Poisoning

History

Obtaining an accurate problem-oriented history is of paramount importance. Intentional poisonings (suicide attempts, drug abuse/misuse) are typically more severe than unintentional, exploratory ingestions. In patients without a witnessed exposure, historical features such as age of the child (toddler or adolescent), acute onset of symptoms without prodrome, multisystem organ dysfunction, or high levels of household stress should suggest a possible diagnosis of poisoning. In patients with a witnessed exposure, determining exactly what the child was exposed to and the circumstances surrounding the exposure is crucial to initiating directed therapy quickly. For household and workplace products, names (brand, generic, chemical) and specific ingredients, along with their concentrations, can often be obtained from the labels. PCC specialists can also help to identify possible ingredients and review the potential toxicities of each component. Poison center specialists can also help identify pills based on markings, shape, and color. If referred to the hospital for evaluation, parents should be instructed to bring the products, pills, and/or containers with them to assist with identifying and quantifying the exposure. If a child is found with an unknown pill, a list of all medications in the child's environment, including medications that grandparents, parents, siblings, caregivers, or other visitors might have brought into the house, must be obtained. In the case of an unknown exposure, clarifying where the child was found (e.g., garage, kitchen, laundry room, bathroom, backyard, workplace) can help to generate a list of potential toxins.

Next, it is important to clarify the timing of the ingestion and to obtain some estimate of how much of the substance was ingested. It is better to overestimate the amount ingested to prepare for the worst-case scenario. Counting pills or measuring the remaining volume of a liquid ingested can sometimes be useful in generating estimates. For inhalational, ocular, or dermal exposures, the concentration of the agent and the length of contact time with the material should be determined, if possible.

Physical Examination

A targeted physical examination is important to identifying the potential toxin and assessing the severity of the exposure. Initial efforts should be directed toward assessing and stabilizing the airway, breathing, circulation, and mental status. Once the airway is secure and the patient is stable from a cardiopulmonary standpoint, a more extensive physical exam can help to identify characteristic findings of specific toxins or classes of toxins.

In the poisoned patient, key features of the physical exam are vital signs, mental status, pupils (size, reactivity), nystagmus, skin, bowel sounds, and muscle tone. These findings might suggest a toxidrome, which can then guide the differential diagnosis and management.

Laboratory Evaluation

A basic chemistry panel (electrolytes, renal function, glucose) is necessary for all poisoned or potentially poisoned patients. Any patient with acidosis (low serum bicarbonate level on serum chemistry panel) must have an anion gap calculated because of the more specific differential diagnoses associated with an elevated anion gap metabolic acidosis ( Table 77.5 ). Patients with a known overdose of acetaminophen should have liver transaminases (ALT, AST) assessed, as well as an international normalized ratio (INR). A serum creatinine kinase level is indicated on any patient with a prolonged “down time” to evaluate for rhabdomyolysis . Serum osmolality is only helpful as a surrogate marker for a toxic alcohol exposure if a serum concentration of the alcohol cannot be obtained in a reasonable time frame. A urine pregnancy test is mandatory for all postpubertal female patients. Based on the clinical presentation and the presumed poison, additional lab tests may also be helpful. Acetaminophen is a widely available medication and a commonly detected co-ingestant with the potential for severe toxicity. There is an effective antidote to acetaminophen poisoning that is time dependent. Given that patients might initially be asymptomatic and might not report or be aware of acetaminophen ingestion, an acetaminophen level should be checked in all patients who present after an intentional exposure or ingestion.

For select intoxications (e.g., salicylates, some anticonvulsants, acetaminophen, iron, digoxin, methanol, ethanol, lithium, ethylene glycol, theophylline, CO, lead), quantitative blood concentrations are integral to confirming the diagnosis and formulating a treatment plan. However, for most exposures, quantitative measurement is not readily available and is not likely to alter management. All intoxicant levels must be interpreted in conjunction with the history. For example, a methanol level of 20 mg/dL 1 hr after ingestion may be nontoxic, whereas a similar level 24 hr after ingestion implies a significant poisoning. In general, patients with multiple or chronic exposures to a drug or other chemical will be more symptomatic at lower drug levels than those with a single exposure.

