Poisoning and drug overdose with acetaminophen, anticholinesterase insecticides, calcium channel blockers, iron, opioids, and weapons of mass chemical poisoning are the focus of the remainder of this chapter. These agents were chosen because they provide examples of different mechanisms of toxicity and the application of general treatment approaches, as well as some agent-specific pharmacotherapeutic interventions.
Acute acetaminophen poisoning characteristically results in hepatotoxicity44 and is a leading cause of acute liver failure in the United States. Clinical presentation is dependent on the time since ingestion, presence of risk factors, and the ingestion of other drugs. During the first 12 to 24 hours after ingestion, nausea, vomiting, anorexia, and diaphoresis may be observed; however, many patients are asymptomatic. During the next 1 to 3 days, which is a latent phase of lessened symptoms, patients often have an asymptomatic rise in liver enzymes and bilirubin. Signs and symptoms of hepatic injury become manifest 3 to 5 days after ingestion and include right upper quadrant abdominal tenderness, jaundice, hypoglycemia, and encephalopathy. Prolongation of the international normalized ratio (INR) worsens as hepatic necrosis progresses and may lead to disseminated intravascular coagulopathy. Patients with severe hepatic damage may develop hepatic coma and hepatorenal syndrome, and death can occur.44,45 Survivors of severe hepatotoxicity usually exhibit no residual functional or histologic abnormalities of the liver within 1 to 6 months of the incident.46
Acetaminophen is metabolized in the liver primarily to glucuronide or sulfate conjugates, which are excreted into the urine with small amounts (<5%) of unchanged drug. Approximately 5% of a therapeutic dose is metabolized by CYPs, primarily CYP2E1, to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). Normally, NAPQI is subsequently conjugated with glutathione, a sulfhydryl-containing compound, in the hepatocyte and excreted in the urine as a mercapturate conjugate (Fig. e9-1).44
Pathway of acetaminophen metabolism and basis for hepatotoxicity. (NAPQI, N-acetyl-p-benzoquinoneimine, a reactive acetaminophen metabolite.)
CLINICAL PRESENTATION Acute Acetaminophen Poisoning General Symptoms
Nausea, vomiting, and abdominal discomfort within 1 to 12 hours after ingestion.
Right upper abdominal quadrant tenderness, typically within 1 to 2 days.
Typically no signs present within first day.
Jaundice, scleral icterus, and bleeding within 3 to 10 days.
Oliguria occasionally within 2 to 7 days.
With severe poisoning, hepatic encephalopathy (delirium, depressed reflexes, and coma) within 5 to 10 days.
Toxic serum acetaminophen concentration no earlier than 4 hours after ingestion by comparison with nomogram.
Elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum bilirubin, and INR; hypoglycemia within 1 to 3 days.
Elevated serum creatinine and blood urea nitrogen (BUN) within 2 to 7 days.
Sulfate stores are depleted in an acute overdose situation. This leads to increased acetaminophen metabolism via CYP2E1 and eventual depletion of the available glutathione used to detoxify NAPQI, which then reacts with other hepatocellular sulfhydryl compounds. This results in centrilobular hepatic necrosis.44 Several other mechanisms, such as cytokine release and oxidative stress, also may be initiated by the initial cellular injury.44
In many cases of severe hepatotoxicity, impaired kidney function also is present and may range from oliguria to acute kidney injury. The etiology of the impaired kidney function may be a direct effect of NAPQI, generated by renal cytochrome oxidase, or a consequence of hepatic injury resulting in hepatorenal syndrome.45
Acetaminophen, also known as paracetamol, is available widely without prescription as an analgesic and antipyretic. It is available in various oral dosage forms, including extended-release preparations and an intravenous formulation. Acetaminophen may be combined with other drugs, such as antihistamines or opioid analgesics, and marketed in cough and cold preparations, menstrual remedies, and allergy products. Some patients may not recognize that they are consuming several products containing acetaminophen, which can increase the total dose, systemic exposure, and the subsequent risk of hepatotoxicity.
Acetaminophen is commonly ingested by small children and is used frequently in suicide attempts by adolescents and adults.3 Each year acetaminophen accounts for approximately 78,000 emergency department visits with 78% related to acts of self-harm.47 The 2014 AAPCC-NPDS report documented 50,331 nonfatal single-drug product exposures and 65 deaths from acetaminophen alone, with 58% of the exposures in children younger than 6 years. Another 22,951 exposures were from combination drug products containing acetaminophen.3
Age-based differences in the metabolism of acetaminophen appear to be responsible for major differences in the incidence of serious toxicity. Despite the common ingestion of acetaminophen by young children, few develop hepatotoxicity from acute overdosage.3 In children younger than 9 to 12 years, acetaminophen undergoes more sulfation and less glucuronidation. The reduced fraction available for metabolism by CYPs may explain the rare development of serious toxicity in young children who take large overdoses. Earlier treatment intervention and spontaneous emesis also may reduce the risk of toxicity in children.
Acute, single-ingestion of at least 10 g or 200 mg/kg, whichever is less, of acetaminophen by patients 6 years or older is associated with development of hepatotoxicity (200 mg/kg or more of acetaminophen in children younger than 6 years).48 Patients have survived much larger doses, particularly with early treatment. Initial symptoms, if present, do not predict the severity of the toxicity that eventually occurs.
Repeated ingestion of supratherapeutic doses of acetaminophen has been associated with hepatotoxicity in adults and children.48,49,50,51 Patients who are fasting or have ingested alcohol in the preceding 5 days appear to be at greater risk.50 Young children have a higher risk when they have been acutely fasting as the result of a febrile illness or gastroenteritis.51 Patients should be referred for medical evaluation if there is evidence that the ingestion exceeded 4 g/day or 100 mg/kg/day, whichever is less for 2 or more days.48
Chronic exposure to drugs that induce CYPs—specifically CYP2E1, which is responsible for most of the formation of NAPQI—may increase the risk of acetaminophen hepatotoxicity. Poorer outcomes have been noted in patients who chronically ingest alcohol and those receiving anticonvulsants, both known to induce CYP2E1.46 Patients with chronic alcoholism have a 3.5 greater odds of mortality with acute acetaminophen poisoning.50
The risk of developing hepatotoxicity with acute ingestion of acetaminophen may be predicted with a commonly used nomogram that is based on the acetaminophen serum concentration and time after ingestion.52 The nomogram used in the United States is readily available in the FDA approved package insert for acetylcysteine (available at: http://dailymed.nlm.nih.gov/) and in several electronic information databases (eg, Micromedex, UpToDate). Treatment should be started if the patient’s serum concentration is above the line on the nomogram that starts at 150 mcg/mL (1,000 μmol/L) at 4 hours. If the plasma concentration plotted on the nomogram falls above the nomogram treatment line, indicating that hepatic damage is possible, a full course of treatment with acetylcysteine is indicated. When the results of the acetaminophen determination will be available later than 8 hours after the ingestion, acetylcysteine therapy should be initiated based on the history and later discontinued if the results indicate nontoxic concentrations.52
The nomogram is not useful for assessing chronic or supratherapeutic exposures to acetaminophen. Some have advocated that patients with chronic alcoholism should be treated with acetylcysteine regardless of the risk estimation.50,54 Assessment and management of IV administered acetaminophen is presently similar to the acute oral overdose.55
Therapy of an acute acetaminophen overdose depends on the amount ingested, time after ingestion, and serum concentration of acetaminophen. When excessive amounts are ingested, the history is unclear, or an intentional ingestion is suspected, the patient should be evaluated at an emergency department and acetaminophen serum concentrations obtained. Prehospital care generally is not indicated.48 If the patient presents to the emergency department within 4 hours of the ingestion or ingestion of other drugs is suspected, one dose of activated charcoal can be administered.
