Clinical toxicology

Primary survey

When a health care team initially evaluates a patient who presents with a potential toxicologically induced health problem, the final diagnosis is often determined by (1) reviewing the history, (2) performing a directed physical examination, (3) using ancillary tests (e.g., electrocardiogram [ECG], radiology), and (4) applying a rational and evidence-based approach to laboratory testing. Often no specific antidote or treatment is available for a poisoned patient and careful supportive care is the most appropriate intervention.

All patients who present with potential toxicity should be thoroughly assessed, and it is imperative that clinicians follow a standard “ABC” approach with attention to “airway, breathing, and circulation,” respectively. The patient’s airway should be open and adequate ventilation ensured. If the patient’s airway is not secure and endotracheal tube intubation is considered, the first diagnostic test that should be performed is a rapid bedside glucose concentration. Hypoglycemia can result in coma or new-onset seizures, thereby mimicking a toxic etiology. In addition, numerous toxins are clinically associated with hypoglycemia (e.g., sulfonylureas, ethanol, Mentha pulegium ). Clinical effects induced by hypoglycemia can be rapidly reversed with intravenous glucose, thus preventing unnecessary and costly procedures and testing.

Too often, health care providers are lulled into a false sense of security when a patient presents with altered mental status and oxygen saturations on pulse oximetry that are adequate on high-flow oxygen. If the patient has inadequate ventilation or a poor gag reflex, then the patient may be at risk for progressive CO ₂ narcosis or aspiration, respectively, and yet may be maintaining adequate oxygen saturation on supplemental oxygen. Capnography (monitoring of the concentration or partial pressure of carbon dioxide in the respiratory gases) should be considered for use in appropriate cases. It is imperative that the health care team avoid the common complication of aspiration pneumonitis by assuring that the airway is secured if necessary. ^, An arterial blood gas (ABG) can rapidly aid the health care team in determining the need for intubation and mechanical ventilation. The ABG can also provide valuable information regarding the patient’s acid-base status and can help the clinician begin to generate a differential diagnosis. For example, in the scenario of a febrile toxic patient who presents with an altered mental status, a normal ABG (lack of acidosis) eliminates the possibility of uncoupling of oxidative phosphorylation as a cause of that patient’s fever. Finally, an ABG with co-oximetry can rapidly assist in determining other toxic etiologies, such as carbon monoxide poisoning (depending on the timing of the blood draw in relation to the exposure) and methemoglobinemia.

The initial treatment of hypotension in all toxic patients consists of the administration of intravenous fluids. The patient’s pulmonary status should be closely monitored to ensure that pulmonary edema (a rare complication in poisoned patients) does not develop as fluids are infused. Symptomatic toxic patients should be placed on continuous cardiac monitoring with pulse oximetry, and the health care team must perform frequent neurologic checks to ensure continued protection of the airway. Acutely poisoned patients should receive a large-bore peripheral intravenous line, and all symptomatic patients should have a second line placed in the peripheral or central venous system, depending on the severity of their clinical status. At this time in patient care, blood can be drawn and sent for appropriate laboratory diagnostic testing. Placement of a urinary catheter should be considered early in the care of hemodynamically unstable poisoned patients to monitor urinary output as an indicator of adequate perfusion. A rapid bedside urine dipstick can provide helpful information quickly as health care team members await further laboratory testing. For example, a urine specific gravity will give insight into the patient’s initial hydration status, and the appearance of tea-colored urine positive for blood may indicate the presence of myoglobinuria in a comatose patient with rhabdomyolysis.

Secondary survey

The secondary survey involves a thorough examination of the entire patient. For adequate access to a toxic patient, the patient must be completely undressed. Exposure of the patient ensures that a complete physical examination is performed. If the patient is not completely undressed, an important diagnostic clue may be missed. For example, skin lesions consistent with pressure necrosis on the back of a comatose patient may indicate the need to obtain other testing including a urine myoglobin concentration. A comatose drug abuser may have attached transdermal drug patches (e.g., fentanyl, clonidine) in atypical locations (e.g., gluteal sulcus) that when found can rapidly lead to a diagnosis, avoiding the need for further laboratory testing. Besides completing a thorough physical review of all organ systems, the secondary survey involves reviewing items brought with the patient (e.g., medication bottles, drug paraphernalia). Searching carefully through the patient’s clothing may assist in providing clues that change the plan for specific laboratory tests or explain specific laboratory findings. For example, the discovery of a cough and cold product in the patient’s pocket that contains dextromethorphan could explain the clinical presentation of an agitated patient with hyperreflexia whose initial urine toxicology screen was positive for phencyclidine but later was found negative on confirmation.

Anticholinergic

Anticholinergic agents block the neurotransmitter, acetylcholine, inhibiting parasympathetic central and peripheral nerve impulses. Characteristics of the anticholinergic syndrome have long been taught using the old medical adage, “dry as a bone, blind as a bat, red as a beet, hot as a hare, and mad as a hatter” (some add Bladder loses its tone, and Heart runs alone) which correspond with a symptomatic person’s anhidrosis, mydriasis, flushing, fever, and delirium, respectively.

Depending on the dose and time post exposure, various central nervous system (CNS) effects may manifest from an anticholinergic agent. Restlessness, apprehension, abnormal speech, confusion, agitation, tremor, picking movements, ataxia, stupor, and coma all have been described following exposure to various anticholinergics. When manifesting delirium, the individual will often stare into space and mutter, fluctuating between occasional lucid intervals with appropriate responses and then descriptions of vivid hallucinations. Phantom behaviors, such as plucking or picking in the air or at garments, are characteristic. Hallucinations are prominent, and they may be benign, entertaining, or terrifying to the patient experiencing them. Exposed patients may have conversations with hallucinated figures and/or they may misidentify persons they typically know well. Simple tasks typically performed well by the exposed person may become difficult. Motor coordination, perception, cognition, and new memory formation are altered.