Both the rapid urine drug-of-abuse screens and the more comprehensive drug screens vary widely in their ability to detect toxins and generally add little information to the clinical assessment. This is particularly true if the agent is known and the patient's symptoms are consistent with that agent. If a drug screen is ordered, it is important to know that the components screened for, and the lower limits of detection, vary from laboratory to laboratory. In addition, the interpretation of most drug screens is hampered by many false-positive and false-negative results. Many opiate toxicology screens poorly detect hydrocodone, and do not detect the fully synthetic opioids at all (e.g., methadone, buprenorphine, fentanyl). Several common benzodiazepines may not be detected, as may not synthetic cannabinoids or “bath salts.” The amphetamine screen, on the other hand, is typically overly sensitive and often is triggered by prescription amphetamines and some over-the-counter cold preparations. As such, the urine drug-of-abuse screen is typically of limited utility for medical clearance, but may serve a useful function for psychiatrists in their evaluation of the adolescent patient. Besides its psychiatric usefulness, urine drug-of-abuse screens are potentially helpful in patients with altered mental status of unknown etiology, persistent unexplained tachycardia, and acute myocardial ischemia or stroke at a young age. These screens can also be useful in the assessment of a neglected or abused child. Consultation with a medical toxicologist can be helpful in interpreting drug screens and directing which specific drug levels or other lab analyses might aid in patient management.

In the case of a neglected or allegedly abused child, a positive toxicology screen can add substantial weight to a claim of abuse or neglect. In these cases and any case with medicolegal implications, any positive screen mus t be confirmed with gas chromatography/mass spectroscopy, which is considered the gold standard measurement for legal purposes.

Additional Diagnostic Testing

An electrocardiogram (ECG) is a quick and noninvasive bedside test that can yield important clues to diagnosis and prognosis. Particular attention should be paid to the ECG intervals ( Table 77.6 ). A widened QRS interval, putting the patient at risk for monomorphic ventricular tachycardia, suggests blockade of fast sodium channels. A widened QTc interval suggests effects at the potassium rectifier channels and portends a risk of torsades de pointes (polymorphic ventricular tachycardia).

Chest radiography may reveal signs of pneumonitis (e.g., hydrocarbon aspiration), noncardiogenic pulmonary edema (e.g., salicylate toxicity), or a foreign body. Abdominal radiography is most helpful in screening for the presence of lead paint chips or other foreign bodies. It may detect a bezoar (concretion), demonstrate radiopaque tablets, or reveal drug packets in a “body packer.” Further diagnostic testing is based on the differential diagnosis and pattern of presentation.

Supportive Care

Careful attention is paid first to the “ABCs” of airway, breathing, and circulation; there should be a low threshold to aggressively manage the airway of a poisoned patient because of the patient's propensity to quickly become comatose. In fact, endotracheal intubation is often the only significant intervention needed in many poisoned patients. An important caveat is the tachypneic patient with a clear lung examination and normal oxygen saturation. This should alert the clinician to the likelihood that the patient is compensating for an acidemia. Paralyzing such a patient and underventilating might prove fatal. If intubation is absolutely necessary for airway protection or a tiring patient, a good rule of thumb is to match the ventilatory settings to the patient's preintubation minute ventilation.

Hypotensive patients often are not hypovolemic but are poisoned, and aggressive fluid resuscitation may lead to fluid overload. If hypotension persists after 1 or 2 standard boluses of crystalloid, infusion of a direct-acting vasopressor, such as norepinephrine or epinephrine, is preferred. Dysrhythmias are managed in the standard manner, except for those caused by agents that block fast sodium channels of the heart, for which boluses of sodium bicarbonate are given.

Seizures should primarily be managed with agents that potentiate the γ-aminobutyric acid (GABA) complex, such as benzodiazepines or barbiturates. The goal of supportive therapy is to support the patient's vital functions until the patient can eliminate the toxin. Patients with an elevated creatine phosphokinase (CPK) should be aggressively hydrated with crystalloid, with a goal urine output of 1-2 mL/kg/hr and close monitoring of CPK trend.