Acetylcysteine (also known as N-acetylcysteine), a sulfhydryl-containing compound, replenishes the hepatic stores of glutathione by serving as a glutathione surrogate that combines directly with reactive metabolites or by serving as a source of sulfate, thus preventing hepatic damage.53 It should be started within 10 hours of the ingestion to be most effective.52 Initiation of therapy 24 to 36 hours after the ingestion may be of value in some patients, particularly those with measurable serum acetaminophen concentrations.53,56 Patients with fulminant hepatic failure may benefit through other mechanisms by the administration or initiation of acetylcysteine several days after ingestion.53,56
Oral and IV formulations of acetylcysteine are available for clinical use. While there is no clear evidence favoring one formulation over the other,57 there are several notable differences between them (Table e9-10).53,57,58 Most notable is the occurrence (approximately 10% of cases) of anaphylactoid reactions (see Chapter 89) following the IV infusion. Acetylcysteine IV was used 4.7 times more frequently than the oral form as reported in the 2014 AAPCC-NPDS.3 When acetaminophen plasma concentrations are below the nomogram treatment line, there is little risk of toxicity, protective therapy with acetylcysteine is not necessary, and medical therapy likely is unnecessary.52,53 The acetaminophen blood sample should be drawn no sooner than 4 hours after the ingestion to ensure that peak acetaminophen concentrations have been reached. If a concentration is obtained less than 4 hours after ingestion, it is not interpretable, and a second determination should be done at least 4 hours after ingestion. Serial determinations of a serum concentration, 4 to 6 hours apart, typically are unnecessary unless there is some evidence of slowed gastrointestinal motility as the result of the ingestion of certain drugs (eg, opioids, or anticholinergics), when an extended-release product is involved or if chronic or supratherapeutic overdoses are suspected. In these circumstances, therapy with acetylcysteine is continued if any concentration is above the treatment line of the nomogram, and provisional therapy is discontinued when both concentrations are below the treatment line. Several alternative dosing regimens for acetylcysteine with different duration, administration technique, and clinical endpoints have been proposed.58,59
TABLE e9-10Comparison of IV and Oral Regimens for Acetylcysteine in the Treatment of Acute Acetaminophen Poisoning |Favorite Table|Download (.pdf) TABLE e9-10 Comparison of IV and Oral Regimens for Acetylcysteine in the Treatment of Acute Acetaminophen Poisoning
|Characteristic ||IV ||Oral |
|Regimen ||150 mg/kg in 200 mL D5W infused over 1 hour, then 50 mg/kg in 500 mL D5W over 4 hours, followed by 100 mg/kg in 1,000 mL D5W over 16 hoursa ||140 mg/kg, followed 4 hours later by 70 mg/kg every 4 hours for 17 doses diluted to 5% with juice or soft drinks |
|Total dose (mg/kg) ||300 ||1,330 |
|Duration (h) ||21 ||72 |
|Adverse effects ||Nausea, vomiting; anaphylactoid reactions (rash, hypotension, wheezing, dyspnea); acute flushing and erythema in first hour of the infusion that typically resolves spontaneously ||Nausea, vomiting |
|Ancillary therapy, if needed ||Antihistamines and epinephrine for severe anaphylactic reactions ||Antiemetics |
|Trade name ||Acetadote ||Mucomyst |
|Available strength ||20% ||10%, 20% |
The 72-hour oral acetylcysteine and the 21-hour IV regimen are satisfactory for most patients, but some state that the 72-hour regimen is too long while others believe the 21-hour regimen is too short. Individualized therapy based on clinical end points, for example, absence of acetaminophen in the blood at the end of a regimen, presence of hepatic encephalopathy or ALT approaching normal range, has been proposed as an alternative to strict adherence to the duration in the package insert. Several alternative dosing regimens have been described recently in the literature, but the number of patients in the studies has been relatively small and the findings are not generalizable. Accepted and validated criteria are lacking at present.
Although young children have an inherently lower risk of acetaminophen-induced hepatotoxicity, these patients are managed in the same manner as adults. When acetaminophen serum concentrations predict that toxicity is probable, young children should receive acetylcysteine in the dosing regimen described previously.59
Hemodialysis may be considered in rare cases when serum acetaminophen concentrations are exceedingly high (>700-1,000 mcg/mL [>4,600-6,600 μmol/L]) with the early development of altered mental status and severe metabolic acidosis prior to the onset of hepatic failure.60 If fulminant hepatic failure develops, the approaches described in Chapter 37 should be considered. In patients unresponsive to acetylcysteine, liver transplantation is a lifesaving option.46
Monitoring and Prevention
Baseline liver function tests (AST, ALT, bilirubin, INR), serum creatinine concentration, and urinalysis should be obtained on admission and repeated at 24-hour intervals until at least 96 hours have elapsed for patients at risk. Most patients with liver injury develop elevated transaminase concentrations within 24 hours of ingestion. Serum concentrations of AST or ALT greater than 1,000 international units per liter (IU/L) (16.7 μkat/L) commonly are associated with other signs of liver dysfunction and have been used as the threshold concentration in outcome studies to define severe liver toxicity.52 The extent of transaminase elevation is not correlated directly with the severity of hepatic injury, with nonfatal cases demonstrating peak concentrations as high as 30,000 IU/L (500 μkat/L) between 48 and 72 hours after ingestion.46
Prevention of acetaminophen poisoning is based on recognition of the maximum daily therapeutic doses (4 g in adults), observance of general poison prevention practices, and early intervention in cases of suspected overdose. The frequent involvement of acetaminophen in poisonings and overdoses, whether or not declared by the patient, has led to the routine determination of acetaminophen concentrations in patients admitted to emergency departments for any overdose.54
The clinical manifestations of anticholinesterase insecticide poisoning include any or all of the following: pinpoint pupils, excessive lacrimation, excessive salivation, bronchorrhea, bronchospasm, and expiratory wheezes, hyperperistalsis producing abdominal cramps and diarrhea, bradycardia, excessive sweating, fasciculations and weakness of skeletal muscles, paralysis of skeletal muscles (particularly those involved with respiration), convulsions, and coma.61 Symptoms of anticholinesterase poisoning and their response to antidotal therapy depend on the action of excessive acetylcholinesterase at different receptor types (Table e9-11).
TABLE e9-11Effects of Acetylcholinesterase Inhibition at Muscarinic, Nicotinic, and CNS Receptors |Favorite Table|Download (.pdf) TABLE e9-11 Effects of Acetylcholinesterase Inhibition at Muscarinic, Nicotinic, and CNS Receptors
|Muscarinic receptors ||Nicotinic-sympathetic neurons |
|Diarrhea ||Increased blood pressure |
|Urination ||Sweating and piloerection |
|Miosisa ||Mydriasisa |
|Bronchorrhea ||Hyperglycemia |
|Bradycardiaa ||Tachycardiaa |
|Emesis ||Priapism |
|Lacrimation ||Nicotinic-neuromuscular neurons |
|Salivation ||Muscular weakness |
|CNS receptors (mixed type) ||Cramps |
|Coma ||Fasciculations |
|Seizures ||Muscular paralysis |
CLINICAL PRESENTATION Anticholinesterase Insecticide Poisoning General Symptoms
Diarrhea, diaphoresis, excessive urination, miosis, blurred vision, pulmonary congestion, dyspnea, vomiting, lacrimation, salivation, and shortness of breath within 1 hour.