Mydriasis causes photophobia; impairment of near vision occurs because of loss of accommodation and reduced depth of field secondary to ciliary muscle paralysis and pupillary enlargement. Tachycardia and exacerbated heart rate responses to exertion are expected. Systolic and diastolic blood pressure may show moderate elevation. A decrease in capillary tone may cause skin flushing. Intestinal motility slows, resulting in nausea, vomiting, and decreased bowel sounds. All glandular cells become inhibited, resulting in dry mucous membranes of the mouth and inhibition of sweating with resultant dry skin. Urination may be difficult, and urinary retention may occur. The exposed patient’s temperature may become elevated from an inability to sweat and dissipate heat. In warm climates, this may result in marked hyperthermia.

Numerous substances can cause the anticholinergic syndrome (see also section Agents Related to the Anticholinergic Toxidrome). More common agents include antihistamines, tricyclic antidepressant (TCA) drugs, phenothiazines, selective serotonin and norepinephrine reuptake inhibitors (SSRIs and SNRIs), and cyclobenzaprine. Several plants of the nightshade family contain deadly alkaloids. Examples include: Belladonna ( Atropa belladonna ), Jimson weed/Devil’s Snare (Datura stramonium), which contain atropine, hyoscyamine, and scopolamine. Mandrake and Henbane also are members of this family of plants.

Cholinergic

Acetylcholine is a neurotransmitter found throughout the CNS, including (1) the sympathetic and parasympathetic autonomic ganglia, (2) the postganglionic parasympathetic nervous system, and (3) the skeletal muscle motor end plate. Acetylcholine binds to and activates muscarinic and nicotinic receptors. Activating muscarinic receptors stimulates or inhibits cellular function at visceral smooth muscle, cardiac muscle, and secretory glands. Alternatively, nicotinic receptors are present at postsynaptic membranes in autonomic ganglia and at skeletal muscle motor end plates. The enzyme acetylcholinesterase (AChE) regulates the activity of acetylcholine within the synaptic cleft. Acetylcholine binds to the active site of AChE, where the enzyme rapidly hydrolyzes acetylcholine to choline and acetic acid. These hydrolyzed products rapidly dissociate from AChE, so that the enzyme is free to act on another molecule.

The respiratory effects of cholinergic poisoning tend to be dramatic and are considered to be the major factor leading to the death of its victims. Respiratory failure typically occurs as a triad of increased airway resistance, neuromuscular failure, and depression of central respiratory centers. Profuse watery nasal discharge, marked salivation, bronchorrhea, and bronchoconstriction result in a prolonged expiratory phase, cough, and wheezing. Because of the widespread presence of cholinergic receptors in the brain, cholinergic poisoning can produce great variation in neurologic signs and symptoms, including centrally mediated respiratory failure, coma, and seizures. Cholinergic cardiotoxicity can result in two clinical scenarios: a period of intense sympathetic activity that results in sinus tachydysrhythmias, or a period of increased parasympathetic tone that leads to bradydysrhythmias, prolongation of the PR interval, and atrioventricular block. Muscular symptoms may be vague and may consist of muscular weakness and difficulty with ambulation that can progress to muscular fasciculations and subsequent paralysis. Cholinergic agents cause constriction of both the sphincter muscle of the iris and the ciliary muscle of the lens, as well as stimulation of the lacrimal gland, resulting in lacrimation and miosis. The dermal sweat glands are innervated by sympathetic muscarinic receptors. When these receptors are stimulated, profuse sweating occurs. Cholinergic gastrointestinal and genitourinary symptoms may result in nausea, vomiting, abdominal cramps, tenesmus, and involuntary defecation and urination. Two mnemonics have been developed to help recall cholinergic clinical effects: DUMB BELS (diarrhea, urination, miosis, bradycardia, and bronchorrhea-bronchoconstriction, emesis, lacrimation, sweating-salivation) and SLUDGE (salivation, lacrimation, urination, defecation, GI distress, emesis-eye findings, miosis).

Agents that cause these cholinergic clinical effects include organophosphates and carbamates (see also section Agents Related to the Cholinergic Toxidrome). These agents, which include pesticides, medications (Irinotecan), some mushroom species, and chemical warfare agents (e.g., nerve agents), inhibit the activity of AChE, thereby prolonging the action of acetylcholine at muscarinic and nicotinic receptors. Cholinergic clinical effects can also follow after poisoning with direct nicotinic receptor agonists (e.g., nicotine, lobeline, conine, and arecoline) and specific drugs with direct muscarinic activity (e.g., methacholine, bethanechol, cevimeline).

Opioids

Opioids can induce coma, respiratory depression, bradycardia, hypotension, hypothermia, miosis, pulmonary edema, decreased bowel sounds, and decreased reflexes. Common causes of this syndrome, in which CNS depression, respiratory depression, and miosis are the cardinal three signs, include morphine, diacetylmorphine (heroin), fentanyl, hydrocodone, hydromorphone, methadone, and oxycodone. Meperidine, and tramadol toxicity has been associated with mydriasis and not with miosis. Numerous drugs can mimic the opioid syndrome triad by inducing coma, respiratory depression, and miosis, including alpha-2 agonists (e.g., clonidine, oxymetazoline) and antipsychotics.

Sedative-hypnotics

Sedative-hypnotics are a broad class of drugs (e.g., benzodiazepines, barbiturates, meprobamate, ethchlorvynol, zolpidem) that can induce sedation, respiratory depression, hypotension, hyporeflexia, nystagmus, dysarthria, staggering gait, apnea, and coma. Numerous sedative-hypnotics have been utilized to commit drug-facilitated crimes (see below), such as the solution of chloral hydrate in ethanol (historically called a “Mickey Finn”). There are few diagnostic clinical features that distinguish the drugs in this large class from one another. These features will be described in the sections below.