Decontamination

The majority of poisonings in children are from ingestion, although exposures can also occur by inhalational, dermal, and ocular routes. The goal of decontamination is to minimize absorption of the toxic substance. The specific method employed depends on the properties of the toxin itself and the route of exposure. Regardless of the decontamination method used, the efficacy of the intervention decreases with increasing time since exposure. Decontamination should not be routinely employed for every poisoned patient. Instead, careful decisions regarding the utility of decontamination should be made for each patient and should include consideration of the toxicity and pharmacologic properties of the exposure, route of the exposure, time since the exposure, and risks vs benefits of the decontamination method.

Dermal and ocular decontamination begins with removal of any contaminated clothing and particulate matter, followed by flushing of the affected area with tepid water or normal saline (NS). Treating clinicians should wear proper protective gear when performing irrigation. Flushing for a minimum of 10-20 min is recommended for most exposures, although some chemicals (e.g., alkaline corrosives) require much longer periods of flushing. Dermal decontamination, especially after exposure to adherent or lipophilic (e.g., organophosphates) agents, should include thorough cleansing with soap and water. Water should not be used for decontamination after exposure to highly reactive agents, such as elemental sodium, phosphorus, calcium oxide, and titanium tetrachloride. After an inhalational exposure, decontamination involves moving the patient to fresh air and administering supplemental oxygen if indicated.

Gastrointestinal (GI) decontamination strategies are most likely to be effective in the 1 or 2 hours after an acute ingestion . GI absorption may be delayed after ingestion of agents that slow GI motility (anticholinergic medications, opioids), massive amounts of pills, sustained-release (SR) preparations, and agents that can form pharmacologic bezoars (e.g., enteric-coated salicylates). GI decontamination more than 2 hr after ingestion may be considered in patients who ingest toxic substances with these properties. However, even rapid institution of GI decontamination with activated charcoal will, at best, bind only approximately 30% of the ingested substance. GI decontamination should never supplant excellent supportive care and should not be employed in an unstable or persistently vomiting patient. Described methods of GI decontamination include induced emesis with ipecac, gastric lavage, cathartics, activated charcoal, and whole-bowel irrigation (WBI). Of these, only activated charcoal and WBI are of potential benefit.

Directed Therapy

Enhanced Elimination

Enhancing elimination results in increased clearance of a poison that has already been absorbed. It is only useful for a few toxins and in these cases is a potentially lifesaving intervention. Methods of enhanced elimination include urinary alkalinization, hemodialysis, and multidose activated charcoal.

Pharmaceuticals

Analgesics

Acetaminophen

Acetaminophen (APAP) is the most widely used analgesic and antipyretic in pediatrics, available in multiple formulations, strengths, and combinations. Consequently, APAP is commonly available in the home, where it can be unintentionally ingested by young children, taken in an intentional overdose by adolescents and adults, or inappropriately dosed in all ages. In the United States, APAP toxicity remains the most common cause of acute liver failure and is the leading cause of intentional poisoning death.

Pathophysiology

APAP toxicity results from the formation of a highly reactive intermediate metabolite, N -acetyl- p -benzoquinone imine (NAPQI). In therapeutic use, only a small percentage of a dose (approximately 5%) is metabolized by the hepatic cytochrome P450 enzyme CYP2E1 to NAPQI, which is then immediately joined with glutathione to form a nontoxic mercapturic acid conjugate. In overdose, glutathione stores are overwhelmed, and free NAPQI is able to combine with hepatic macromolecules to produce hepatocellular necrosis. The single acute toxic dose of APAP is generally considered to be >200 mg/kg in children and >7.5-10 g in adolescents and adults. Repeated administration of APAP at supratherapeutic doses (>90 mg/kg/day for consecutive days) can lead to hepatic injury or failure in some children, especially in the setting of fever, dehydration, poor nutrition, and other conditions that serve to reduce glutathione stores.

