not exposed to ethylene gly-col, almost all of them had urinary fluorescence (84). Because of the limitations in these laboratory studies, treatment should be started empirically as soon as the diagnosis is considered.

Management

There are several clinical presentations that suggest poisoning with a toxic alcohol, and each requires different management considerations. The first type of patient presents without aci-dosis and either a history of ingesting ethylene glycol or meth-anol or a very elevated osmolar gap. The physician should immediately begin an ADH inhibitor and obtain toxic alcohol concentrations, when available. Later, the decision to con-tinue treatment or begin hemodialysis can be made based on the presence of a toxic alcohol in a high concentration. If the result is not expected in a timely manner, dialysis should be presumptively performed.

The second scenario is the patient who presents with an unexplained elevated anion gap metabolic acidosis that is not explained by the presence of lactate, ketoacids, or uremia. In such cases, the diagnosis should be considered, and ADH inhi-bition and hemodialysis should be instituted. One test that is very helpful in this scenario is a serum ethanol concentration. As long as there is elevated ethanol concentration present in the serum, toxic alcohols cannot be converted into their metabo-lites. Therefore, if a patient has a very elevated ethanol concen-tration, his or her elevated anion gap metabolic acidosis cannot be explained by toxic alcohol poisoning, unless the ethanol was consumed only hours after the ingestion of the toxic alcohol.

If a serum toxic alcohol concentration is available, the diag-nosis can be established rapidly, and management is straightfor-ward. From clinical experience, if the serum concentration of methanol is less than 25 mg/dL (or ethylene glycol <50 mg/dL) and there is no metabolic acidosis, treatment is not necessary. If treatment is required, the clinician must determine whether to use an ADH inhibitor alone or in conjunction with hemo-dialysis. There are two important considerations when deter-mining whether hemodialysis is necessary. The first concern is the presence of toxic metabolites such as formate. Although these metabolites cannot easily be measured directly, the pres-ence of a metabolic acidosis suggests that some of the parent

compound has already been metabolized to a toxic metabolite, and dialysis should be employed. The second consideration is the duration of time needed to eliminate the toxic alcohol without dialysis. The half-life of methanol is approximately 2 days when ADH is inhibited. If the initial serum concentra-tion is 200 mg/dL, about 6 days in an ICU may be necessary to reach a concentration of 25 mg/dL. In contrast, if dialysis were performed, the patient may only require a day of hospitaliza-tion, depending on the reason for ingestion of the alcohol.

The two ADH inhibitors available are fomepizole and etha-nol. While considerably more expensive than ethanol, fomepi-zole is the treatment of choice. Fomepizole is administered by empiric weight–based dosing, while ethanol infusion requires serum concentrations to be obtained frequently. Unlike etha-nol, fomepizole does not cause CNS or respiratory depression. Fomepizole should be given as a 15 mg/kg IV loading dose, followed in 12 hours by 10 mg/kg every 12 hours for 48 hours. If continued dosing is required, the infusion rate should be increased to 15 mg/kg. When fomepizole is unavailable, etha-nol should be given intravenously, or orally if necessary. We recommend a loading dose of ethanol at 0.8 g/kg over 20 to 60 minutes, followed by an initial infusion of 100 mg/kg/hr (85). The goal of ethanol therapy is to maintain an ADH inhibitory concentration of 100 mg/dL. The serum ethanol concentration should be obtained frequently and the rate adjusted accord-ingly. ADH blockade should continue during hemodialysis; fomepizole should be dosed every 4 hours and ethanol should be administered at a rate of 250 to 350 mg/kg/hr (85). Sev-eral hemodialysis sessions may be needed to remove the toxic alcohol, depending on the initial concentration. Symptoms of isopropanol can usually be managed with fluids and support-ive care alone, although rarely, hemodialysis may be indicated.

Folate is a cofactor in the conversion of formic acid to a nontoxic metabolite, and thiamine and pyridoxine assist in transforming toxic metabolites following ethylene glycol poi-soning. Therefore, 1 to 2 mg/kg of folic acid should be given every 4 to 6 hours in the first 24 hours of methanol poisoning, and thiamine hydrochloride (100 mg IM or IV) and pyridox-ine (100 mg/d IV) should be administered for ethylene glycol poisoning. It is reasonable to administer sodium bicarbonate to a target pH of 7.2 to shift the equilibrium from formic acid to the less toxic formate.

cholInergIc poIsonIng

Acetylcholine is the neurotransmitter found throughout the parasympathetic nervous system, in the sympathetic nervous system at the level of the ganglia and sweat glands, and at the neuromuscular junction (Fig. 151.6). The cholinergic syndrome describes the condition of excess acetylcholine characterized by the sum of the parasympathetic, somatic, and sympathetic effects. Cholinergic compounds are used as medications, pesticides, and weapons. In 2013, the AAPCC received reports of 3 fatalities and 13 major effects related to organophosphate and carbamate insecticides (3). The World Health Organization estimates that at least 1 million uninten-tional poisonings and 2 million suicide attempts occur annu-ally worldwide from these insecticides (86).

Acetylcholine is inactivated in the synapse by acetylcho-linesterase (AChE). Inhibition of AChE causes an excess of the neurotransmitter in the synapse. The two most important

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classes of AChE inhibitors are the carbamates and the organic phosphorous compounds. The carbamates inactivate AChE by carbamylation, while the organic phosphorous compounds do so by phosphorylation. The carbamates and organic phos-phorous compounds are both absorbed by ingestion, by inha-lation, and through skin. Organic phosphorous compounds exhibit “aging,” whereby the reversible inhibition of AChE becomes permanent. Aging can take minutes to days, depend-ing on the particular compound. Carbamates, however, spon-taneously hydrolyze from the active site of AChE and do not age. ICU admission is required for those with respiratory com-promise, hemodynamic instability, or the need for administra-tion of large amounts of atropine.


Many of the carbamates have peak concentrations within 40 minutes following ingestion and may be almost completely eliminated from the serum within days (87–89). They are not particularly lipophilic and do not readily cross the blood–brain barrier, resulting in a predominance of peripheral symp-toms (90).

In contrast, after ingestion, peak concentrations of the organic phosphorous compounds have been reported at 6 hours (91). Many of these agents are activated in the liver, resulting in a further delay to peak action. They are also gener-ally very lipophilic and redistribution from fat allows measur-able serum concentrations for up to 48 days (88,89). Their lipophilicity results in the demonstration of both peripheral and CNS clinical effects (90).

Diagnosis is often established by recognition of the mus-carinic signs: salivation, lacrimation, urination, defecation, bradycardia, bronchorrhea, and bronchospasm. Acetylcholine initially acts as an agonist, but in excess becomes an antago-

nist at the neuromuscular junction, producing weakness, fas-ciculations, and paralysis. Simulation of nicotinic receptors at the sympathetic ganglia produces tachycardia and mydriasis.