Sympathomimetic

Norepinephrine is the neurotransmitter for postganglionic sympathetic fibers (adrenergic) that enervate skin, eyes, heart, lungs, gastrointestinal tract, exocrine glands, and some neuronal tracts in the CNS. Physiologic responses to activation of the adrenergic system are complex and depend on the type of receptor (α ₁ , α ₂ , β ₁ , β ₂ ) activated; some are excitatory and others have opposing inhibitory responses. Stimulation of the sympathetic nervous system produces CNS excitation (agitation, anxiety, tremors, delusions, and paranoia), tachycardia, hypertension, mydriasis, hyperpyrexia, and diaphoresis. In severe cases, seizures, cardiac arrhythmias, and coma may occur. Examples of drugs that produce an excitatory sympathomimetic response include amphetamines, cocaine, phencyclidine, ephedrine, methcathinone, and pseudoephedrine.

Hyperthermic syndromes

Toxin-induced hyperthermic syndromes are potentially devastating and require rapid management. Even though the patient’s temperature is one of the vital signs, the temperature often is not obtained in clinical practice. Fever in a poisoned patient can be associated with several hyperthermic syndromes: sympathomimetic toxicity, uncoupling of oxidative phosphorylation, serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic poisoning, and withdrawal syndromes. Sympathomimetics, such as amphetamines and cocaine, may produce hyperthermia as the result of excess serotonin and dopamine, leading to thermal deregulation. Uncoupling of oxidative phosphorylation, as seen in severe salicylate poisoning, occurs when the process of oxidative phosphorylation is disrupted, leading to heat generation and a reduced ability to aerobically generate adenosine-5′-triphosphate (ATP).

Serotonin syndrome occurs when a relative excess of serotonin is present at both peripheral and central serotonergic receptors. Patients may present with hyperthermia, alterations in mental status, and neuromuscular abnormalities (rigidity, hyperreflexia, clonus), although individual variability is noted in these findings. Serotonin syndrome is associated with drug interactions such as those associated with the combination of monoamine oxidase (MAO) inhibitors and meperidine, but it may also occur with single-agent therapeutic dosing or overdosing with serotonergic agents.

Neuroleptic malignant syndrome is a condition caused by relative deficiency of dopamine within the CNS. It has been associated with dopamine receptor antagonists and the withdrawal of dopamine agonists such as levodopa/carbidopa products. Malignant hyperthermia occurs when genetically susceptible individuals are exposed to specific depolarizing neuromuscular blocking agents or volatile general anesthetics. It clinically is associated with elevated temperature, tachycardia, muscle rigidity, and hypercarbia. Anticholinergic poisoning may result in hyperthermia through impairment of normal cooling mechanisms such as sweating. Withdrawal syndromes can produce excessive adrenergic responses (e.g., sedative-hypnotic withdrawal, ethanol withdrawal) and subsequent heat generation. It should be noted that opioid withdrawal is not associated with fever or altered mental status. Overall, differentiating between the toxic hyperthermic syndromes may be challenging, and additional causes of hyperthermia such as heat stroke and infection should be explored.

Carbon monoxide

Carbon monoxide (CO) is a colorless, odorless, tasteless gas that is a product of incomplete combustion of carbonaceous material. Common exogenous sources of carbon monoxide include cigarette smoke, gasoline engines, and improperly ventilated home heating units. Small amounts of carbon monoxide are produced endogenously in the metabolic conversion of heme to biliverdin. This endogenous production of carbon monoxide is accelerated in hemolytic anemias.

Methemoglobin-forming agents

The heme iron in hemoglobin is normally present in the ferrous state (Fe ²⁺ ). When oxidized to the ferric state (Fe ³⁺ ), methemoglobin is formed, and this form of hemoglobin cannot bind oxygen. Congenital methemoglobinemia may result from a deficiency of NADH-methemoglobin reductase or, more rarely, from hemoglobin variants (hemoglobin M) in which heme iron is both more susceptible to oxidation and more resistant to reduction by the methemoglobin reductase system (for more information on methemoglobinemia, refer to Chapters 40 and 78 ).

Cyanide

Cyanide consists of one atom of carbon bound to one atom of nitrogen by three molecular bonds (C[N). Inorganic cyanides (also known as cyanide salts) contain cyanide in the anion form ( CN ⁻ ) and are used in numerous industries, such as metallurgy, photographic developing, plastic manufacturing, fumigation, and mining. Organic compounds that have a cyano group bonded to an alkyl residue are called nitriles; for example, acetonitrile, also known as methyl cyanide (CH ₃ CN). Hydrogen cyanide (HCN) is a colorless gas at standard temperature and pressure with a rarely reported associated “bitter almond” odor. Cyanogen gas, a dimer of cyanide, reacts with water and breaks down into the cyanide anion. Many plants, such as Manihot spp. (cassava), Linum spp., Lotus spp., Prunus spp., Sorghum spp., and Phaseolus spp., contain cyanogenic glycosides. Iatrogenic cyanide poisoning may occur during use of nitroprusside as a vasodilator given to reduce blood pressure and afterload. Each nitroprusside molecule contains five cyanide molecules, which are slowly released in vivo. If endogenous sulfate stores are depleted, as in the malnourished or postoperative patient, cyanide may accumulate even with therapeutic nitroprusside infusion rates (2 to 10 μg/kg/min) infused for long periods of time.

Ethanol

Ethanol is the most widely used and often abused chemical substance. Consequently, measurement of ethanol is one of the more frequently performed tests in the toxicology laboratory. Ethanol is considered a CNS depressant whose effects vary depending on the blood ethanol concentration ( Table 43.5 ) but are also heavily influenced by an individual’s tolerance. Symptoms vary from euphoria and decreased inhibitions, to increased disorientation and incoordination, and then to coma and death. A blood alcohol concentration of 80 mg/dL (0.08 g/100 mL or 0.08% w/v, 17.4 mmol/L) or less (50 mg/dL in some states) has been established as the statutory limit for operation of a motor vehicle in most countries.

Because of many factors, not all individuals experience the same degree of CNS dysfunction at similar blood alcohol concentrations. Moreover, the CNS actions of ethanol are more pronounced when the blood ethanol concentration is increasing (absorptive phase) than when it is declining (elimination phase), in part because of the phenomenon of acute tolerance. In addition, heavy alcohol use leads to a more chronic form of tolerance. When consumed with other CNS depressant drugs, ethanol exerts a potentiation or synergistic depressant effect. This can occur at relatively low alcohol concentrations, and numerous deaths have resulted from combined ethanol and drug ingestion.