Headache, confusion, coma, and seizures possible within 1 to 6 hours.
Increased bronchial secretions, tachypnea, rales, and cyanosis within 1 to 6 hours.
Muscle weakness, fasciculations, and respiratory paralysis within 1 to 6 hours.
Bradycardia, atrial fibrillation, atrioventricular block, and hypotension within 1 to 6 hours.
Other Diagnostic Tests
Markedly depressed serum pseudocholinesterase activity.
Altered arterial blood gases (acidosis), serum electrolytes, BUN, and serum creatinine in response to respiratory distress and shock within 1 to 6 hours.
Chest radiographs for progression of pulmonary edema or hydrocarbon pneumonitis in symptomatic patients.
Electrocardiogram (ECG) with continuous monitoring and pulse oximetry for complications from toxicity and hypoxia.
The time of onset and severity of symptoms depend on the route of exposure, potency of the agent, and total dose received. Toxic signs and symptoms develop most rapidly after inhalation or IV injection and slowest after skin contact. Anticholinesterase insecticides are absorbed through the skin, lungs, conjunctivae, and gastrointestinal tract. Severe symptoms can occur from absorption by any route. Most patients are symptomatic within 6 hours, and death may occur within 24 hours without treatment. Death typically is caused by respiratory failure resulting from the combination of pulmonary and cardiovascular effects (Fig. e9-2).61 Poisoning may be complicated by aspiration pneumonia, urinary tract infections, and sepsis.61,62
Pathogenesis of life-threatening effects of organophosphate poisoning.
Organophosphate poisoning has been associated with several residual effects, such as intermediate syndrome, extrapyramidal symptoms, neuropsychiatric effects, and delayed chronic neuropathy. Intermediate syndrome becomes manifest in some patients approximately 1 to 3 days after exposure and generally resolves within weeks of onset without further treatment. It is characterized by muscle weakness of proximal limbs, cranial nerve innervated muscles, and muscles of respiration. The inability of the patient to raise his or her head is often an initial sign. Extrapyramidal symptoms, which may develop 1 to 7 days after exposure, usually resolve spontaneously within a few days of onset. Neuropsychiatric effects, such as confusion, lethargy, memory impairment, headache, and depression, typically begin weeks to months after exposure and may last for years. Chronic neuropathy often presents as cramping muscle pain in the legs (upper extremities are sometimes involved), followed by rapidly progressive weakness and paralysis and develops 1 to 5 weeks after recovery from the acute poisoning exposure. Paresthesia and pain may persist and are unresponsive to further atropine or pralidoxime therapy. Improvement may be delayed for months to years, and in some cases the patient develops permanent disability. Chronic neuropathy is not associated with all organophosphates.61
Anticholinesterase insecticides phosphorylate the active site of cholinesterase in all parts of the body.61 Inhibition of this enzyme leads to accumulation of acetylcholine at affected receptors and results in widespread toxicity. Acetylcholine is the neurotransmitter responsible for physiologic transmission of nerve impulses from preganglionic and postganglionic neurons of the cholinergic (parasympathetic) nervous system, preganglionic adrenergic (sympathetic) neurons, neuromuscular junction in skeletal muscles, and multiple nerve endings in the central nervous system (Fig. e9-3).
Organization of neurotransmitters of the peripheral nervous system and site of acetylcholinesterase action. (ACh, acetylcholine; ACh-ase, acetylcholinesterase; M, muscarinic receptor; N, nicotinic receptor; NE, norepinephrine.)
Anticholinesterase insecticides include organophosphate and carbamate insecticides. These insecticides are currently in widespread use throughout the world for eradication of insects in dwellings and crops. Carbamates typically are less potent and inactivate cholinesterase in a more reversible fashion through carbamylation compared with organophosphates.61 The prototype anticholinesterase agent is the organophosphate, which is the focus of this discussion. A large number of organophosphates are used as pesticides (eg, dichlorovos, disulfoton, malathion, parathion, mevinphos, and phosmet), and several were specifically developed for use as potent chemical warfare agents and adapted as terrorist chemical weapons (see the section later in this chapter).7,61 An anticholinesterase insecticide typically is stored in a garage, chemical storage area, or living area. Anticholinesterase agents also can be found in occupational (eg, pest exterminators) or agricultural (eg, crop dusters or farm workers) settings. These agents also have been used as a means for suicide or homicide.
Anticholinesterase insecticides are among the most poisonous substances commonly used for pest control and are a frequent source of serious poisoning in children and adults in rural and urban settings. The 2014 AAPCC-NPDS report documented 4,208 nonfatal single-product exposures and 4 deaths and 30 severe cases from anticholinesterase insecticides alone or in combination with other pesticides, with 38% of exposures in children younger than 6 years.3
The triad of miosis, bronchial secretions, and muscle fasciculations should suggest the possibility of anticholinesterase insecticide poisoning and warrants a therapeutic trial of the antidote atropine. In cases of low-level exposure, failure to develop signs within 6 hours indicates a low likelihood of subsequent toxicity.61 Ruling out other chemical exposures may be guided initially by symptoms at presentation.6,7
Although the lethal dose for parathion is approximately 4 mg/kg, as little as 10 to 20 mg can be lethal to an adult and 2 mg (0.1 mg/kg) to a child. Small children may be more susceptible to toxicity because less pesticide is required per body weight to produce toxicity.61 Estimation of an exact dose is impossible in most cases of acute poisoning; thus, tabulated “toxic” doses generally are not helpful in assessing risk of toxicity. Generally, ingestion of a small mouthful (approximately 5 mL in adults) of the concentrated forms of an organophosphate intended to be diluted for commercial or agricultural use will produce serious, life-threatening toxicity, whereas a small mouthful of an already diluted household product, such as an aerosol insecticide for household use, typically does not produce serious toxic effects.63
Measurement of acetylcholinesterase activity at the neuronal synapse is not feasible clinically. Cholinesterase activity can be measured in the blood as the pseudocholinesterase (butyrylcholinesterase) activity of the plasma and acetylcholinesterase activity in the erythrocyte. Both cholinesterases will be depressed with anticholinesterase insecticide poisoning.61,63 Severity can be estimated roughly by the extent of depressed activity in relation to the low end of normal values. Because there are several methods to measure and report cholinesterase activity, each particular laboratory’s normal range must be considered. Clinical toxicity usually is seen only after a 50% reduction in enzyme activity, and severe toxicity typically is observed at levels 20% or less of the normal range.61 The intrinsic activity of acetylcholinesterase may be depressed in some individuals, but the absence of any manifestations in most people does not permit recognition of the relative deficiency in the general population. Therapy should not be delayed pending laboratory confirmation when insecticide poisoning is clinically suspected. Based on a history of an exposure and presence of typical symptoms, anticholinesterase toxicity should be readily recognized.6
At the scene of the incident, move the patient away from area containing the organophosphate and decontaminate affected body surfaces with conventional first aid measures (see Table e9-8). Remove all contaminated clothing. People handling the patient should wear gloves and aprons to protect themselves against contaminated clothing, skin, or gastric fluid of the patient.61,63 Because many insecticides are dissolved in a hydrocarbon vehicle, there is an additional risk of pulmonary aspiration of the hydrocarbon leading to pneumonitis when ingested. The risks and benefits of gastric decontamination (eg, gastric lavage, activated charcoal) should be considered carefully and should involve consultation with a poison control center or clinical toxicologist. Symptomatic cases of anticholinesterase insecticide exposure typically are referred to an emergency department for evaluation and treatment.