AChE inhibitor poisoning is a clinical diagnosis. Although red blood cell cholinesterase and butyrylcholinesterase are inhibited by carbamates and organic phosphorous com-pounds, their activity may remain depressed after clinical signs and symptoms have resolved. There may be a clinical role for these tests in mild cases when the diagnosis is unclear. Elec-tromyography (EMG) may be a sensitive indicator of toxicity before clinically apparent symptoms have occurred (92).

Management

The first management priorities involve ensuring a secure air-way and decontaminating the patient’s skin to protect caregiv-ers and prevent further absorption. After initial stabilization, atropine should be administered. The presence of tachycardia is not a contraindication to atropine. The goal of “atropin-ization” is reversal of the muscarinic symptoms. Atropine is titrated to effect the resolution of bronchospasm and bron-chorrhea. The initial dose of 1 mg IV atropine (0.05 mg/kg in children) can be doubled every 2 minutes until muscarinic signs are controlled. There is variation in the amount of atropine required, ranging from one to hundreds of milligrams (89).

If CNS anticholinergic toxicity develops prior to resolu-tion of peripheral muscarinic signs, the peripherally acting antimuscarinic agent, glycopyrrolate, may be given, initially at 1 mg IV and then titrated to symptomatic relief. A com-mon clinical pitfall is to interpret froth from the patient’s mouth as a sign of cardiogenic pulmonary edema and respond with fluid restriction. On the contrary, cholinergic-poisoned patients have large volume losses from diaphoresis and bronchorrhea.

Sympathetic Parasympathetic

ACh

Adrenal medulla

↑ circulatingepinephrine

Skin(diaphoresis) ACh

ACh

CNS• Confusion• Agitation• Hallucinations• Coma• ConvulsionsMydriasisBronchodilationTachydysrhythmiaHypertensionUrinary retentionHyperglycemia

NM

N

NACh

�/�NE

Somatic

AChNeuromuscular junction• Weakness• Fasciculations• Paralysis

CNS• Confusion• Agitation• Coma• SeizuresMiosisLacrimationSalivationBronchorrheaBronchospasmBradydysrhythmia↑ Gl motilityUrinary incontinence

N

NACh

MACh

FIgure 151.6 Sympathetic and parasympathetic nervous system. (adapted from clark rF. insecticides: organic phosphorous compounds and carba-mates. in: Flomenbaum ne, goldfrank lr, hoffman rS, et al., eds. Goldfrank’s Toxicologic Emergencies. 8th ed. new york: mcgraw-hill; 2006:1447–1459.)

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Oximes are used to supplement antimuscarinic therapy. The oximes improve both muscarinic and nicotinic signs, pri-marily by restoring activity to phosphorylated AChE. Since oximes will not restore activity once aging has occurred, they must be administered early in the clinical course of AChE inhibitor poisoning. Oxime therapy is recommended for both organic phosphorous compounds and carbamates because oximes may have salutary effects following carbamate poi-soning and because the toxic agent in question is not always known with certainty. Even in carbaryl poisoning, adequate atropinization overcomes any deleterious effect of pralidox-ime (93). Pralidoxime (2-PAM) is the oxime most frequently available in the United States. Administer 1 to 2 g IV over 30 minutes (20 to 40 mg/kg in children, to a maximum of 2 g). Significant poisoning may require a continuous infu-sion of 500 mg/hr (10 to 20 mg/kg/hr in children, up to adult dose) (94).

Diazepam should be administered to patients severely poi-soned by organic phosphorous compounds. Although human data are not available, animal studies show a survival benefit possibly unrelated to the GABAergic effects of diazepam (95). Because severely poisoned patients will require endotracheal intubation, diazepam can be administered very safely.

Delayed Manifestations

In the acute setting, the physician should be vigilant for recur-rence of cholinergic signs after apparent resolution and for a distinct form of toxicity called the intermediate syndrome. The intermediate syndrome—so called because it occurs after acute, but before delayed, toxicity—may occur 24 to 96 hours after organic phosphorous poisoning and consists of upper body weakness, cranial nerve palsies, and areflexia. The syn-drome appears to be self-limited, but can last up to 30 days and be severe enough to require intubation (96,97). We recom-mend continuing pralidoxime infusion at 500 mg/hr when this diagnosis is considered.

Delayed toxicity may occur days after apparent resolution of symptoms due to redistribution of the agent from fat stores. Discharge can be considered when the patient has been asymp-tomatic without additional treatment for 1 to 2 days (98).

cyAnIde poIsonIng

Cyanide salts are widely available and may be used in suicidal or homicidal poisoning. Because jewelers, laboratory workers, and industrial workers often have ready access to cyanide, a relationship to these industries may be an important historical clue. Cyanide poisoning should also be considered in all fire victims, as it is released when certain synthetic and natural fibers undergo combustion.

Cyanide poisoning most frequently occurs after the inges-tion of a cyanide salt or inhalation of the gas hydrogen cyanide. In both forms, cyanide is rapidly absorbed. The most important toxic effect of cyanide is inhibition of cytochrome oxidase in the electron transport chain (99). Despite the presence of oxy-gen, cells cannot offload electrons from nicotinamide adenine dinucleotide (NADH) to oxygen, and generate ATP, resulting in anaerobic metabolism and producing lactic acid. Small quanti-ties of cyanide are detoxified by the enzyme, rhodanese, which catalyzes the transfer of sulfur from thiosulfate, yielding thio-

cyanate. Poisoning results when this system is overwhelmed by large concentrations of cyanide.


The history may be very helpful in establishing the diagno-sis. Cyanide should be considered in anyone who rapidly loses consciousness after ingestion or inhalational exposure. Signs and symptoms resemble those of hypoxia: headache, lethargy, seizures, and coma in the absence of cyanosis.

Management

Cyanide poisoning requires treatment before laboratory con-firmation is available, so treatment must be instituted based on clinical suspicion. As soon as cyanide poisoning is considered, 100% oxygen should be administered, IV access established, and fluids given. The remainder of treatment depends on the route of exposure.

Because the symptoms of cyanide poisoning are similar to those associated with hypovolemia or carbon monoxide poi-soning, the diagnosis is difficult to establish with certainty. Laboratory studies will show a lactic acidosis. In one series, a plasma lactate concentration more than 8 mmol/L in patients with clinical suspicion of poisoning was 94% sensitive and 70% specific for cyanide toxicity (100). An older cyanide anti-dote kit consisted of amyl nitrite, sodium nitrite, and sodium thiosulfate. Sodium thiosulfate, the final component of the kit, functions by providing substrate to rhodanese, facilitat-ing conversion of cyanide to thiocyanate. The dose is 50 mL in adults and 1.65 mL/kg in children, and the drug may be repeated in 2 hours at half the initial dose if symptoms per-sist. Hydroxocobalamin is largely replacing the older kit as the antitode of choice in cyanide poisoning. Hydroxocobala-min combines with cyanide to form cyanocobalamin (vitamin B12) (101). In animal models, it has synergism with thiosulfate (102). Hydroxocobalamin should be given IV at 70 mg/kg (to a maximum of 5 g) in a separate infusion site from thiosulfate.