The pharmacologic mechanisms for the CNS depressant actions of ethanol are complex and incompletely understood, but probably involve both enhancement of major inhibitory neurons and impairment of excitatory neurons. The principal CNS inhibitory neuronal system is mediated by the neurotransmitter γ-aminobutyric acid (GABA). When GABA binds to its postsynaptic receptor subtype GABA _A , this oligomeric ion-gated complex “opens” to allow inward flux of Cl, leading to membrane hyperpolarization and subsequent decreased electrical response. This GABA-mediated inhibitory response is enhanced by ethanol and sedative, hypnotic, and anesthetic agents, including barbiturates, benzodiazepines, and volatile anesthetics. Neuronal nicotinic acetylcholine receptors also may be prominent molecular targets of alcohol. Both enhancement and inhibition of nicotinic acetylcholine receptor function have been reported depending on receptor subunit concentration and the concentrations of ethanol tested. Ethanol also inhibits the function of the N -methyl-d-aspartate (NMDA)- and kainate-receptor subtypes; however, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors are largely resistant to ethanol.

The aforementioned chronic tolerance to ethanol is considered to be mediated by ethanol-induced increased responsiveness and upregulation in the synthesis of NMDA receptors, attained by concomitant downregulation and desensitization through phosphorylation of GABA _A and glutamate receptors. ^{, ,} Largely because of these adaptive changes, abrupt withdrawal from chronic, heavy ethanol use leads to a physical abstinence syndrome that has prominent features which are the opposite of those produced by intoxication. This include features of CNS excitation, anxiety, irritability, insomnia, muscle tremor and cramps, hallucinations, and increased temperature, blood pressure, heart rate, and seizures. This syndrome can be fatal if the patient is not monitored properly.

Ethanol is metabolized principally by liver alcohol dehydrogenase (ADH) to acetaldehyde, which is subsequently oxidized to acetic acid by aldehyde dehydrogenase ( Fig. 43.1 ). The rate of elimination of ethanol from blood approximates a zero-order process. This rate varies among individuals, averaging about 15 mg/dL/h for males and 18 mg/dL/h for females. ^, At both low (<20 mg/dL) and high (>300 mg/dL) ethanol concentrations, elimination more closely resembles first-order kinetics, and it is accelerated at high concentrations. The elimination rate is also influenced by drinking habits (e.g., alcoholics have increased elimination rates caused by enzyme induction).

Ethanol is a teratogen, and alcohol consumption during pregnancy can result in a baby with fetal alcohol spectrum disorder (FASD). FASD is an umbrella term that describes the variety of effects that can occur in an individual whose mother drank alcohol during pregnancy. These effects may include physical, mental, behavioral, and/or learning disabilities with possible lifelong implications and are 100% preventable when a woman completely abstains from alcohol during her pregnancy.

Isopropanol and acetone

Isopropanol is readily available to the general population as a 70% aqueous solution for use as rubbing alcohol, but can also be found in cleaners, disinfectants, antifreezes, cosmetics, solvents, inks, and pharmaceuticals. It has about twice the CNS depressant action as ethanol. Isopropanol has a short t _½ of 2.5 to 3.0 hours and is rapidly metabolized by ADH. Since it is a secondary alcohol (the hydroxyl group is attached to a central, rather than a terminal, carbon), consequently it is metabolized to a ketone, not an acid, and therefore ingestions do not cause significant metabolic acidosis (see Table 43.3 ). ^, Acetone is eliminated much more slowly, therefore concentrations of acetone in serum often exceed those of isopropanol during the elimination phase following isopropanol ingestion. Acetone has CNS depressant activity similar to that of ethanol, and because of its longer t _½ , it may prolong the apparent CNS effects of isopropanol intoxications.

Interestingly, like most enzymatic reactions, the conversion of isopropanol to acetone by ADH exists in an equilibrium; its balance is dependent on the ratio of NAD+ and NADH. In patients with severe diabetic ketoacidosis there is an excess of NADH, and the equilibrium reaction favors the formation of isopropanol. Therefore it is not uncommon in these patients to see not only the acetone expected in the diabetic ketoacidosis, but small amounts of isopropanol.

Methanol

Methanol is used as a solvent in several commercial products, as a constituent in windshield wiper fluid, copy machine fluids, fuel additives (octane boosters), paint remover or thinner, antifreeze, canned heating sources, de-icing fluid, shellacs, and varnishes. It may be consumed intentionally by individuals as an ethanol substitute or accidentally when present as a contaminant in illegal whiskey, or inadvertently by children.

The CNS effects of methanol are substantially less severe than those of ethanol. Methanol is oxidized by liver ADH (at about one tenth the rate of ethanol) to formaldehyde. Formaldehyde in turn is rapidly oxidized by aldehyde dehydrogenase to formic acid. Formic acid’s main mechanism of toxicity is its binding to cytochrome oxidase and blockade of oxidative phosphorylation. This leads to anaerobic metabolism and development of lactic acidosis. In addition, metabolism of methanol increases the NADH/NAD ⁺ ratio, which favors the conversion of pyruvate to lactate and thereby worsens lactic acidosis. Falling pH also favors the undissociated form of formic acid (as opposed to formate ion), which moves more readily across tissue barriers. Therefore at lower pH, more formic acid can enter the brain and ocular tissues, worsening CNS depression and causing retinal and optic nerve injury, resulting in the characteristic profound metabolic acidosis, optic neuropathy, potential blindness, CNS bleeds, and death. ^,

Ethylene glycol

Ethylene glycol is present in antifreeze products, de-icing products, detergents, paints, and cosmetics. It may be ingested accidentally or for the purpose of inebriation or suicide. Because it tastes sweet, some animals are attracted to it. Veterinarians are often familiar with ethylene glycol toxicity because of cases involving dogs or cats that drank radiator fluid.