Any child with a history of acute ingestion of >200 mg/kg (unusual in children <6 yr) or with an acute intentional ingestion of any amount should be referred to a healthcare facility for clinical assessment and measurement of a serum APAP level.

Clinical and Laboratory Manifestations

Classically, 4 general stages of APAP toxicity have been described ( Table 77.10 ). The initial signs are nonspecific (i.e., nausea and vomiting) and may not be present. Thus the diagnosis of APAP toxicity cannot be based on clinical symptoms alone, but instead requires consideration of the combination of the patient's history, symptoms, and laboratory findings.

Table 77.10

Classic Stages in Clinical Course of Acetaminophen Toxicity

STAGE	TIME AFTER INGESTION	CHARACTERISTICS
I	0.5-24 hr	Anorexia, vomiting, malaise Lab tests typically normal, except for acetaminophen level
II	24-48 hr	Resolution of earlier symptoms; right upper quadrant abdominal pain and tenderness; elevated hepatic transaminases (aspartate > alanine), INR
III	3-5 days	Peak transaminase elevations; development of liver failure, multi organ-system failure, death or recovery begins
IV	4 days to 2 wk	Resolution of liver function abnormalities Clinical recovery precedes histologic recovery

If a toxic ingestion is suspected, a serum APAP level should be measured 4 hr after the reported time of ingestion. For patients who present to medical care more than 4 hr after ingestion, a stat APAP level should be obtained. APAP levels obtained <4 hr after ingestion, unless “nondetectable,” are difficult to interpret and cannot be used to estimate the potential for toxicity. Other important baseline lab tests include hepatic transaminases, renal function tests, and coagulation parameters.

Treatment

When considering the treatment of a patient poisoned or potentially poisoned with APAP, and after assessment of the ABCs, it is helpful to place the patient into one of the following four categories.

1

Prophylactic

By definition, these patients have a normal aspartate transaminase (AST). If the APAP level is known and the ingestion is within 24 hr of the level being drawn, treatment decisions are based on where the level falls on the Rumack-Matthew nomogram ( Fig. 77.1 ). Any patient with a serum APAP level in the possible or probable hepatotoxicity range per the nomogram should be treated with N -acetylcysteine (NAC). This nomogram is only intended for use in patients who present within 24 hr of a single acute APAP ingestion with a known time of ingestion. If treatment is recommended, they should receive NAC as either oral Mucomyst or IV Acetadote for 24 or 21 hr, respectively. Repeat AST and APAP concentration drawn toward the end of that interval should be obtained. If the AST remains normal and the APAP becomes nondetectable, treatment may be discontinued. If the AST becomes elevated, the patient moves into the next category of treatment (injury). If APAP is still present, treatment should be continued until the level is nondetectable. In the case of a patient with a documented APAP level, normal AST, and an unknown time of ingestion, treatment should ensue until the level is nondetectable, with normal transaminases.

The importance of instituting therapy with either IV or oral NAC no later than 8 hr from the time of ingestion cannot be overemphasized. No patient, regardless of the size of the ingestion, who receives NAC within 8 hr of overdose should die from liver failure. The longer from the 8 hr mark the initiation of therapy is delayed, the greater the risk of acute liver failure. Any patient presenting close to or beyond the 8 hr mark after an APAP overdose should be empirically started on NAC pending laboratory results.

2

Hepatic Injury

These patients are exhibiting evidence of hepatocellular necrosis, manifested first as elevated liver transaminases (usually AST first, then alanine transaminase [ALT]), followed by a rise in the INR. Any patient in this category requires therapy with NAC (IV or oral). When to discontinue therapy in the clinically well patient remains controversial, but in general the transaminases and INR have peaked and fallen significantly “toward” normal (they do not need to be normal). Most patients' liver enzymes will peak 3 or 4 days after their ingestion.