If the poison has been ingested within 1 hour, gastric lavage should be considered and followed by the administration of activated charcoal. For the patient with large-surface skin contamination, contaminated clothing should be removed and the patient washed with copious amounts of soap and water before he or she is transported and admitted to the emergency department or other patient care area. An alcohol wash may be useful for removing residual insecticide because of its lipophilic nature. A surgical scrub kit for the hands, feet, and nails may be useful for exposure to those areas. Supportive therapy should include maintenance of an airway (including bronchotracheal suctioning), provision of adequate ventilation, and establishment of an IV line.
Pharmacologic management of organophosphate intoxication relies on the administration of atropine and pralidoxime.61,63 Atropine has no effect on inhibited cholinesterase, but it competitively blocks the actions of acetylcholine on cholinergic and some central nervous system receptors. It thereby alleviates bronchospasm and reduces bronchial secretions. Although atropine has little effect on the flaccid muscle paralysis or the central respiratory failure of severe poisoning, it is indicated in all symptomatic patients and can be used as a diagnostic aid. It should be given IV and in larger than conventional doses of 0.05 to 0.1 mg/kg in children younger than 12 years and 2 to 5 mg in adolescents and young adults.62 It should be repeated at 5- to 10-minute intervals until bronchial secretions and pulmonary rales resolve. Some recommend aggressive escalation of doses (eg, doubling of each successive dose) in cases with severe toxicity.64 Therapy may require large doses over a period of several days until all absorbed organophosphate is metabolized, and acetylcholinesterase activity is restored.
Gastric lavage for organophosphate ingestions is performed routinely by some clinicians within 1 hour of ingestion. Evidence for the use of gastric lavage for organophosphates is based on reports of the lavage fluid having the odor of the insecticide. Others argue that excessive bronchial secretions and decreased mental status introduce substantial risk of pulmonary aspiration during gastric lavage.
Restoration of enzyme activity is necessary for severe poisoning, characterized by a reduction of cholinesterase activity to less than 20% of normal, profound weakness, and respiratory distress. Pralidoxime (Protopam), also called 2-PAM or 2-pyridine aldoximemethiodide, breaks the covalent bond between the cholinesterase and organophosphate and regenerates enzyme activity. Organophosphate-cholinesterase binding is reversible initially, but it gradually becomes irreversible. Therefore, therapy with pralidoxime should be initiated as soon as possible, preferably within 36 to 72 hours of exposure.63 The drug should be given at a dose of 25 to 50 mg/kg up to 1 g IV over 5 to 20 minutes. If muscle weakness persists or recurs, the dose can be repeated after 1 hour and again if needed. A continuous infusion of pralidoxime has been shown to be effective in adults when administered at 2 to 4 mg/kg/h preceded by a loading dose of 4 to 5 mg/kg65 and in children at 10 to 20 mg/kg/h with a loading dose of 15 to 50 mg/kg.66 Both atropine and pralidoxime should be given together because they have complementary actions (Table e9-12). Carbamate insecticide poisonings typically do not require the administration of pralidoxime.
TABLE e9-12Comparative Characteristics of Atropine and Pralidoxime for Anticholinesterase Poisoning |Favorite Table|Download (.pdf) TABLE e9-12 Comparative Characteristics of Atropine and Pralidoxime for Anticholinesterase Poisoning
|Characteristic ||Atropine ||Pralidoxime |
|Interaction ||Synergy with pralidoxime ||Reduces atropine dose requirement |
|Indication ||Any anticholinesterase agent ||Typically needed for organophosphates |
|Primary sites of action ||Muscarinic, CNS ||Nicotinic > muscarinic > CNS |
|Adverse effects ||Coma, hallucinations, tachycardia ||Dizziness, diplopia, tachycardia, headache |
|Daily dosea ||2-1,600 mg ||1-12 g |
|Total dosea ||2-11,422 mg ||1-92 g |
One of the pitfalls of therapy is the delay in administering sufficient doses of atropine or pralidoxime.61,64 The adverse effects of atropine and pralidoxime, which can be minimized by decreasing the dose, are predictable extensions of their anticholinergic actions and are minimally important compared with the life-threatening effects of severe anticholinesterase poisoning.
Monitoring and Prevention
Poisoned patients may require monitoring of vital signs, measurement of ventilatory adequacy such as blood gases and pulse oximetry, leukocyte count with differential to assess development of pneumonia, and chest radiographs to assess the degree of pulmonary edema or development of hydrocarbon pneumonitis. Workers involved in the formulation and application of pesticides should be monitored by periodic measurement of cholinesterase activity in their bloodstream. Untreated, acetylcholinesterase activity returns to normal values in approximately 120 days. Long-term follow-up for severe cases of poisoning may be necessary to detect the presence of delayed or persistent neuropsychiatric effects.
Many anticholinesterase insecticide poisonings are unintentional as a result of misuse, improper storage, failure to follow instructions for mixing or application, or inability to read directions for use. Training and vigilant adherence to directions may minimize some poisonings. Storing pesticides in original or labeled containers can minimize the risk of unintentional ingestion. Keeping pesticides out of children’s reach may decrease the risk of childhood poisoning.67
Overdosage with calcium channel blockers typically results in bradycardia and hypotension (Fig. e9-4). Many patients become lethargic and may develop agitation and coma. If the degree of hypotension becomes severe or is prolonged, the secondary effects of seizures, coma, and metabolic acidosis usually develop. Pulmonary edema, nausea and vomiting, and hyperglycemia are frequent complications of calcium channel blocker overdoses. Paralytic ileus, mesenteric ischemia, and colonic infarction have been observed in patients with severe hypotension. Many symptoms become manifest within 1 to 2 hours of ingestion. If a sustained-release formulation is involved, the onset of overt toxicity may be delayed by 6 to 18 hours from the time of ingestion. Severe poisoning can result in refractory shock and cardiac arrest. Death can occur within 3 to 4 hours of ingestion.68,69,70,71
Pathophysiologic changes associated with calcium channel blocker poisoning.
Most toxic effects of calcium channel blockers are produced by three basic actions on the cardiovascular system: vasodilation through relaxation of smooth muscles, decreased contractility by action on cardiac tissue, and decreased automaticity and conduction velocity through slow recovery of calcium channels. Calcium channel blockers interfere with calcium entry by inhibiting one or more of the several types of calcium channels and binding at one or more cellular binding sites. Selectivity of these actions varies with the calcium channel blocker and provides some therapeutic distinctions, but these differences are less clear with overdosage.71 Calcium channel blockers also inhibit insulin secretion, which results in hyperglycemia and changes in fatty acid oxidation in the myocardium that alter myocardial calcium flow and reduce contractility.72 Current experiences suggest that the signs and symptoms of calcium channel blocker toxicity upon overdose or poisoning are similar among the drugs in this class.
CLINICAL PRESENTATION Calcium Channel Blocker Poisoning General
Life-threatening cardiac toxicity (bradycardia, depressed contractility, and dysrhythmias) within 1 to 3 hours of ingestion, delayed by 12 to 18 hours if a sustained-release product is involved.
Nausea and vomiting within 1 hour.
Dizziness, lethargy, coma, and seizures within 1 to 3 hours.
Hypotension and bradycardia within 1 to 6 hours.
Unresponsiveness and depressed reflexes within 1 to 6 hours.
Atrioventricular block, intraventricular conduction defects, and ventricular dysrhythmias on ECG.
Other Diagnostic Tests
Significant hyperglycemia (greater than 250 mg/dL [13.9 mmol/L]) may indicate severe toxicity and consideration for aggressive therapy.