Ethylene glycol has initial CNS effects resembling those of ethanol. Ethylene glycol is metabolized by ADH to glycolaldehyde which is then metabolized to glycolic, glyoxylic, and oxalic acids. ^, Oxalate readily precipitates with calcium to form insoluble calcium oxalate crystals. Tissue injury is caused by widespread deposition of oxalate crystals and the toxic effects of glycolic and glyoxylic acids. ^{, ,} Clinically, ethylene glycol poisoning is characterized by CNS depression, metabolic acidosis, and renal failure; however, multiple other organ systems may be affected. Poisonings have historically been divided into three stages, although the timing and stages may overlap. The first stage typically begins 30 minutes to 12 hours after ingestion due to the intoxicating effects of the ethylene glycol and may range from mild CNS depression to coma. ^, Ethylene glycol is directly irritating to the GI tract, so abdominal pain, nausea, and vomiting may be present. The formation of toxic metabolites generally takes 4 to 12 hours. The CNS effects of glycolic acid and calcium oxalate crystals include cerebral edema, basal ganglia hemorrhagic infarction, and meningoencephalitis. Hypocalcemia, which occurs when calcium combines with oxalate, may contribute to seizures. Metabolic acidosis appears as toxic metabolites are generated. The second stage begins 12 to 24 hours after ingestion and is characterized by metabolic acidosis, oxalate crystal deposition in tissues, multi-organ system failure, including heart failure, acute lung injury, and myositis. Most deaths occur during this stage. The third stage is often delayed 24 to 72 hours after ingestion and is characterized by renal failure due to calcium oxalate crystal deposition in the proximal tubules, the most common major complication of serious ethylene glycol poisoning. And if patients survive, delayed neuropathies may occur 5 to 20 days after ethylene glycol poisoning.

Treatment

In cases of isopropanol poisoning, there is little value in altering isopropanol metabolism because its major metabolite, acetone, is no more toxic than isopropanol itself, and slowing isopropanol metabolism would only serve to prolong the overall CNS depressant effect. For this reason, supportive care is the treatment of choice. In cases of severe isopropanol intoxication, dialysis may be indicated.

The basic principles of treatment for both methanol and ethylene glycol poisoning are essentially the same; correct the acidosis, reduce the formation of toxic metabolites (formaldehyde and formic acid from methanol; glycolaldehyde, glycolic acid, and oxalic acid from ethylene glycol), and enhance the clearance of the parent compound and its toxic metabolites from circulation. Serum concentrations of methanol ≥ 20 mg/dL (6 mmol/L) or ethylene glycol ≥ 20 mg/dL (3 mmol/L) warrants intervention. Mainstays of therapy include the administration of the ADH competitive inhibitors fomepizole (Antizol) or ethanol. They will compete with methanol or ethylene glycol for ADH and thereby impede the formation of the toxic metabolites. Hemodialysis may be required if the measured methanol or ethylene glycol concentrations are greater than 50 mg/dL in order to remove the parent compound and toxic metabolites. ^, Adjunctive treatment with B vitamins (including folate) is often provided, as these vitamins are thought to assist in the clearance of the toxic metabolites, although definitive evidence to support this hypothesis does not currently exist. ^,

Analysis of ethanol

Ethanol biomarkers

Ethyl glucuronide (EtG), ethyl sulfate (EtS), and phosphatidylethanols (PEth) are biomarkers of ethanol consumption. EtG and EtS are phase II metabolites of ethanol detected in urine. EtG is a phase II metabolite of ethanol formed through the UDP-glucuronosyltransferase catalyzed conjugation of ethanol with glucuronic acid. EtS is also formed directly by the conjugation of ethanol with sulfate group. PEth are detected in whole blood and are formed by phospholipase D in the presence of ethanol.

Because EtG has a long urinary elimination time (≤80 hours), its specificity for ethanol exposure, and the low detection limits, EtG is utilized as a marker of recent ethanol intake in a variety of clinical and legal settings, including medical monitoring for relapse, emergency department patient evaluation, postmortem assessment, and transportation accident investigation. ^,

Monitoring both EtG and EtS in urine improves sensitivity when using ethanol biomarkers for monitoring recent drinking. There are challenges associated with establishing appropriate cut-off concentrations capable of distinguishing between drinking and incidental exposure such as nonbeverage sources of ethanol exposure (i.e., hand sanitizers, mouthwash), ^, nonuniform laboratory reporting limits, sample stability, and microbial activity may complicate interpretation of results. EtG can be produced in postspeciman collection, and upper respiratory infections and beta glucuronidase hydrolysis in urine sample with certain stains of Escherichia coli may lower levels of EtG; however, mEtS seems to not be affected. However, some interpretive guides have been proposed. EtG greater than 1000 ng/mL may indicate heavy drinking in the previous 48 hours or light drinking the same day. An EtG from 500 to 1000 ng/mL may indicate heavy drinking in the previous 3 days, light drinking in the past 24 hours, or intense “extraneous exposure” within 24 hours. Values less than 500 ng/mL may indicate heavy drinking in the previous 3 days, light drinking in the past 36 hours, or recent “extraneous” exposure.

PEth are a group of phospholipids with a common phosphoethanol head group with two fatty acid chains which differ in chain length and degree of unsaturation. PEth is a promising marker because of PEth’s persistence in blood for as long as 3 weeks after even only a few days of moderately heavy drinking (about four drinks per day). Therefore PEth may be utilized in conjunction with EtG and EtS to discriminate incidental ethanol exposure from moderate to heavy “binge” alcohol drinking. ^,

Analysis of volatile alcohols (methanol, isopropanol, and acetone)

Methanol poisoning can be lethal if not recognized early. Unfortunately, in some instances, a latent period can be as long as 12 to 24 hours before toxicity is recognized, making laboratory identification of this poisoning critical. Development of gas chromatographic methods for volatiles in 1964 ^157, was a significant step in the recognition and treatment of this very toxic alcohol.