3

Acute Liver Failure

The King's College criteria are used to determine which patients should be referred for consideration of liver transplant. These criteria include acidemia (serum pH <7.3) after adequate fluid resuscitation, coagulopathy (INR >6), renal dysfunction (creatinine >3.4 mg/dL), and grade III or IV hepatic encephalopathy (see Chapter 391 ). A serum lactic acid >3 mmol/L (after IV fluids) adds to both sensitivity and specificity of the criteria to predict death without liver transplant. The degree of transaminase elevation does not factor in to this decision-making process.

4

Repeated Supratherapeutic Ingestion

APAP is particularly prone to unintentional overdose through the ingestion of multiple medications containing the drug or simply because people assume it to be safe at any dose. Ingestion of amounts significantly greater than the recommended daily dose for several days or more puts one at risk for liver injury. Because the Rumack-Matthew nomogram is not helpful in this scenario, a conservative approach is taken. In the asymptomatic patient, if the AST is normal and the APAP is <10 µg/mL, no therapy is indicated. A normal AST and an elevated APAP warrants NAC dosing for at least long enough for the drug to metabolize while the AST remains normal. An elevated AST puts the patient in the “hepatic injury” category previously described. A patient presenting with symptoms (i.e., right upper quadrant pain, vomiting, jaundice) should be empirically started on NAC pending lab results.

NAC is available in oral and IV forms, and both are considered equally efficacious (see Table 77.7 for the dosing regimens of the oral vs IV form). The IV form is used in patients with intractable vomiting, those with evidence of hepatic failure, and pregnant patients. Oral NAC has an unpleasant taste and smell and can be mixed in soft drink or fruit juice or given by NG tube to improve tolerability of the oral regimen. Administration of IV NAC (as a standard 3% solution to avoid administering excess free water, typically in 5% dextrose), especially the initial loading dose, is associated in some patients with the development of anaphylactoid reactions (non–immunoglobulin E mediated). These reactions are typically managed by stopping the infusion; treating with diphenhydramine, albuterol, and/or epinephrine as indicated; and restarting the infusion at a slower rate once symptoms have resolved. IV NAC is also associated with mild elevation in measured INR (range: 1.2-1.5) because of laboratory interference. IV dosing, however, delivers less medication to the liver compared with the oral regimen. As a result, many toxicologists now recommend higher doses of the IV formulation in patients with large overdoses. Transaminases, synthetic function, and renal function should be followed daily while the patient is being treated with NAC. Patients with worsening hepatic function or clinical status might benefit from more frequent lab monitoring. A patient-tailored approach is now the norm for when to stop NAC therapy, for deciding whom to refer for transplantation evaluation, and often for the dose of IV NAC in patients with either very high APAP levels or signs of injury. Consultation with the regional PCC and medical toxicologist can help streamline the care of these patients, ultimately shortening their length of stay with potentially improved outcomes.

Salicylates

The incidence of salicylate poisoning in young children has declined dramatically since APAP and ibuprofen replaced aspirin as the most commonly used analgesics and antipyretics in pediatrics. However, salicylates remain widely available, not only in aspirin-containing products but also in antidiarrheal medications, topical agents (e.g., keratolytics, sports creams), oil of wintergreen, and some herbal products. Oil of wintergreen contains 5 g of salicylate in 1 teaspoon (5 mL), meaning ingestion of very small volumes of this product has the potential to cause severe toxicity.

Pathophysiology

Salicylates lead to toxicity by interacting with a wide array of physiologic processes, including direct stimulation of the respiratory center, uncoupling of oxidative phosphorylation, inhibition of the tricarboxylic acid cycle, and stimulation of glycolysis and gluconeogenesis. The acute toxic dose of salicylates is generally considered to be >150 mg/kg. More significant toxicity is seen after ingestions of >300 mg/kg, and severe, potentially fatal, toxicity is described after ingestions of >500 mg/kg.