Altered arterial blood gases (metabolic acidosis), serum electrolytes, BUN, and serum creatinine in response to shock within 1 to 6 hours.
ECG with continuous monitoring and pulse oximetry to monitor for toxicity and shock.
Monitor for complications of pulmonary aspiration such as hypoxia and pneumonia by physical findings and chest radiographs.
Several calcium channel blockers are marketed in the United States for treatment of hypertension, certain dysrhythmias, and some forms of angina. The calcium channel blockers are classified by their chemical structure as phenylalkylamines (eg, verapamil), benzothiapines (eg, diltiazem), and dihydropyridines (eg, amlodipine, felodipine, nicardipine, and nifedipine). Several of these drugs, including diltiazem, nicardipine, nifedipine, and verapamil, are formulated as sustained-release oral dosage forms or have a slow onset of action and longer half-life (eg, amlodipine), allowing once-daily administration.
In 2014, the AAPCC-NPDS report documented 5,001 single-product toxic exposures to a calcium channel blocker; 86 patients exhibited and survived major toxic effects, and 20 died.3
Ingestion of an amount that exceeds the usual maximum single therapeutic dose or a dose equal to or greater than the lowest reported toxic dose (whichever is less) warrants referral to a poison control center and/or an emergency department. The threshold doses of several agents and dosage forms vary (eg, diltiazem: adults, greater than 120 mg for immediate release and chewed sustained release, greater than 360 mg for sustained release, greater than 540 mg for extended release; children younger than 6 years: >1 mg/kg).73 Patients on chronic therapy with these agents who acutely ingest an overdose may have a greater risk of serious toxicity. Elderly patients and those with underlying cardiac disease may not tolerate mild hypotension or bradycardia. Concurrent ingestion of β-adrenergic blocking drugs, digoxin, class I antiarrhythmics, and other vasodilators may worsen the cardiovascular effects of calcium channel blockers.69,71,73 The presence of persistent and significant hyperglycemia (>250 mg/dL [13.9 mmol/L]) has been suggested as a sign of grossly disturbed cardiac metabolism and physiology that merits attention and aggressive intervention.72
There is no accepted specific prehospital care for calcium channel blocker poisoning, except to summon an ambulance for symptomatic patients.84 The therapeutic options for management of calcium channel blocker poisoning include supportive care, gastric decontamination, and adjunctive therapy for the cardiovascular and metabolic effects. Supportive care consists of airway protection, ventilatory support, IV hydration to maintain adequate urine flow, and maintenance of electrolyte and acid-base balance. Maintaining vital organ perfusion is critical for successful therapy in order to allow time for calcium channel blocker toxicity to resolve.70,71
A single dose of activated charcoal should be considered if instituted generally within 1 to 2 hours after ingestion. Besides exhibiting a slower onset of symptoms, sustained-release formulations can form concretions in the intestine.70,71 Whole-bowel irrigation with polyethylene glycol electrolyte solution may accelerate intestinal elimination of the sustained-release tablets and should be considered for ingestions of sustained-release calcium channel blocker formulations. However, it should be used with caution if hemodynamic instability is present.28
Adjunctive therapy is focused on treating hypotension, bradycardia, and resulting shock. Hypotension is treated primarily by correction of coexisting dysrhythmias (eg, bradycardia, heart block) and implementation of conventional measures to treat decreased blood pressure. Infusion of normal saline and placement of the patient in the Trendelenburg position are initial therapies. Further fluid therapy should be guided by central venous pressure monitoring. Dopamine and epinephrine in conventional doses for cardiogenic shock should be considered next; consider norepinephrine or phenylephrine when caused by vasodilation.74 If hypotension persists, dysrhythmias are present, or other signs of serious toxicity are present, more specific therapy is indicated and intravenous lipid emulsion therapy should be considered.42,43,71
A calcium chloride bolus test dose (10-20 mg/kg up to 1-3 g) is the next specific therapy for patients with serious toxicity. In adults, calcium chloride 10% can be diluted in 100 mL normal saline and infused over 5 minutes through a central venous line. If a positive cardiovascular response is achieved with this test dose, a continuous infusion of calcium chloride (20-50 mg/kg/h) should be started. Calcium gluconate is less desirable to use because it contains less elemental calcium per milligram of final dosage form. Atropine also may be considered for treatment of bradycardia, but it is seldom sufficient as a sole therapy.70,74
Some clinicians believe that hyperinsulinemia-euglycemia or glucagon therapy for calcium channel blocker poisoning should be used early in the course of therapy. Others reserve it for life-threatening symptoms not responsive to other therapy. More safety and effectiveness data are needed to define the place of these two agents in therapy.
For severe cases of calcium channel blocker toxicity refractory to conventional therapy, an infusion of high-dose insulin with supplemental dextrose and potassium to produce a state of hyperinsulinemia and euglycemia should be considered.38,74,75 Case reports suggest that an IV bolus of regular insulin (0.5-1 U/kg) with 50 mL dextrose 50% (0.25 mg/kg for children) followed by a continuous infusion of regular insulin (0.5-1 U/kg/h) may improve myocardial contractility. The effect of insulin is presently unclear, but it may improve myocardial metabolism that is adversely affected by calcium channel blocker overdoses, such as decreased cellular uptake of glucose and free fatty acids and a shift from fatty acid oxidation to carbohydrate metabolism.68,70,75 This insulin regimen is titrated to improvement in systolic blood pressure over 100 mm Hg and heart rate over 50 beats/min. Serum glucose concentrations should be monitored closely to maintain euglycemia. Patients with serum potassium concentrations less than 2.5 mEq/L (mmol/L) may need supplemental potassium IV (see Chapter 51). The insulin infusion rate can be reduced gradually as signs of toxicity resolve. Sodium bicarbonate IV may be also necessary to establish acid-base balance and correct the metabolic acidosis that is common with serious calcium channel blocker overdoses.
If the bradycardia and hypotension are refractory to the foregoing therapy, a bolus infusion of glucagon (0.05-0.20 mg/kg, initial adult dose is 3-5 mg over 1-2 min) should be considered. Benefit typically is observed within 5 minutes of administration and can be sustained with a continuous IV infusion (0.05-0.1 mg/kg/h) titrated to clinical response, but response is variable and its value is uncertain.38,74 Glucagon possesses chronotropic and inotropic effects in part by stimulating adenylatecyclase and increasing cyclic adenosine monophosphate, which may promote intracellular entry of calcium through calcium channels. It thereby may improve hypotension and bradycardia.38 Vomiting is not uncommon with these large doses of glucagon, and the airway should be protected to prevent pulmonary aspiration. Hyperglycemia may occur or be exacerbated in those patients receiving glucagon therapy. Therapies with glucagon and insulin are based on animal studies and case reports; clinical trials demonstrating effectiveness have not been performed to date.38,75 Animal studies and case reports suggest that the emergent IV infusion of lipid emulsion can rapidly reverse the severe cardiac toxicity of calcium channel blockers by sequestering the drug in the circulation or serving as an energy substrate for the myocardium.42,43 Further evidence is needed to define its place in therapy.
Several lifesaving options may be warranted for patients with cardiogenic shock that is refractory to conventional therapy, such as electrical cardiac pacing, intraaortic balloon counterpulsation or cardiopulmonary bypass. Measures to enhance elimination from the bloodstream by hemodialysis or multiple-dose activated charcoal have not been shown to be effective and are not indicated for calcium channel blocker poisoning.32,69,71
CLINICAL PRESENTATION Acute Iron Poisoning General Symptoms
Signs Laboratory Tests
Vomiting, abdominal pain, and diarrhea within 1 to 6 hours.