cyAnIde, ThIocyAnATe, And nITroprussIde

Nitroprusside contains an iron molecule coordinated to five cyanide molecules and one nitric oxide. Cyanide molecules are slowly liberated after nitroprusside is infused, but usually at a rate that can be detoxified by endogenous pathways. Risk fac-tors for accumulation of cyanide are prolonged infusion, high infusion rate, and poor nourishment. If the diagnosis is sus-pected, the infusion should be discontinued and hydroxocobal-amin and thiosulfate administered. A more likely complication of nitroprusside use is thiocyanate toxicity. Thiocyanate, which does not cause any symptoms at low concentrations, is cleared renally. Bioaccumulation occurs in patients with impaired renal function, causing delirium, hallucinations, seizures, and rash. In patients receiving more than 2 μg/kg/min of nitroprusside, and in those with renal insufficiency, serum thiocyanate concentra-tions should be checked after 48 to 72 hours of infusion. The infusion should be discontinued if the thiocyanate concentra-tion is more than 10 mg/dL (103). Dialysis can be effective for thiocyanate accumulation, but should be reserved for only the most severely compromised patients (104).

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meThemogloBInemIA

Methemoglobinemia results from the formation of dyshemo-globin, which is caused by inappropriate oxidation of heme iron. Under normal conditions, iron in deoxyhemoglobin remains in the reduced ferrous state, Fe2+, and the heme is available to bind oxygen. After oxygen binds, iron assumes the oxidized ferric state, Fe3+. Methemoglobin, which is normally formed in small quantities, is seen when a hemoglobin iron moiety is exposed to oxidative stress and converted to the ferric state in the absence of binding oxygen. Methemoglobin is unable to bind oxygen and increases the affinity of normal hemoglobin for oxygen. Thus, the result of methemoglobin formation is decreased oxygen delivery and a leftward shift in the oxygen dissocia-tion curve. Due to the physiologic systems available to reduce methemoglobin to functional hemoglobin, low-level methe-moglobin production may be a protective mechanism against oxidant damage to erythrocytes. The most important mecha-nism of methemoglobin reduction is catalyzed by the enzyme, methemoglobin reductase (cytochrome b5 reductase), using NADH generated from the Embden–Meyerhof glycolytic path-way. Congenital methemoglobinemia is a rare condition caused by methemoglobin reductase deficiency (105). This enzyme is also relatively deficient until approximately 4 months, making infants prone to methemoglobin formation (106).

Most individuals with methemoglobinemia can be treated and discharged from the emergency department. Patients with methemoglobinemia may require ICU admission when it recurs following initial treatment, either from continued absorption of an inducer or continued metabolism of a drug to a methemoglobin inducer.


Although the diagnosis of methemoglobinemia is commonly confirmed by co-oximetry, it can be established presump-tively based on symptoms and signs, and via pulse oximetry. Symptoms of methemoglobinemia are those associated with hypoxia. The severity of symptoms is determined by the con-centration of methemoglobin and the patient’s underlying comorbidities. At low concentrations of methemoglobin (0% to 15%), patients may be asymptomatic, and as concentra-tions rise (20% to 50%), patients may manifest decreased exercise tolerance and dyspnea. At higher concentrations (50% to 70%), metabolic acidosis, seizures, and coma result. Concentrations greater than 60% or 70% can cause death in previously healthy individuals (107).

Pulse oximetry aids in diagnosis before co-oximetry has been obtained. Methemoglobin interferes with pulse oximetry in a somewhat predictable manner (108). Pulse oximetry reads absorbance of light at two wavelengths (660 and 940 nm), so chosen because they are the best to distinguish the absorp-tion spectra of oxyhemoglobin and deoxyhemoglobin. Based on the ratio of absorption between the two wavelengths, the pulse oximeter uses an algorithm to estimate the percentage of total hemoglobin as oxyhemoglobin. Methemoglobin, however, has greater absorption than either oxyhemoglobin or deoxyhemoglobin at those wavelengths. When it is present in modest concentrations, the pulse oximeter will no longer be able to meaningfully calculate oxygen saturation. In a dog model, increasing methemoglobin concentrations caused the

pulse oximeter oxygen saturation (SpO2) to decrease and then plateau at 84% to 86%. In the clinical setting, methemoglobin does not produce this straightforward plateau in SpO2, but does consistently generate readings between 70% and 90% (107). The oxygen saturation derived from the arterial blood gas analysis is not measured in the same fashion as SpO2, and will not reflect the methemoglobin concentration. The oxygen saturation from an arterial blood gas analysis is a calculated saturation based on the PaO2, and should be normal in the setting of methemoglobinemia. A difference between the SpO2 and arterial blood gas–calculated oxygen saturation may sug-gest methemoglobinemia.

Methemoglobin Inducers

Acquired methemoglobinemia is most frequently seen after exposure to a drug, although it can also be found in infants without drug exposure who are ill with a metabolic acidosis or diarrhea (109,110). The drugs that have been associated with methemoglobin formation are extensive. Dapsone, nitrites, nitrates, benzocaine, and sulfonamides are consistently implicated in producing methemoglobinemia (Table 151.5) (111). It is not entirely clear why some individuals develop methemoglobinemia after exposure to these drugs and others

TABLE 151.5 Common Causes of Methemoglobinemia

HEREDITARY•hemoglobin m•cytochrome b5 reductase deficiency

ACQUIRED•Medications

• amyl nitrate• benzocaine• dapsone• lidocaine• nitric oxide• nitroglycerin• Phenacetin• Phenazopyridine• Prilocaine• Quinones• Sulfonamides

•Other xenobiotics• aniline dye derivatives• butyl nitrite• chlorobenzene• Fire• Food adulterated with nitrites• Food high in nitrates• isobutyl nitrite• naphthalene;• nitrate• nitrite• nitrophenol• nitrous gases• Silver nitrate• trinitrotoluene• well water (nitrates)

PEDIATRIC•reduced nadh methemoglobin reductase activity in infants

(<4 months of age)•associated with low birth weight, prematurity, dehydration,

acidosis, diarrhea, and hyperchloremia

adapted from Price d. methemoglobin inducers. in: Flomenbaum ne, goldfrank lr, hoffman rS, et al, eds. Goldfrank’s Toxicologic Emergencies. 8th ed. new york, ny: mcgraw-hill; 2006:1734–1745.

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do not. Although there is clearly a dose–response effect, host factors such as coexisting medical illness and metabolic vari-ables play a role in methemoglobin development.

Management

When cyanosis is recognized and methemoglobinemia is con-sidered, administer 100% oxygen by nonrebreather mask. Unless the patient is asymptomatic, methylene blue should be administered intravenously, 1 to 2 mg/kg over 5 minutes. Methylene is reduced by nicotinamide adenine dinucleotide phosphate (NADPH) to leukomethylene blue. Leukometh-ylene blue, in turn, reduces methemoglobin to hemoglo-bin. Clinical improvement should be seen within minutes of administration. Because the medication itself has a blue color, oxygen saturation reported by pulse oximetry may transiently worsen. A repeat dose of methylene blue may be required if the methemoglobin concentration is high or if there is ongoing oxidative stress.