Flame ionization GC remains the most common method for the detection and quantitation of volatile alcohols in biological samples. Not only does it distinguish between ethanol, methanol, isopropanol, and acetone, it has the capability to measure concentrations as low as 10 mg/dL (0.01%). Specimens are prepared by a variety of methods; the two most common are direct injection and headspace analysis. Direct injection involves injection of a sample prepared by diluting it with an aqueous solution of internal standard (thus reducing the amount of matrix introduced into the GC). Repeated injection of biological aqueous matrix into the GC will cause buildup on the injector and front of the analytical column, requiring frequent maintenance and column replacement. This can be alleviated by the use of headspace injection. The volatility of the alcohols is used to separate them from the matrix. Specifically, the “Gas Law” states that at a given temperature, the amount of volatile substance in the air space above the liquid—headspace—is proportional to the concentration of the volatile alcohol in the solution. Therefore the sample in the headspace allows for calculation of the concentration in the specimen.

Headspace gas chromatographic analysis is another excellent method for the measurement of methanol, isopropanol, acetone, and ethanol. In addition, an adaptation of this technique may be used to measure formate, the toxic metabolite of methanol, after esterification to methyl formate. Conversely, direct injection GC is the method of choice for ethylene glycol because it has a higher boiling point and is not as amenable to headspace analysis. A modification of the GC procedure described in 2005 has the potential of combining both toxic alcohols in a single GC analysis. Assessment of ethylene glycol metabolites is a clinically useful method that allows for the simultaneous determination of ethylene glycol and glycolic acid; such a method that is free from interference by propylene glycol (a diluent for parenteral drugs) or 2,3-butanediol (may be present in serum from some alcoholics) would be highly desirable. ^, Similar techniques are used to measure volatile alcohols in blood, serum, oral fluid, urine, other clinical specimens, and postmortem specimens (e.g., vitreous fluid, skeletal muscle).

Acetaminophen

Acetaminophen ( N -acetyl- p -aminophenol; paracetamol) has analgesic and antipyretic actions. In common with the group of drugs referred to as nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., aspirin, ibuprofen, indomethacin), the pharmacologic actions of acetaminophen are related to its nonselective inhibition of cyclooxygenase enzymes (COX). This results in decreased production of prostaglandins, which are important mediators of inflammation, pain (low to moderate), and fever. Contrary to other NSAIDs, acetaminophen has very weak anti-inflammatory activity—a consequence of its weak inhibition of peripheral tissue cyclooxygenase compared with that in the brain. In normal doses, acetaminophen is safe and effective, but it may cause severe hepatic toxicity or death when consumed in overdose quantities. Less frequently, nephrotoxicity with or without associated hepatotoxicity may also occur.

Acetaminophen is normally metabolized in the liver to glucuronide (50 to 60%) and sulfate (<30%) conjugates. A smaller amount (<10%) is metabolized by a cytochrome P450 mixed-function oxidase pathway that is thought to involve formation of a highly reactive intermediate ( Fig. 43.2 ), N -acetyl- p -benzoquinone imine (NAPQI). This intermediate normally undergoes electrophilic conjugation with glutathione and then subsequent transformation to cysteine and mercapturic acid conjugates of acetaminophen. With acetaminophen overdose, the sulfation pathway becomes saturated; consequently, a greater portion is metabolized by the P450 mixed-function oxidase pathway. When the tissue stores of glutathione become depleted, arylation of cellular molecules by the benzoquinoneimine intermediate leads to hepatic necrosis.

The initial clinical findings in acetaminophen toxicity can be absent or relatively mild and nonspecific (nausea, vomiting, and abdominal discomfort) and thus are not predictive of impending hepatic necrosis, which typically begins 24 to 36 hours after toxic ingestion and becomes most severe by 72 to 96 hours. Although uncommon with severe overdose, coma and metabolic acidosis may occur before development of hepatic necrosis.

Specific therapy for acetaminophen overdose is the administration of N-acetylcysteine (NAC), which probably acts as a glutathione substitute. NAC may also provide substrate to replenish hepatic glutathione or to enhance sulfate conjugation, or both. The time of administration of NAC is critical. Maximum efficacy is observed when NAC is administered within 8 hours, and efficacy declines with time, therefore it is most effective when administered before hepatic injury occurs, as signified by elevations of AST and ALT. However, NAC treatment may provide beneficial effects even after liver injury has occurred, presumably through its ability to improve tissue oxygen delivery and use.

The measurement of serum acetaminophen concentrations becomes paramount for proper assessment of the severity of overdose and for appropriate decision making for antidotal therapy. If serum acetaminophen results are not available locally within 8 hours of suspected ingestion, treatment with NAC should begin until levels are available. The Rumack-Matthew nomogram relates serum acetaminophen concentration and time following acute ingestion to the probability of hepatic necrosis ( Fig. 43.3 ).

Several qualifications pertain to the use of this nomogram. First, to utilize the nomogram, blood samples should not be obtained earlier than 4 hours after ingestion to ensure that absorption is complete. Second, the nomogram applies only to an acute single ingestion and not to chronic ingestion. Toxicity from chronic ingestion of acetaminophen or other drugs is cumulative and typically occurs at lower blood concentrations than in acute overdose. Third, the nomogram is not useful if the time of ingestion is unknown or is considered unreliable. In this case, when the exact time of ingestion is unknown, clinicians should err on the side of treating with NAC until the acetaminophen concentration is not detectable and no transaminase elevation is seen. Fourth, if acetaminophen is coingested with a substance that may delay absorption (i.e., anticholinergic), the patient should be clinically monitored for clinical effects. If, for example, no anticholinergic signs or symptoms develop after the 4-hour acetaminophen concentration is measured, one may assume that absorption will not be delayed and the concentration can be plotted normally. If, however, the patient develops anticholinergic signs and symptoms, and the acetaminophen concentration is detectable, that patient should be treated with NAC as absorption is most likely delayed, and the concentration should not be plotted. Alcoholic patients, fasting or malnourished patients, and patients on long-term therapy with microsomal enzyme-inducing drugs (e.g. phenobarbital) may have increased susceptibility to acetaminophen hepatotoxicity, presumably as a result of induction of cytochrome P450 (see later) and, in the case of alcoholics or fasting patients, depletion of glutathione (see later). In these cases, it has been proposed that the decision line in the nomogram should be lowered by 50 to 70%. ^, Others do not advocate any change in the therapeutic decision line for such patients with acute ingestion. These risk factors may be more important in chronic acetaminophen poisoning. Although therapeutic guidelines for chronic acetaminophen poisoning have not been established, it is recommended to administer NAC if the transaminases are elevated or the acetaminophen level is greater than10 μg/mL (66.2 μmol/L), until improvement is noted.