Lethargy, coma, seizures, bloody vomiting, bloody diarrhea, and shock within 6 to 24 hours.
Other Diagnostic Tests
Toxic serum iron concentrations greater than 500 mcg/dL (90 μmol/L).
Altered arterial blood gases and serum electrolytes associated with a high anion gap metabolic acidosis within 3 to 24 hours.
Elevated BUN, serum creatinine, AST, ALT, and INR within 1 to 2 days.
Monitoring and Prevention
Regular monitoring of vital signs and ECG is essential in suspected calcium channel blocker poisoning. Determinations of serum electrolytes, serum glucose, arterial blood gases, urine output, and kidney function are indicated to assess and monitor symptomatic patients. If serious toxicity is likely to develop, overt symptoms will manifest within 6 hours of ingestion.73 For ingestions of sustained-release products in toxic doses, observation for 24 hours in a critical care unit may be prudent because the onset of symptoms may be slow and delayed up to 12 to 18 hours after ingestion.68,73,75 Serum concentrations of these drugs in overdose patients do not correlate well with the ingested dose, degree of toxicity, or outcome.
Poisonings resulting from these drugs may be the result of an intentional suicide or unintentional ingestion by young children. Prevention of calcium channel blocker poisonings in children rests with the education of patients receiving these agents, particularly of grandparents and those who have children visit their homes infrequently, of their dangers on overdosage. Safe storage and use of child-resistant closures may reduce the opportunities for unintentional poisonings by children.69
In the first few hours after ingestion of toxic amounts of iron, symptoms of gastrointestinal irritation (eg, nausea, vomiting, and diarrhea) are common. In certain severe cases, acidosis and shock can become manifest within 6 hours of ingestion. Some have observed a quiescent phase between 6 and 48 hours after ingestion when symptoms improve or abate, but this phenomenon is poorly characterized.76 Continued gastrointestinal symptoms, poor peripheral perfusion, and oliguria should suggest the development of severe toxicity, with other effects still to become manifest. Generally, within 24 to 36 hours of the ingestion, central nervous system involvement with coma and seizures; hepatic injury characterized by jaundice, increased INR, increased bilirubin, and hypoglycemia; cardiovascular shock; and acidosis also develop.76,77 Adult respiratory distress syndrome (ARDS) may develop in patients with severe cardiovascular shock and further compromise recovery. Coagulopathy with decreased thrombin formation is one of the early direct effects of excessive iron concentrations, and later disturbances of coagulation (after 24-48 hours of ingestion) are a consequence of hepatotoxicity.78 Mucosal injury, an iron-rich circulation, or deferoxamine therapy may promote septicemia with Yersinia enterocolitica during iron overdose; other bacteria or viruses also may cause septicemia.76 Two to 4 weeks after the exposure, a small percentage of patients experience persistent vomiting from gastric outlet obstruction as the result of pyloric and duodenal stenosis from the earlier gastric mucosal injury. Autopsy findings in children indicate prominent iron deposition in intestinal mucosa and periportal necrosis of the liver that correlate with the primary symptoms of serious iron poisoning.79
The toxicity of acute iron poisoning includes local effects on the gastrointestinal mucosa and systemic effects induced by excessive iron in the body.76 Iron is irritating to the gastric and duodenal mucosa, which may result in hemorrhage and occasional perforations. Once absorbed, iron is taken up by tissues, particularly the liver, and acts as a mitochondrial poison. It occasionally causes hepatic injury. Iron may inhibit aerobic glycolysis and perturb the electron transport system. Further, iron may shunt electrons away from the electron transport system, thereby reducing the efficiency of oxidative phosphorylation. These biochemical factors, along with the cardiovascular effects of iron, lead to metabolic acidosis. The pathogenesis of shock is not well understood but may involve the development of hypovolemia and lactic acidosis, release of endogenous vasodilators, and the direct vasodepressant effects of iron and ferritin on the circulation (Fig. e9-5).
Pathophysiology of acute iron poisoning.
Iron poisoning results from the ingestion and absorption of excessive amounts of iron from iron tablets, multiple vitamins with iron, and prenatal vitamins. Different iron salts and formulations contain varying amounts of elemental iron (see Chapters 44 and 101). Generally, children’s chewable vitamins are less likely to produce systemic iron poisoning in part because of their lower iron content.80
Acute iron poisoning can produce death in children and adults.79,80 The 2014 AAPCC-NPDS report documented 4,024 single-agent iron ingestions, with 3.3% of the exposures exhibiting moderate to severe toxicity. Children younger than 6 years accounted for 52% of the exposures. Multiple vitamins with iron were involved in 11,354 cases, with 0.2% exhibiting moderate-severe toxicity. One death was associated with an iron product during this year.3
A patient who exhibits lethargy, paleness, persistent or bloody emesis, or diarrhea should be immediately referred to an emergency department.80 Ingestion of 10 to 20 mg/kg elemental iron usually elicits mild gastrointestinal symptoms. Ingestion of 20 to 40 mg/kg is not likely to produce systemic toxicity, and typically these patients can be conservatively managed at home. Ingestions of 40 mg/kg or more of elemental iron are often associated with serious toxicity and require immediate medical attention.80 Psychiatric as well as medical intervention is indicated for adults and adolescents who intentionally ingest iron as a suicide gesture.76,80
An abdominal radiograph may help to confirm the ingestion of iron tablets and indicate the need for aggressive gastrointestinal evacuation with whole-bowel irrigation. An abdominal radiograph is most useful within 2 hours of ingestion. The visualization of radiopaque iron tablets is confounded by the presence of other hard-coated tablets and some extended-release tablets that also are radiopaque. Furthermore, the radiopacity of iron tablets diminishes as the tablets disintegrate, and chewable and liquid formulations typically are not radiopaque.81
Iron poisoning causes vomiting and diarrhea, but these symptoms are poor indicators of later serious toxicity. The presence of a combination of findings such as coma, radiopacities, leukocytosis, and increased anion gap, however, is associated with dangerously high serum concentrations greater than 500 mcg/dL (90 μmol/L). The presence of single signs and symptoms, such as vomiting, leukocytosis, or hyperglycemia, is not a reliable indicator of the severity of iron poisoning in adults or children.82,83
Once iron is absorbed, it is eliminated only as the result of blood loss or sloughing of the intestinal and epidermal cells. Thus, iron kinetics essentially represent a closed system with multiple compartments. The serum iron concentration represents a small fraction of the total-body content of iron and is at its greatest concentration in the postabsorptive and distributive phases, typically 2 to 10 hours after ingestion. Serum iron concentrations greater than 500 mcg/dL (90 μmol/L) have been associated with severe toxicity, whereas concentrations less than 350 mcg/dL (62.7 μmol/L) typically are not associated with severe toxicity; however, exceptions have been reported for both thresholds.84 Serious toxicity is best determined by assessing the development of gross gastrointestinal bleeding, metabolic acidosis, shock, and coma regardless of the serum iron concentration. The serum iron concentration serves as a guide for further assessment and treatment options. The ratio of the serum iron concentration to the total iron-binding capacity is unreliable, insensitive, and has little relationship to acute toxicity.83
Many patients vomit spontaneously, and no iron-specific prehospital care is indicated.80 At the emergency department, gastric lavage with normal saline can be considered if emesis with tablet fragments has not occurred. Lavage with normal saline may remove iron tablet fragments and dissolved iron, but because the lumen of the tube is often smaller than some whole tablets, effective removal is unlikely.76 Activated charcoal administration is not useful because it adsorbs iron poorly. If abdominal radiographs reveal a large number of iron tablets, whole-bowel irrigation with polyethylene glycol electrolyte solution typically is necessary.28 Early and aggressive decontamination and evacuation of the gastrointestinal tract usually will be adequate to minimize iron absorption and thereby reduce the risk of systemic toxicity. Lavage solutions of phosphate or deferoxamine have been proposed previously as a means to render iron insoluble, but they were found to be ineffective and dangerous.80
Deferoxamine is a highly selective chelator of iron that theoretically binds ferric (Fe3+) iron in a 1:1 molar ratio (100 mg deferoxamine to 8.5 mg ferric iron) that is more stable than the binding of iron to transferrin. Deferoxamine removes excess iron from the circulation and some iron from transferrin by chelating ferric complexes in equilibrium with transferrin. The resulting iron—deferoxamine complex, ferrioxamine, is then excreted in the urine. The action of deferoxamine on intracellular iron is unclear, but it may have a protective intracellular effect or may chelate extramitochondrial iron. The parenteral administration of deferoxamine produces an orange-red-colored urine within 3 to 6 hours because of the presence of ferrioxamine.76 For mild-to-moderate cases of iron poisoning, where its use is unclear, the presence of discolored urine indicates the persistent presence of chelatable iron and the need to continue deferoxamine. The reliance on discolored urine as a therapeutic end point has been challenged because it is not sensitive and is difficult to detect.85
Patients with systemic symptoms (eg, shock, coma, or gross gastrointestinal bleeding or metabolic acidosis) should receive parenteral deferoxamine as soon as possible. If the serum iron concentration is greater than 500 mcg/dL (90 μmol/L), deferoxamine is also indicated because serious systemic toxicity is likely.76 Its use is less clear in patients with serum iron concentrations in the range from 350 to 500 mcg/dL (62.790 μmol/L) because many of these patients do not develop systemic symptoms.84
There is little evidence to support the dose or duration of deferoxamine treatment for iron poisoning. The dosage regimen should balance the benefits of increased iron removal in patients with exceedingly high serum iron concentrations versus the risk of developing ARDS when therapy lasts for more than 1 to 3 days.