Some authors recommend against giving methylene blue, an oxidizing agent, to individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Patients with this condi-tion suffer from hemolytic anemia when exposed to drugs that create oxidative stress. Because G6PD is required to activate methylene blue, a deficiency in the enzyme may lead to a lack of efficacy of the antidote. The administration of methylene blue is appropriate when clinically indicated unless there is a strong history of G6PD deficiency. In such cases, hyperbaric oxygen (HBO) or exchange transfusion should be considered. If the G6PD-deficient patient presents with severe methemo-globinemia, methylene blue should be administered and the patient monitored closely for hemolysis.

Both dapsone and its hydroxylamine metabolites are responsible for methemoglobin formation. The cytochrome P450 conversion of dapsone to these metabolites is inhibited by cimetidine (112). Cimetidine should be administered intra-venously, 300 mg every 6 hours, to patients with dapsone-induced methemoglobinemia.

cArBon monoxIde poIsonIng

In their latest annual report, the AAPCC received more than 14,289 reports of carbon monoxide (CO) exposure, including 157 major effects and 60 fatalities (3). These figures, while very concerning, underestimate morbidity and mortality from carbon monoxide, which is considered the leading cause of poisoning death in the United States. Carbon monoxide results from the incomplete combustion of carbonaceous fuels and is tasteless, odorless, and colorless. The initial clue to the pres-ence of CO in the home may be the alarm from a CO detector. During natural disasters, when electricity is unavailable, peo-ple may use generators indoors, allowing CO from exhaust to permeate the home. Even when a home heater is used appropri-ately, it can lead to CO poisoning if the outflow is obstructed. In automobiles, a functioning catalytic converter minimizes the release of CO. Other internal combustion engines, such as lawnmowers, Zambonis, and outboard motors on boats, do not usually have catalytic converters and can cause CO poi-soning. Methylene chloride, an important source of CO that is not a product of combustion, is hepatically metabolized to CO by the liver. Methylene chloride is used as a paint stripper

and can be absorbed dermally, inhalationally, or by ingestion (113). Unlike other sources of CO poisoning, where carboxy-hemoglobin begins to decline as soon as the patient is removed from the exposure, peak carboxyhemoglobin concentration will occur hours after exposure to methylene chloride as the parent compound is metabolized to CO.

Carbon monoxide is a hemotoxin, a neurotoxin, a cardiac toxin, and an inhibitor of cytochrome oxidase. It binds to hemoglobin with greater affinity than oxygen, and causes a leftward shift of the oxyhemoglobin dissociation curve, caus-ing a decrease in delivery of oxygen to cells. Although the formation of carboxyhemoglobin can impair oxygen delivery sufficiently to cause mortality, inhibition of oxygen delivery alone does not fully explain why carboxyhemoglobin concen-trations of 50% are often fatal whereas a similar degree of anemia might be well tolerated. The formation of carboxy-hemoglobin is inadequate to explain the chronic cardiac and neurologic sequelae of CO. Carbon monoxide inhibition of cytochrome oxidase persists for days after carboxyhemoglo-bin concentration has normalized (114) and is associated with damage to the brain endothelium, resulting in lipid peroxida-tion (115,116). It also binds to myoglobin with high affinity, making it a direct skeletal and cardiac muscle toxin (117).

CO poisoning does not usually require ICU admission; this is only necessary for patients who are comatose or obtunded, those with signs of cardiotoxicity, and those with significant burns or other comorbidities.


Initially, patients complain of headache, nausea, and dizziness. Because of the vague nature of the complaints, CO poisoning may be misdiagnosed as a viral illness. The diagnosis should be considered when more than one person in a home presents with the same symptoms. Alteration in mental status, coma, seizures, and syncope are signs of severe poisoning. Indicators of tissue hypoxia, such as tachypnea, tachycardia, and ECG changes, may be seen as well. Carbon monoxide can cause dysrhythmias or an acute MI (118); the intensity of signs and symptoms is related to the duration and severity of exposure, and comorbid conditions. Pulse oximetry will interpret car-boxyhemoglobin as hemoglobin, so the SpO2 will be falsely normal (119). For those who survive an acute CO exposure, there may be significant chronic neurologic and cardiovascular effects. Delayed neurologic sequelae (DNS) follow the resolu-tion of initial symptoms, sometimes days to weeks later, and include dementia, movement disorders, and memory impair-ment (120).

Diagnosis

The diagnosis of CO poisoning is aided by obtaining the car-boxyhemoglobin concentration, which can be taken from either a venous or arterial sample. The normal carboxyhemo-globin concentration is less than 5%, but smokers may have a concentration of up to 10% (121). Carboxyhemoglobin con-centrations are an indicator of exposure, but do not correlate with the degree of toxicity (122). When there is a delay from exposure to measurement of carboxyhemoglobin, the concen-tration loses further value as a clinical tool. This is more likely if the patient has been receiving supplemental oxygen, which decreases the half-life of carboxyhemoglobin.

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In patients with chest pain, shortness of breath, palpi-tations, or neurologic deficits indicating severe exposure, an ECG should be performed and serum cardiac markers obtained. Pregnancy status should be determined in women of childbearing age. Elevated serum cardiac markers during moderate and severe acute toxicity predict long-term mortality (123). The pathophysiology of chronic cardiovascular effects of carbon monoxide poisoning probably involves CO poison-ing of cardiac myoglobin, but needs further study.

Within 12 hours of exposure, changes on a computed tomography (CT) scan of the brain may be seen. Characteristic findings include symmetric, low-density changes in the globus pallidus, putamen, and caudate nuclei (124). A normal CT scan is a good prognostic indicator. In a series of 18 patients, a negative CT within 1 week of admission was associated with good outcome (125).

Management

As soon as the diagnosis is considered, the patient should be administered 100% oxygen, and the carboxyhemoglobin con-centration should be obtained. Without supplemental oxygen, studies have found that the half-life of carboxyhemoglobin in blood is 4 to 6 hours. With oxygen, it has been noted to range from 1 to 2 hours (126). Thus, oxygen is the mainstay of therapy in CO poisoning. When considering pregnant women exposed to CO, any disturbance in maternal oxygen deliv-ery will be magnified in the fetus as fetal circulation relies on maternal oxyhemoglobin for oxygenation. Even though fetal hemoglobin has less affinity for CO than adult hemoglobin, there is a high incidence of fetal CNS damage and sponta-neous abortion after severe maternal poisoning (127,128). In contrast, pregnant women who have lesser exposures have normal pregnancies and deliver healthy children (129). We recommend treating these patients similarly to those who are not pregnant.