Clinical and Laboratory Manifestations

Salicylate ingestions are classified as acute or chronic, and acute toxicity is much more common in pediatric patients. Early signs of acute salicylism include nausea, vomiting, diaphoresis, and tinnitus. Moderate salicylate toxicity can manifest as tachypnea and hyperpnea, tachycardia, and altered mental status. The tachycardia largely results from marked insensible losses from vomiting, tachypnea, diaphoresis, and uncoupling of oxidative phosphorylation. Thus, careful attention should be paid to volume status and early volume resuscitation in the significantly poisoned patient. Signs of severe salicylate toxicity include mild hyperthermia, coma, and seizures. Chronic salicylism can have a more insidious presentation, and patients can show marked toxicity (e.g. altered mental status, noncardiogenic pulmonary edema, acidemia) at significantly lower salicylate levels than in acute toxicity.

Classically, laboratory values from a patient poisoned with salicylates reveal a primary respiratory alkalosis and a primary, elevated anion gap metabolic acidosis. Early in the course of acute salicylism, respiratory alkalosis dominates and the patient is alkalemic. As the respiratory stimulation diminishes, the patient will move toward acidemia. Hyperglycemia (early) and hypoglycemia (late) have been described. Abnormal coagulation studies and acute kidney injury may be seen but are not common.

Serial serum salicylate levels should be closely monitored (every 2-4 hr initially) until they are consistently downtrending. Salicylate absorption in overdose is unpredictable and erratic, especially with an enteric-coated product, and levels can rapidly increase into the highly toxic range, even many hours after the ingestion. The Done nomogram is of poor value and should not be used. Serum and urine pH and electrolytes should be followed closely. An APAP level should be checked in any patient who intentionally overdoses on salicylates, because APAP is a common co-ingestant, and people often confuse or combine their nonprescription analgesic medications. Salicylate toxicity can cause a noncardiogenic pulmonary edema, especially in chronic overdose; consequently, a chest radiograph is recommended in any patient in respiratory distress.

Treatment

For the patient who presents soon after an acute ingestion, initial treatment should include gastric decontamination with activated charcoal. Salicylate pills occasionally form bezoars, which should be suspected if serum salicylate concentrations continue to rise many hours after ingestion or are persistently elevated despite appropriate management. Gastric decontamination is typically not useful after chronic exposure.

Initial therapy focuses on aggressive volume resuscitation and prompt initiation of sodium bicarbonate therapy in the symptomatic patient, even before obtaining serum salicylate levels. Therapeutic salicylate levels are 10-20 mg/dL, and levels >25 or 30 mg/dL warrant treatment.

The primary mode of therapy for salicylate toxicity is urinary alkalinization . Urinary alkalinization enhances the elimination of salicylates by converting salicylate to its ionized form, “trapping” it in the renal tubules, thus enhancing elimination. In addition, maintaining an alkalemic serum pH decreases CNS penetration of salicylates because charged particles are less able to cross the blood-brain barrier. Alkalinization is achieved by administration of a sodium bicarbonate infusion at approximately 2 times maintenance fluid rates. The goals of therapy include a urine pH of 7.5-8, a serum pH of 7.45-7.55, and decreasing serum salicylate levels. In general, in the presence of an acidosis, an aspirin-poisoned patient's status can be directly related to the patient's serum pH: the lower the pH, the greater the relative amount of salicylate in the uncharged, nonpolar form and the greater the penetration of the blood-brain barrier by the drug. Careful attention should also be paid to serial potassium levels in any patient on a bicarbonate infusion, since potassium will be driven intracellularly and hypokalemia impairs alkalinization of the urine. For these reasons, potassium is often added to the bicarbonate drip. Repeat doses of charcoal may be beneficial because of the often delayed and erratic absorption of aspirin. Parenteral glucose should be provided to any salicylate-poisoned patients with altered mental status because they may have CNS hypoglycemia (i.e., neuroglycopenia) not seen in a peripheral serum glucose test.

In patients with severe toxicity, hemodialysis may be required. Indications for dialysis include severe acid-base abnormalities (specifically severe acidosis and acidemia), a rising salicylate level (despite adequate decontamination and properly alkalinized urine), pulmonary edema, cerebral edema, seizures, and renal failure. Serum salicylate concentrations alone are not a clear indicator of the need for dialysis and should always be interpreted along with the clinical status of the patient.

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