An area of some controversy is whether acetaminophen screening should be performed on all intentional overdose patients. One of the most worrisome aspects of acetaminophen poisoning is that initial clinical symptoms (e.g., nausea, vomiting, abdominal pain) may be vague or even absent in the first 24 hours. ^, This possible delay in diagnosis is particularly problematic because the antidote, NAC, has been shown to be most effective when initiated within the first 8 hours. Studies recommend screening all patients with suicidal ingestion and those with altered mental status in whom ingestion is suspected. ^,

Salicylate

Acetylsalicylic acid (aspirin) has analgesic, antipyretic, and anti-inflammatory properties. These therapeutic benefits derive from its ability to inhibit biosynthesis of prostaglandins by acetylation of active site serine and subsequent irreversible inhibition of cyclooxygenase enzymes (COX-1; COX-2 isoenzymes). Salicylate, the metabolite of aspirin, also reduces prostaglandin synthesis by uncertain mechanisms. Aspirin also interferes with platelet aggregation and thus prolongs bleeding time. The platelet inhibitory effect is a consequence of the ability of aspirin to acetylate and irreversibly inhibit platelet cyclooxygenase, thereby reducing the formation of thromboxane A ₂ , a potent mediator of platelet aggregation. Platelets have little or no capacity for protein synthesis; therefore the duration of this enzyme inhibition is the normal life span of the platelets (8 to 11 days). Because of this platelet inhibitory activity, low-dose aspirin has been recommended as prophylactic therapy for some individuals at risk for thromboembolic disease. ^, An epidemiologic association has been noted between aspirin ingestion and Reye syndrome in children and adolescents with viral infection (e.g., varicella, influenza). Therefore aspirin use in these patients is done so cautiously. However, because of the therapeutic benefits and the overall lack of serious side effects at normal doses in most patients, aspirin is widely available and frequently consumed.

Absorption of normal doses of regular aspirin from the GI tract is generally rapid, with peak serum concentration achieved within an hour. This peak value may be delayed for 12 hours or longer for enteric-coated or slow-release formulations. Once absorbed, aspirin has a very short half-life (t _½ = 15 minutes) because of its rapid hydrolysis to salicylate. Salicylate is eliminated mainly by conjugation with glycine to form salicyluric acid, and to a lesser extent with glucuronic acid to form phenol and acyl glucuronides. A very small amount is hydroxylated to gentisic acid. These metabolic pathways may become saturated even at high therapeutic doses. Consequently, serum salicylate concentration may increase disproportionately with dosage. At high therapeutic or toxic doses, the salicylate elimination half-life is prolonged (15 minutes to 30 hours versus 2 to 3 hours at low dose) and a much larger portion of the dose is excreted in urine as salicylate. Therapeutic serum salicylate concentrations are generally lower than 60 mg/L (0.5 mmol/L) for analgesic-antipyretic effects, and 150 to 300 mg/L (1.0 to 2.0 mmol/L)for anti-inflammatory actions.

Salicylates directly stimulate the central respiratory center and thereby cause hyperventilation and respiratory alkalosis. Additionally, salicylates cause uncoupling of oxidative phosphorylation. As a result, heat production (hyperthermia), oxygen consumption, and metabolic rate may be increased. Salicylates also enhance anaerobic glycolysis but inhibit the Krebs cycle and transaminase enzymes, which leads to accumulation of organic acids and thus to metabolic acidosis. ^,

The primary acid-base disturbance observed with salicylate overdosage depends on age and severity of intoxication. Respiratory alkalosis predominates in children over the age of 4 years and in adults, except in very severe cases that may progress through a mixed respiratory alkalosis–metabolic acidosis to metabolic acidosis. In children younger than age 4, the initial period of respiratory alkalosis may be brief and therefore may not be observed; in such cases, metabolic acidosis predominates. ^, CNS depression is more pronounced when acidemia is severe, which is a consequence of increased brain uptake of nonionized salicylic acid. Respiratory acidosis, a result of severe CNS depression or pulmonary edema, may sometimes occur and is indicative of a poor prognosis.

Following acute salicylate overdose, patients initially may be asymptomatic, especially if that product is enteric coated. Salicylate toxic patients may develop nausea, vomiting, abdominal pain, tinnitus, tachypnea, oliguria, and altered mental status ranging from agitation to lethargy to coma. Toxic doses of aspirin may form concretions or bezoars and produce pylorospasm, thereby delaying absorption. Serum salicylate in such instances may not reach maximum concentration for 6 hours or longer. ^, Therefore a concentration drawn soon after the original ingestion may not be reflective of the potential peak concentration—an important consideration when assessment of the severity of toxicity is based on such measurements. Use of salicylate concentrations to guide management must be done cautiously and only in conjunction with careful evaluation of a patient’s clinical status. The nomogram developed by Done is no longer recommend in the management of the salicylate poisoned patient. Toxic salicylate concentrations alone are of poor prognostic value; however, certain clinical findings predict a poor prognosis, including pulmonary edema, fever, coma, and acidosis. Initial serial concentrations should be performed every 2 hours while the patient is monitored clinically. When the concentrations begin to decline and the patient’s clinical status is improved, concentrations can be measured less frequently.