Controversies

The use of HBO for CO poisoning is controversial. Many clini-cians do not advocate its use. Whereas the animal data and case series suggest a benefit, large randomized clinical trials report mixed results. Some trials show a benefit for HBO in prevent-ing neurologic sequelae, and some do not indicate any differ-ence (for a detailed review of the literature, see Tomaszewski et al. [126]). While HBO decreases CO half-life faster than 100% normobaric oxygen, this is not a clinically important objective. Most patients who are brought to a hospital will sur-vive whether or not they receive HBO; its reported value is in its potential to decrease morbidity, not mortality. Specifically, it may reduce DNS. In animal models, HBO prevents brain lipid peroxidation and regenerates CNS cytochrome oxidase after CO exposure (130,131).

All of the trials conducted to date have limitations, and the ideal trial may never be performed because of the ethical concerns of randomizing patients to nonhyperbaric therapy. In light of the demonstrable benefit of HBO and the relative safety of the therapy, we recommend HBO in patients with moderate to severe poisoning. The patient should receive the therapy as early as safely possible; in one series, a delay greater than 6 hours was associated with a worse outcome (132). The following are indications for HBO: (a) syncope,

coma, seizure, or any other hard neurologic findings; (b) signs of cardiac ischemia or dysrhythmias; and (c) carboxyhemoglo-bin greater than 20%. Because all prospective trials of HBO have excluded pregnant women, the literature is not clear as to whether this population would benefit from the therapy.

cAusTIc IngesTIon

Caustics are chemicals that produce damage during contact with tissues. They are generally acid or alkali, and are com-mercially available as toilet bowl cleaners, drain cleaners, and other products. There are myriad caustics available in both the home and work environment. Commonly encoun-tered alkalis include ammonium hydroxide (ammonia) and sodium hydroxide (lye, found in drain cleaners). Hydrochloric acid and sulfuric acid are both used as drain cleaners, with the latter used in automobile batteries as well. Alkali drain cleaners accounted for more than 2,797 reported exposures in 2013, more than any other caustic chemical. Of these, 37 were major and 2 fatal (3). The amount of damage caused by caustics is determined by pH, quantity, duration of contact, and the titratable alkaline (or acid) reserve (TAR). Ingested caustics can potentially produce damage to the oropharynx, esophagus, stomach, and respiratory tract. Acid and alkali produce different types of injury. Alkaline exposure produces dissociated OH− ion, resulting in fat saponification, membrane dissolution, and cell death—a process known as liquefactive necrosis (133). Acid exposure releases H+ ions, producing an eschar and desiccation, a process referred to as coagulation necrosis. Both acid and alkali produce stomach and esopha-geal injury (134).

Esophageal burns can be described by the following com-monly used classification system (135,136). Grade I burns demonstrate hyperemia without ulceration; grade II burns demonstrate ulcers, but do not damage periesophageal tissues; grade II lesions are subdivided into IIa (noncircumferential) and IIb (circumferential) lesions; and grade III describes burns with deep ulceration and damage to surrounding tissues. The classification of the burn predicts chronic sequelae; grade IIb and III injuries may heal with strictures and dysphagia, and may perforate. When esophageal perforation is suspected, or when there is airway injury, patients should be admitted to the ICU.


The lack of oral burns does not exclude significant esophageal injury, nor does the presence of oral lesions guarantee visceral burns. The physical examination following caustic ingestion can be deceiving. A series of pediatric patients found visceral burns in 37.5% of patients without oral burns and 50% of patients with oral burns (137). Drooling, odynophagia, and abdominal pain are common findings following significant caustic exposure. However, a series of acid ingestions noted abdominal pain or tenderness in less than half of patients with gastric injury (134).

Pulmonary aspiration may lead to coughing and respira-tory distress. Absorption of acid from the stomach may cause acidemia following ingestion. Alkalis are not systemically absorbed in consequential amounts, but a metabolic acidosis may be present if significant injury has occurred.

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Management

Endoscopy should be performed in all adult patients presumed to have significant exposures in order to establish the sever-ity of the burn. If endoscopy is normal, the patient can be safely discharged, while patients with severe injury are rapidly stabilized and referred for surgical care before their condition worsens. Endoscopy should be performed as early as possi-ble, ideally within 12 hours. Wound strength is the weakest between 5 days and 2 weeks postingestion, when the perfora-tion risk is the greatest. The exception to universal endoscopy may be a subset of pediatric exposures based upon a series of 79 patients younger than 20 years of age when no serious esophageal injuries were found in patients who lacked stridor or the combination of vomiting and drooling (138). Another group of investigators found no lesions in asymptomatic pedi-atric patients (139).

The presence of endoscopic evidence of perforation man-dates immediate surgery. Other indications for operative repair include pleural effusions, ascites, and a serum pH less than 7.2 (140). If endoscopy demonstrates grade I injury, the patient can be started on a soft diet and the diet advanced as tolerated. The presence of grade II esophageal burns with gastric sparing warrants placement of a nasogastric tube under direct visualization. More severe injury may require parenteral nutrition or a jejunostomy. Silicone rubber esophageal stents have been used to prevent stricture (141).

Administer antibiotics that cover anaerobic bacteria and gram-positive and gram-negative aerobic organisms as soon as perforation is considered. Piperacillin/tazobactam is an appropriate choice, as is levofloxacin and clindamycin. Cor-ticosteroids have been recommended to help prevent scar-ring and stricture formation in grade II lesions; randomized controlled trials have provided conflicting results. A recent meta-analysis could not find a benefit for the administration of corticosteroids following exposure to caustics (142).

hydroFluorIc AcId exposure

HF is a weak acid with important tissue-corrosive proper-ties. HF and ammonium bifluoride have numerous industrial uses. HF dissolves metal oxides and glass, making it useful in rust removal and glass etching. It penetrates deeply into tissues before dissociating into protons and fluoride ions. Although the protons cause some damage, the most important toxic effects result from fluoride ions binding the divalent cations calcium and magnesium (143). The consumption of these cat-ions leads to neuropathic pain and cell death. HF ingestions and exposures resulting in electrolyte abnormalities require ICU admission.


HF produces a clinical syndrome distinct from the caustic agents and requires specific therapy. In small dermal expo-sures, HF produces severe pain with limited dermal findings. Large exposures by any route, including dermal, can produce severe hypocalcemia and death.

Most unintentional HF exposures are dermal. The severity of the exposure is determined by the duration of exposure, concentration, and extent of surface area exposed. Solutions

with low fluoride concentration may cause severe pain begin-ning hours after the exposure, with a very unremarkable physical examination. An area that appears normal or merely mildly erythematous may be extremely painful. High-concen-tration industrial preparations may cause immediate pain, with hyperemia and ulceration (144). Similarly, ophthalmic exposures result in pain, chemosis, and damage to conjunctiva and corneal epithelium (145).

The most consequential effects of HF poisoning are sys-temic. Systemic toxicity can result from ingestions or dermal exposures. Dermal exposures to concentrated HF covering as little as 2.5% body surface area have resulted in systemic toxicity, although typical fatal dermal exposures are larger (146,147). Fluoride ions scavenge divalent cations, causing life-threatening hypocalcemia and hypomagnesemia. Hyper-kalemia may be seen as well (148). The ECG may reflect these electrolyte abnormalities. Lengthening of the QRS and QT intervals or presence of peaked T waves may be early indica-tors of toxicity. The proximal cause of death is usually dys-rhythmias; ventricular fibrillation and sudden cardiac arrest have been described (149,150).