Generally, an initial IV infusion of deferoxamine 15 mg/kg/h is administered, although some have used up to 30 mg/kg/h for life-threatening cases. In these situations, the dose must be titrated carefully to minimize deferoxamine-induced hypotension.76 The rapid IV infusion of deferoxamine (greater than 15 mg/kg/h) has been associated with tachycardia, hypotension, shock, generalized erythema, and urticaria.76,86 Anaphylaxis has been reported rarely. The use of deferoxamine for more than 24 hours at doses used for treatment of acute poisoning has been associated with exacerbation or development of ARDS.86,87 Although the manufacturer states that the total dose in 24 hours should not exceed 6 g, the basis for this recommendation is unclear, and daily doses as high as 37.1 g have been administered without incident.88 Good hydration and urine output may moderate some of the secondary physiologic effects of iron toxicity and ensure urinary elimination of ferrioxamine. In the patient who develops acute kidney injury, hemodialysis or hemofiltration does not remove excess iron but it will remove ferrioxamine.76
The desired end point for deferoxamine therapy is not clear. Some have suggested that deferoxamine therapy should cease when the serum iron concentration falls below 150 mcg/dL (26.9 μmol/L). The decline of serum iron concentrations, however, may not account for the potential cellular action of deferoxamine irrespective of its effect on iron elimination. The cessation of orange-red urine production that is indicative of ferrioxamine excretion is not reliable because many individuals cannot distinguish its presence in the urine.85 Considering these shortcomings, deferoxamine therapy should be continued for approximately 12 hours after the patient is asymptomatic and the urine returns to normal color or until the serum iron concentration falls below 350 mcg/dL (62.7 μmol/L) and approaches 150 mcg/dL (26.9 μmol/L).
Monitoring and Prevention
Once a poisoning has occurred, acid-base balance (anion gap and arterial blood gases), fluid and electrolyte balance, and peripheral perfusion should be monitored. Other indicators of organ toxicity, such as ALT, AST, bilirubin, INR, serum glucose and creatinine concentrations, as well as markers of physiologic stress or infection such as leukocytosis, also should be monitored.
Iron poisoning often is not recognized as a potentially serious problem by parents or victims until symptoms develop; thus, valuable time to institute treatment is lost. Parents should be made aware of the potential risks and asked to observe basic poison prevention measures. Some hard-coated iron tablets resemble candy-coated chocolates and are confused easily by children. Iron tablets are typically packaged in child-resistant containers, often in blister packs.
Acute opioid poisoning can produce life-threatening effects that typically include respiratory depression and coma that may lead to death.89 Virtually all opioids produce these symptoms and some agents have additional toxic effects. The time of onset and severity of symptoms depend on the route of exposure, formulation of the drug product, potency of the opioid total dose received, concurrent drugs, coexisting conditions and pharmacogenetic characteristics. Toxic signs and symptoms develop most rapidly after IV injection (within minutes) or inhalation of fumes (heroin), followed by inhalation from snorting particles, powder, or solutions. Immediate-release tablets typically have an onset of toxicity within 1 to 4 hours, followed by sustained-release tablets and dermal patches on the skin, which exhibit the slowest onset. Severe symptoms can occur from absorption by any route. Death typically is caused by respiratory failure, the metabolic consequences of hypoxia, noncardiogenic pulmonary edema and, in some cases, pulmonary aspiration of gastric contents after vomiting. Opioid poisoning may be complicated by hypothermia, rhabdomyolysis, and resultant acute kidney injury. Seizures, arrhythmias, concurrent exposure to and toxicity from other medications and illicit drugs, and the presence of adulterants and contaminants may complicate the person’s presentation. Finally, hepatotoxicity from the co-ingestion of acetaminophen-containing medications, and infectious diseases from IV drug use may occur.89
Action at the μ opioid receptor is primarily responsible for many of the life-threatening effects of opioids, such as respiratory depression and sedation, and all opioid analgesics appear to have some activity at this receptor. Meperidine’s metabolite, normeperidine, produces CNS excitation that leads to delirium, tremor, and seizures. Meperidine also blocks the reuptake of serotonin and may produce serotonin syndrome particularly in patients taking monoamine oxidase inhibitors.90 Methadone acts on the myocardium to block potassium efflux leading to arrhythmias, syncope, and sudden death.91 Tapentadol and tramadol block reuptake of norepinephrine and serotonin, respectively, and are associated with seizures at high doses.89
Many opioid drugs are available in the United States for the management of moderate to severe pain (see Chapter 44). These include drugs that are naturally found in opium (ie, opiates such as morphine and codeine), synthetic opiates (eg, fentanyl, methadone, and meperidine), and semisynthetic opiate derivatives (eg, hydromorphone, hydrocodone, and oxycodone). Heroin is a schedule I controlled substance and illicit drug. It produces a greater degree of euphoria than many other opioids and also produces the same life-threatening effects with added complications of adulterants and infections from IV drug use. Chemical analogs of legitimate opioids such as fentanyl are produced by clandestine laboratories. Illicitly manufactured analogs often have much greater potency unbeknownst to the user and thus increase the risk of a lethal overdose.92
Acute poisoning and overdose from opioids have become the most frequent cause of drug-related death in the United States with a 200% increased death rate from 2000 to 2014 and accounted for 61% of all drug-related deaths in 2014.93 During this same period heroin-related, age-adjusted death rates have increased by 340%.93,94 Poisoning from opioids occurs in all age groups, from neonates through intrauterine exposure to the elderly, and in rural and urban areas. Poisoning can occur from a variety of circumstances such as the unintentional ingestion of medicines by young children. Inadvertent overdoses can occur in adolescents or adults from taking single or multiple “therapeutic” doses of opioids with several sedating drugs (particularly benzodiazepines). Using opioids to produce self-harm can end in suicide and abusing opioids as part of a substance use disorder may also lead to death. The 2014 AAPCC-NPDS report documented 19,645 nonfatal single-product exposures that were voluntarily reported to poison centers, 283 with severe symptoms, and 43 deaths from opioids alone; 40% of the cases were associated with intentional use and 22% of exposures occurred in children younger than 6 years of age.3
CLINICAL PRESENTATION Acute Opioid Poisoning General
Life-threatening respiratory depression (12 or less breaths per minute) within minutes to hours of use depending upon the drug, route of administration, product formulation, and coexisting conditions; often delayed by 8 or more hours with ingestion of a sustained-release product.