The need to screen all intentional overdose patients for salicylates is debated. ^{, ,} Diagnosis of salicylate poisoning based solely on clinical examination is not without pitfalls. Although large, acute ingestions are usually detected through history and clinical symptoms, chronic salicylate toxicity often is more difficult to diagnose. Chronic intoxication can present in a similar fashion as acute exposures, yet such exposures typically are more insidious and therefore are often misdiagnosed. In these cases, patients present with nonspecific symptoms such as fever, abdominal pain, and encephalopathy and subsequently are misdiagnosed with surgical abdomen, myocardial infarction, sepsis, encephalitis, and alcoholic ketoacidosis. ^, Because products containing salicylates are readily available, the clinical effects of salicylate toxicity are nonspecific, and lack of metabolic acidosis does not rule out the potential for salicylate toxicity, clinicians should have a low threshold for obtaining serum salicylate concentrations. Some suggest that in any patient with a history of salicylate ingestion or possessing characteristic signs or symptoms of salicylate poisoning, a serum salicylate concentration should be obtained. Early identification of salicylate toxicity can be lifesaving.

Treatment for salicylate intoxication is directed toward (1) decreasing further absorption, (2) increasing elimination, and (3) correcting acid-base and electrolyte disturbances. Activated charcoal binds aspirin and prevents its absorption. Elimination of salicylate may be enhanced by alkaline diuresis and in severe cases by hemodialysis. Sodium bicarbonate may be given to alleviate metabolic acidosis and enhance elimination. Indications for emergent hemodialysis include serum salicylate greater than 1000 mg/L, CNS changes, intractable metabolic acidosis, pulmonary edema, hepatic failure with coagulopathy, and renal failure.

Tricyclic antidepressants

TCAs, so named because of their three-ring structure ( Fig. 43.4 ), represent a class of drugs frequently prescribed for the treatment of depression and neuropathic pain (see Chapter 42 ). The TCAs have been largely supplanted by the newer, less toxic selective serotonin reuptake inhibitors (SSRIs) and other atypical agents for depression, which now are accepted broadly as drugs of first choice, particularly for medically ill or potentially suicidal patients and for the elderly and the young. Fatalities are much less common since modern antidepressants have widely replaced these drugs. However, because of their continued use and narrow therapeutic range, TCAs are frequently associated with severe or fatal toxicity following overdose.

TCAs block neuronal uptake of serotonin and/or norepinephrine. TCAs have many other pharmacologic actions that apparently do not contribute to the therapeutic effects but do contribute to the side effects. TCAs have at least moderate affinity for blockade of α ₁ -adrenergic receptors, much less for α ₂ , and virtually none for β-receptors, leading to vasodilation and hypotension. TCAs have sedative effects and the potential for seizures related to antihistamine activity. TCAs exert central and peripheral anticholinergic effects (dry skin and mouth, flushing, hyperpyrexia, dilated pupils, constipation, urinary retention, and decreased GI motility) through their blockade of M1 muscarinic receptors. TCAs close GABA channels resulting in an increased risk of seizures.

Cardiovascular effects, the most serious manifestation of TCA overdose, accounts for the majority of fatalities. Several mechanisms may contribute to cardiovascular toxicity :

• 1.

  Anticholinergic effects and inhibition of neuronal reuptake of catecholamines result in tachycardia and potential for early hypertension.

• 2.

  Peripheral α-adrenergic blockade causes vasodilation and contributes to hypotension.

• 3.

  Cardiac fast sodium channel blockade and potassium efflux channel blockade resulting in QRS and QT prolongation, respectively, and risk for decreased cardiac output and ventricular dysrhythmias.

• 4.

  Metabolic and/or respiratory acidosis that may further contribute to inhibiting the cardiac fast sodium channel.

Some tolerance to the sedative and autonomic effects of TCAs tends to develop with continued drug use. Occasionally, patients show physical dependence, with malaise, chills, muscle aches, and sleep disturbance following abrupt discontinuation, particularly of high doses. Some withdrawal effects may reflect increased cholinergic activity following its inhibition. Some of these reactions have been confused with clinical worsening of depressive symptoms. Emergence of agitated or manic reactions has been observed after abrupt discontinuation of TCAs.

In general, antidepressants are associated with several clinically important drug interactions (e.g., serotonin syndrome), and they potentiate the effects of alcohol and probably other sedatives. TCAs are oxidized by hepatic cytochrome P450 (CYP) microsomal enzymes, followed by conjugation with glucuronic acid. The N -demethylated metabolites of several tricyclic antidepressants are pharmacologically active and may accumulate in concentrations approaching or exceeding those of the parent drug, to contribute variably to overall pharmacodynamic activity.

Antipsychotic drugs

The antipsychotic drugs are generally used for primary psychiatric disorders, for example (1) schizophrenia, (2) bipolar disorder, (3) schizoaffective disorder, and (4) psychotic depression. In addition to their psychotherapeutic effects, these drugs have a number of other actions, so that certain members of this group are used as antiemetics (prochlorperazine), as antihistaminics (promethazine), and for sedation or potentiation of analgesia and general anesthesia. Antipsychotic compounds are traditionally divided and subdivided according to their chemical structure ( Table 43.6 and Fig. 43.5 ). ^,

The primary pharmacologic effect of all antipsychotic drugs is thought to be blockade of D2 receptors in the CNS. ^, It has been shown that classical antipsychotics reduce psychotic symptoms and that this correlates with their affinity for the D2 receptor. However, the drugs bind to many other receptors, including histamine (H ₁ , H ₂ ), GABA _A , muscarinic receptors, α ₁ - and α ₂ -adrenoreceptors, and sodium and potassium voltage-gated ion channels. The atypical antipsychotics on the other hand have a different mechanism that my involve other dopamine receptors, serotonin receptors, or both.

The principal manifestations of phenothiazine toxicity involve the CNS and the cardiovascular system. ^, The most common effects in significant phenothiazine overdose include (1) sedation, (2) hypotension, (3) anticholinergic effects, and (4) ECG changes. Phenothiazines are relatively safe and rarely cause death when ingested alone.

All of the neuroleptic drugs are metabolized in the liver. Many have active metabolites and complex metabolic pathways. The main enzymes involved in metabolism are cytochrome P450 (CYP) enzymes, specifically CYP1A2, CYP2D6, and CYP3A4. ^{, ,} Many sources of variation are found in CYP-mediated metabolism; however, where multiple enzymes are involved, such variability has only a relatively small effect on clearance and drug concentrations.