Management

The most important concern in small dermal injuries is pain control. The mainstay of therapy is calcium gluconate. The calcium derives its efficacy from binding fluoride ions. Cal-cium chloride should only be used topically. Other analgesics and regional anesthesia are not contraindicated, but calcium has the advantage of halting tissue damage in addition to pro-viding pain relief. Following decontamination with water, cal-cium gluconate gel should be applied to the injured area. If the hands are involved, the gel can be held in contact by placing it in a sterile glove and putting the glove on the hand. Prepare the gel by mixing 25 mL of 10% calcium gluconate in 75 mL of water-based lubricant (151). If the wound is located in an area where compartment syndrome is not a concern, 0.5% calcium gluconate can be injected intradermally, 0.5 mL/cm2 (147). If these techniques fail to give relief, consider intra-arte-rial calcium gluconate. The obvious advantage of this route is that calcium can be administered directly and by continu-ous infusion to the affected area. Add 10 mL of 10% calcium chloride to 40 mL of 0.9% sodium chloride and infuse over 4 hours (152). In the case of ingestion, a nasogastric tube should be carefully placed and any material in the stomach should be aspirated and followed by instillation of a calcium solution. The benefits of this practice are not established, but it seems reasonable in view of the severity of the ingestion and the

relative safety of the intervention.IV calcium and magnesium should be given liberally, and

electrolytes should be obtained hourly. Calcium can be admin-istered as calcium gluconate or calcium chloride. One gram of calcium gluconate contains 4.5 mEq of elemental calcium, and 1 g of calcium chloride contains 13.6 mEq. Both calcium salts can produce vasodilation and dysrhythmias when adminis-tered too quickly. IV calcium should be administered no faster than 0.7 to 1.8 mEq/min (153). One patient required 267 mEq of calcium over 24 hours (154,155). Dysrhythmias should be expected in severely poisoned patients. Place defibrillator pads on the patient and perform continuous cardiac monitoring. When systemic toxicity occurs, electrolyte abnormalities are most severe in the first several hours of toxicity. Those who

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have no signs or symptoms of systemic toxicity for 24 hours can be transferred to a lower level of care.

AnTIdIABeTIc AgenT exposure

Diabetes is characterized by an inability to maintain normal blood glucose concentration due to deficiency of insulin, resis-tance to insulin, or a combination of both. The medications used to treat diabetes are collectively known as antidiabetic agents, while a subset of these drugs are properly called hypo-glycemic agents. The hypoglycemics include insulin and those drugs that promote the release of endogenous insulin. In 2013, the AAPCC received reports of 12,179 exposures to sulfonyl-ureas and biguanides, including 68 major exposures and 12 deaths (3).

The sulfonylureas, meglitinides, and thiazolidinediones are very highly protein bound, and thus not amenable to extracor-poreal removal. Insulin and metformin are completely renally eliminated, while most of the sulfonylureas have active hepatic metabolites with urinary excretion of both active metabolites and the parent drug. By far, the most important pharmacoki-netic parameter of the hypoglycemics is duration of action, which may be greatly increased in overdose. Insulin is available in multiple forms. In therapeutic subcutaneous doses, Lispro has onset of action within an hour and duration of action of less than 5 hours. Ultralente insulin, the longest-acting insulin commonly used, does not take effect for 4 to 6 hours but lasts as long as 36 hours (156). Regular insulin, lente, and NPH fall in between Lispro and Ultralente insulin. In overdose, the formation of depots of the drug in tissues can slow release and greatly prolong the duration of action. The vascularity of the site of injection will also influence the duration of hypoglyce-mia. The sulfonylureas generally have a duration of action of 12 to 24 hours in therapeutic doses. Chlorpropamide, a first-generation sulfonylurea, may promote insulin release for up to 72 hours (157). Meglitinides, intended to prevent postprandial hyperglycemia, induce insulin release for only 1 to 4 hours. There are not yet enough data on their pharmacokinetics in overdose, but it appears likely that duration of action would be increased in overdose.


The most important signs and symptoms of the aptly classified hypoglycemics are manifestations of decreased serum glucose. In one study, the serum glucose threshold for symptoms of hypoglycemia was 78 mg/dL in poorly controlled diabetics and 53 mg/dL in nondiabetics (158). Manifestations of hypo-glycemia can be classified as either autonomic or neuroglyco-penic. The former result from an increase in counterregulatory hormones (e.g., epinephrine), while the latter are due to a lack of glucose substrate available for the brain. The autonomic symptoms include tremor, diaphoresis, hunger, and nausea. Neuroglycopenic features of hypoglycemia can manifest as almost any conceivable neurologic deficit, including coma, agitation, seizure, hemiplegia, or mild confusion. Typically, the autonomic symptoms precede neuroglycopenic symptoms, thereby serving as a warning of hypoglycemia before the brain is deprived of a critical level of glucose. However, the auto-nomic symptoms may be blunted or absent in diabetics or patients taking β-adrenergic antagonists (159). The onset and

duration of hypoglycemia is unpredictable after overdose. Of less clinical importance, the hypoglycemics can also produce electrolyte abnormalities such as hypokalemia, hypomagnese-mia, and hypophosphatemia (160). These are reported more frequently in very large insulin overdoses (161).

Metformin does not produce hypoglycemia itself, but is often formulated with drugs that do, such as glipizide or gly-buride. Metformin and its biguanide predecessor, phenformin, are associated with lactic acidosis. The biguanides promote anaerobic metabolism and inhibit lactate metabolism (162). Lactic acidosis is rare, but is more likely in the setting of liver disease, renal insufficiency, heart failure, other acute illness, or acute overdose (163,164). Hepatotoxicity is reported from the therapeutic use of thiazolidinediones and acarbose, but there are limited data on acute overdose of these drugs (165,166).

Management

A rapid bedside serum glucose concentration should be obtained as soon as hypoglycemia is considered. If the diagno-sis of hypoglycemia is established, 1-g/kg IV dextrose should be given. Because high concentrations of dextrose can be irri-tating, children should receive 25% dextrose solution and infants 10% dextrose solution. As soon as a normal mental status is restored, the patient should be fed. Each 50-mL vial of 50% dextrose supplies 100 kcal of short-lived simple carbohy-drate. In contrast, a meal will supply hundreds of “sustained-release” kilocalories. Glucagon should not be administered unless IV access is delayed and the patient cannot be fed. Glu-cagon will not be effective in patients with depleted glycogen stores.

If hypoglycemia recurs after it is initially corrected, the treatment is determined by the causative agent. Recurrent insulin-induced hypoglycemia should be treated with a dex-trose infusion. Administer a 10% to 20% solution and titrate to maintain glucose in a normal range; a 5% dextrose solution is inappropriate for glucose maintenance.

Octreotide, a somatostatin analogue, is indicated for hypo-glycemia following sulfonylurea use. Octreotide should be given subcutaneously, 50 μg every 6 hours (4 to 5 μg/kg/d in divided doses in children). Dextrose alone might not be sufficient to manage sulfonylurea-induced hypoglycemia. Because sulfonyl-ureas potentiate endogenous β-islet cell insulin release, supple-mental dextrose will induce more insulin release, with transient corrections and subsequent recurrence of hypoglycemia. Octreotide inhibits the β-islet cell calcium channel, inhibiting sulfonylurea-induced insulin release (167,168). There are no significant adverse effects of short-term octreotide use. Octreo-tide should be continued for 24 hours. After octreotide is dis-continued, the patient should be observed for 24 hours. There are limited data in the literature regarding meglitinide toxicity. With a mechanism of action similar to the sulfonylureas, the meglitinides are shorter acting. Based on their shorter duration of action, we would expect they would be less likely to produce recurrent hypoglycemia, but we have no data to support this assumption. Until we have more experience with overdose of these drugs, it is prudent to manage meglitinide overdose simi-larly to sulfonylureas.

Metformin-associated lactic acidosis should be considered in patients taking an overdose of metformin, children exposed to more than one or two tablets, and those patients who take metformin therapeutically who also have renal insufficiency,

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hepatic insufficiency, heart failure, or another acute illness. The diagnosis is established by obtaining serum chemistry, lactate concentration, and serum pH. The primary therapy is supportive. Although the role of bicarbonate in metformin-associated lactic acidosis is unclear, supplemental bicarbonate should be used to maintain the pH above 7.1. Although met-formin is highly protein bound, hemodialysis can be used to correct refractory acidosis (169).

Adults who present with a history of sulfonylurea over-dose and children who may have been exposed to sulfonyl-ureas should be observed for 24 hours, even in the absence of hypoglycemia. Similarly, patients who present with hypoglyce-mia from long-acting forms of insulin should be observed for 24 hours as well.

nATurAl ToxIns

This brief discussion focuses on a few important plants that might necessitate intensive care management. In 2013, there were 48 reported major outcomes and 2 deaths resulting from plant exposure (3).

Belladonna Alkaloids

Plants such as jimsonweed (Datura stramonium) contain numerous anticholinergic compounds. They are used rec-reationally, often in the form of teas, for their hallucinatory effects. Toxicity is identified by the presence of anticholiner-gic symptoms: tachycardia; hyperthermia; dry, flushed skin; urinary retention; and agitation. One hundred jimsonweed seeds contain nearly 6 mg of atropine and similar alkaloids (170). In addition to supportive care, physostigmine can be given when the diagnosis is relatively certain. Physostigmine is administered 1 to 2 mg IV slowly over 5 minutes, and should be discontinued and the diagnosis reconsidered if cholinergic symptoms develop. If there is improvement or no change in the patient’s condition, physostigmine can be readministered after a 10- or 15-minute delay.

Nicotine and Nicotine-Like Alkaloids

Nicotine poisoning occurs from inhaled, transdermal, and ingested nicotine. A dose of 1 mg/kg can be lethal in an adult (171). A cigarette contains 13 to 30 mg of nicotine, but most of it is not delivered to the smoker when the cigarette is used as intended. The largest portion of the nicotine is pyrolyzed but not inhaled. As much as 5 to 7 mg of nicotine remains in the cigarette butt, a potentially lethal dose for a child (172). Workers handling tobacco can be poisoned from nicotine as well (173). Signs and symptoms of nicotine toxicity result from activation and then inhibition (from overstimulation) of nicotinic receptors. Gastrointestinal signs include nausea, vomiting, and diarrhea. Early cardiovascular toxicity involves hypertension from nicotinic stimulation of the sympathetic ganglia, but hypotension eventually occurs. The most impor-tant signs and symptoms result from nicotinic agonist effects at the neuromuscular junction. Early toxicity causes fascicula-tion, which gives way to paralysis. Management is supportive. Vasoactive agents may be necessary to maintain blood pres-sure, and intubation may be indicated to support respiration during paralysis.

Cicutoxin

Cicutoxin is found in Cicuta spp. such as water hemlock. The toxin is found throughout the plant, which is often eaten by adults who misidentify it as wild parsley, turnip, or parsnip (174). The mechanism of cicutoxin poisoning is unclear. Early symptoms are primarily gastrointestinal and begin soon after ingestion. Later, cicutoxin can cause status epilepticus, renal failure, and rhabdomyolysis (175).

Sodium Channel–Altering Plants

Aconitine, from Aconitum spp., opens sodium channels, increas-ing cellular excitability (174,176). Increased sodium influx delays repolarization, which in turn delays conduction. Slow conduction of peripheral nerves can lead to decreased sensa-tion, weakness, paralysis, and CNS seizures. Vagal and cardiac myocyte sodium channel effects lead to bradycardia, AV block-ade, increased automaticity, or asystole. Aconitine is found in Aconitum napellus (monkshood) and Chinese herbal remedies. Management is supportive; gastrointestinal decontamination should be performed. Cardiac complications have been success-fully managed with a ventricular assist device (177).

Mushrooms

Thirty-one major outcomes and one death from mushroom ingestions were reported to poison control centers in 2013 (3). The vast majority of mushroom exposures do not result in significant morbidity, and most of the fatalities that occur are caused by only a few of the many mushroom species in North America. Identification of mushrooms is challenging and best left to the mycologist. However, because each of the clinically important toxic mushrooms causes a distinct clinical syn-drome, the physician should be able to identify the toxicologic manifestations of several mushrooms. Mushroom toxins have been divided into 10 groups (178). We will discuss the most common exposures and those most likely to require ICU care.

Gastrointestinal Toxin–Containing Mushrooms

Most reported exposures are to mushrooms containing gas-trointestinal toxins. Hundreds of types of mushrooms fall into this category. The most notable clinical feature of ingestion of these mushrooms is the development of vomiting and diarrhea within several hours of ingestion. With few exceptions, mush-rooms that cause gastrointestinal symptoms within 6 hours belong to this category and will not cause life-threatening symptoms. The early onset of vomiting following exposure to gastrointestinal toxin–containing mushrooms clinically differ-entiates them from the cyclopeptide-containing mushrooms. Treatment of exposure to these mushrooms is supportive, and symptoms are generally self-limited. These mushrooms rarely lead to toxicity requiring ICU admission.

Cyclopeptide-Containing Mushrooms

Historically, mortality from these mushrooms is high, although improvements in critical care have improved the prognosis. The most prominent member of this group is Amanita phal-loides and other Amanita species. Amanita phalloides contains numerous cyclopeptides, but the most important are a group called the amatoxins. Amatoxins are heat stable and present in lethal concentrations in mushrooms as small as 20 g (178).

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Amatoxins cause endocrine, renal, and CNS injury, but the hepatic effects are the most consequential. Patients will be asymptomatic for the first few hours after ingestion, pro-gressing in 5 to 24 hours to watery diarrhea. Hepatic toxic-ity is evident on day 2 with elevations in bilirubin, AST, and ALT; signs of fulminant hepatic failure such as encephalopa-thy and coagulopathy follow. Hypoglycemia results not just from hepatic failure, but from direct pancreatic toxicity (179). Cyclopeptides may also cause decreased levels of thyroid hor-mone and increased calcitonin.

Because patients do not seek help until symptoms develop, it is not uncommon for patients to present to a healthcare facility with volume depletion and early hepatic injury. Good supportive care and prevention of secondary complications are the keys to management. Activated charcoal should be admin-istered 1 g/kg every 2 to 4 hours in order to adsorb any toxin remaining in the gut and interrupt the potential enterohepatic circulation (180). Many therapies to mitigate hepatotoxicity have been investigated, with no substantial or reproducible evidence of efficacy.

Although there are no data to support its use in Amanita poisoning, NAC effectively treats hepatic failure from other hepatotoxins, such as acetaminophen. Administer NAC intra-venously, according to the acetaminophen protocol. Continue the final infusion until the patient expires, definitively recov-ers, or receives liver transplant.

Silibinin, extracted from milk thistle, improved hepatic markers and mortality in a dog model of Amanita poisoning, but was not found beneficial in a meta-analysis of human stud-ies (181). Legalon SIL is an investigational silibinin derivative available in the United States for patients suspected of ingest-ing Amanita mushrooms. The loading dose of Legalon SIL is 5 mg/kg IV over 1 hour, followed by a maintenance does of 20 mg/kg IV as a continuous infusion over 24 hours. Legalon SIL can be obtained by calling the 24-hour, toll-free hotline: 1-866–520-4412.

High-dose penicillin had some effectiveness in a dog model of Amanita poisoning, possibly by blocking hepatocyte uptake of amatoxin (182). Therapy includes IV penicillin G, 1 million units/kg/d in divided doses (183).

The criteria for liver transplantation have not been clearly established. Transplantation is not without risk, and those who survive fulminant hepatic failure from Amanita without transplantation are expected to make a full recovery. Ideally, the decision to transplant should be delayed until it is clear the patient will not recover. Some consider transplantation for those with encephalopathy and prolonged PT, persistent hypoglycemia, metabolic acidosis, increased serum ammonia, aminotransferases, and hypofibrinogenemia (178). Patients should be referred to transplantation centers early in their clinical course so that they may be listed early, and transport should be avoided when they are gravely ill.

Gyromitrin-Containing Mushrooms

Gyromitra mushrooms are found throughout the United States. These mushrooms contain gyromitrin (N-methyl-N-formyl hydrazone), which is hydrolyzed to monometh-ylhydrazine (MMH). MMH inhibits the formation of pyridoxal-5′-phosphate (PLP), an enzyme cofactor synthesized from pyridoxine (vitamin B6). Of great importance, PLP is a cofactor for glutamic acid decarboxylase, the enzyme in the CNS that converts glutamate to GABA. Inhibition of PLP by

monomethylhydrazine results in excessive excitation relative to inhibition.

The initial phase of toxicity, occurring 5 to 10 hours after ingestion, is manifested by nonspecific clinical features includ-ing nausea, vomiting, diarrhea, and headache, and ultimately leads to intractable seizures (178). Patients ingesting Gyromi-tra spp. should receive activated charcoal, 1 g/kg. Seizures may not respond to benzodiazepines alone. If Gyromitra spp. ingestion is considered, or if a patient presents with seizures after mushroom ingestion, pyridoxine 70 mg/kg IV should be given. Pyridoxine serves as substrate for pyridoxine phospho-kinase, allowing some PLP to be generated despite inhibition by MMH.

Allenic Norleucine–Containing Mushrooms

The nephrotoxic Amanita smithiana contains the amino acid toxins allenic norleucine (amino-hexadienoic acid) and pos-sibly 1–2-amino-4-pentynoic acid (178). All known exposures to these mushrooms have occurred in the Pacific Northwest-ern United States. These serve as important exceptions to the “rule” that mushrooms that cause early gastrointestinal toxic-ity do not cause significant end-organ damage later.

Initial symptoms, which include nausea, vomiting, diarrhea, and abdominal cramping, may begin within an hour of inges-tion. The most important clinical features of toxicity develop later. Acute renal failure, indicated by elevations in blood urea nitrogen (BUN) and creatinine, manifest 4 to 6 days after ingestion (184).

Activated charcoal should be administered when patients present after ingesting mushrooms from the Pacific Northwest. Management of nephrotoxicity is supportive. Patients who required hemodialysis underwent the procedure two to three times per week for approximately 1 month (178).

Orellanine- and Orellinine-Containing Mushrooms

Cortinarius orellanus, found in North America, contains the toxin orellanine, which is converted by photochemical deg-radation to another toxin, orellinine (178). Orellanine and orellinine are important causes of mushroom-induced nephro-toxicity. Orellanine is activated by the P450 system. These mol-ecules generate oxidative damage by sustained redox cycling.

Symptoms begin 24 to 36 hours after ingestion. Patients report headache, chills, polydipsia, nausea, and vomiting. Early laboratory findings of hematuria, leukocyturia, and proteinuria indicate interstitial nephritis. Later, renal failure develops, characterized histologically by tubular damage and fibrosis of tubules with relative glomerular sparing (185,186). Hepatotoxicity is an uncommon feature.

Management is supportive. Administer activated charcoal if patients present early. Some patients will rapidly improve, whereas others require chronic hemodialysis (187).

oTher resources

This chapter is intended to be a review of common and conse-quential xenobiotic exposures. Goldfrank’s Toxicologic Emer-gencies (McGraw-Hill, 2015) contains a more comprehensive review of all the substances discussed here. The regional poison center (1-800-222-1222) is an excellent resource for further information and recommendations specific to your patient.

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Owing a great deal to the success of prevention measures, significant poisonings are relatively rare events. In 2013, of the 2.1 million human exposures reported to the AAPCC, only 1,218 were fatal. Although this figure underestimates total poisoning, it represents a very small number of patients per hospital per year. Because each ICU sees a paucity of these patients, many critical care physicians do not see enough of them to develop familiarity with their care. We encourage close collaboration between ICU physicians, regional poison centers, and toxicologists to provide the best possible care to poisoned patients.

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• Classic toxic syndromes can be differentiated based on vital signs, mental status, pupil size, presence of peri-stalsis, diaphoresis, and urinary retention.

• A comprehensive history should include, when avail-able, the specific xenobiotic exposure, the size of expo-sure, reason, and time of ingestion.

• Serum glucose and ECGs are essential initial bedside tools in the assessment of the poisoned patient.

• Serum chemistries are warranted in all critically ill patients.

• Routine urine toxicologic screens rarely aid in manage-ment.

• Treat the patient not the poison.• Stabilize airway, breathing, and circulation first.• Specific antidotes may be warranted.• Hemodynamic or neurologic instability, potential for

dysrhythmias, ingestion of sustained release products, or ingestion of potentially lethal dose are indications for ICU admission.

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chapter 151 · chapter 151 toxicology ... in any patient with an abnormal neurologic examination....

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