Lethargy progressing to coma.
Seizures associated with meperidine and tramadol.
Acute muscular rigidity with rapid injection of fentanyl.
Deafness with some overdoses.
Depressed respiratory depth and rate leading to apnea.
Pinpoint pupils (uncommon with meperidine, tramadol, and severe hypoxia).
Unresponsiveness and depressed reflexes.
Mild hypotension and bradycardia, worsening with increasing hypoxia.
Absent bowel sounds, gastrointestinal hypomotility.
Hypothermia if exposed to cold conditions.
Frothy pink sputum, end-inspiratory crackles on auscultation, and shortness of breath several hours after exposure consistent with pulmonary edema.
QT-interval prolongation leading to torsade de pointes on ECG with methadone.
One or more opioid-containing drug patches (eg, fentanyl) on the skin.
“Needle tracks” or skin infections if IV drug user.
Other Diagnostic Tests
Altered arterial blood gases (acidosis) and serum electrolytes in response to hypoxia.
Serum glucose concentration.
Determine serum acetaminophen concentration no earlier than 4 hours after ingestion and ALT in case an opioid-acetaminophen combination product ingested.
Pulse oximetry and ECG with continuous monitoring.
Monitor for complications of pulmonary aspiration such as hypoxia and pneumonitis by physical findings and chest radiographs.
Monitor for complications of rhabdomyolysis (creatine kinase, electrolytes) and subsequent acute kidney injury (blood urea nitrogen [BUN], creatinine) if patient has been lying immobile for several hours.
Evaluate for infectious diseases if IV drug use, and local- or systemic-infection suspected.
A patient’s symptoms, presence of drugs or substance abuse paraphernalia at the scene, and availability of opioids can be helpful indicators of risk. The triad of depressed respirations (12 or less breaths per minute), coma, and pinpoint pupils (miosis) with relatively acute onset should strongly suggest opioid poisoning and warrants a therapeutic trial of the antidote naloxone.6,89 Measurement of opioid serum concentrations are not available in clinical laboratories and are not necessary to guide appropriate therapy. Therapy should not be delayed pending laboratory confirmation of an opioid in a routine drug screen because many opioids are not detected (see Table e9-6) and critical time will be lost awaiting results that will not guide therapy.
The foundation of treatment of opioid poisoning is adequate respiratory support, and the administration of the opioid antagonist naloxone.89 Symptomatic cases of opioid overdoses should be transported to an emergency department for evaluation and treatment. There is no conventional prehospital care except for cardiopulmonary resuscitation; however, naloxone can be administered at the scene by trained personnel.
If the opioid has been ingested within 1 hour, the administration of activated charcoal should be considered after weighing the risks of pulmonary aspiration (ie, if vomiting occurs in a patient with altered or worsening mental status).25,89 Based on a history of an exposure, presence of typical symptoms and the response to naloxone, an acute opioid poisoning should be recognizable in most cases. Whole bowel irrigation should be considered for ingestions of extended-release formulations, packets of drugs such as heroin intended for smuggling, and fentanyl dermal patches once the patient is stabilized.28,29,89
Naloxone is a competitive opioid receptor antagonist that acts on known opioid receptors to reverse the toxic effects of opioids (Table e9-13) and can be life-saving. The goal of therapy is to restore adequate spontaneous respirations. It is typically administered by rapid IV injection, acts within 2 minutes and has a short duration of action of 20 to 90 minutes.38 Intramuscular, intraosseous, intralingual injection and intranasal and intratracheal instillation are also effective if the IV route is not immediately available, but oral administration is ineffective. Naloxone for injection is available in concentrations of 0.02, 0.4, and 1.0 mg/mL. The effect of naloxone may not be evident in several circumstances (see Table e9-13) and the initial dose may not be sufficient.
TABLE e9-13Responses to Naloxone in Opioid Poisoning |Favorite Table|Download (.pdf) TABLE e9-13 Responses to Naloxone in Opioid Poisoning
|Therapeutic Reversal of Toxicity ||Factors for Poor or No Response |
|Respiratory depression ||Polydrug overdose (eg, benzodiazepines, sedatives, muscle relaxants, ethanol) |
|CNS depression ||Inadequate dose of naloxone |
|Miosis ||Concurrent head injury |
|Cardiovascular depression ||Hypoglycemia |
|Gastrointestinal hypomotility ||Hypoxic state (CNS, acid/base disorders) |
|Euphoria ||Postictal state |
|Dependence leading to withdrawal ||No opioid involved |
The initial dose of naloxone for opioid overdose varies. Earlier observations of inadequate response to an initial dose of 0.4 mg in some patients led to the dose being changed to 0.4 to 2.0 mg. Currently, initial doses of 0.04 to 0.05 mg are proposed by some clinicians to minimize the risks of abrupt withdrawal associated with adverse effects.
The dosing of naloxone should consider a balance of reversing toxic effects without causing abrupt withdrawal symptoms, which can produce agitation, hypertension, tachycardia, emesis with the risk of aspiration, and harm to the patient and caregivers from disorientation.95 Dosage regimens have evolved from clinical experience and differ from the recommended starting dose of 0.4 to 2.0 mg in the package insert. A typical approach involves administering 0.04 to 0.05 mg (0.01 mg/kg in a young child) as the first dose. If there is no improvement in respirations within 2 minutes, 0.5 mg is administered to adults and children. At 2-minute intervals the dose can be increased to 2, 4, 10, and 15 mg until adequate respirations are achieved.38,95 If there is no response at the 10 to 15 mg dose, confounding or other causes of the patient’s condition should be considered. Other regimens with similar progressive increases in dose have been proposed. Overdoses with buprenorphine, fentanyl, and methadone often require doses in the upper range for a response.95 The duration of naloxone’s effect is generally shorter than many opioids, particularly for methadone and extended-release formulations, and requires close monitoring and repeated administration. If repeated doses of naloxone are required for maintenance of adequate respiration, a continuous infusion should be considered that is approximately two-thirds of the single-dose that produces a response given at an hourly rate.38 The IM autoinjector delivers naloxone 0.4 mg per injection and the intranasal spray delivers 4 mg per use.
The adverse effects of large doses of naloxone are rare, minimal, and insignificant and it can be given safely to persons with acute poisonings of any cause. Rare isolated reports of hypertension, hyperventilation, and tachycardia in opioid-dependent patients may be related to the release of catecholamines and other mediators in response to stress from abrupt withdrawal.95 The progressive escalation of naloxone doses to prevent abrupt withdrawal is partially based on its potential association with acute lung injury that may produce or exacerbate pulmonary edema.38,96
Monitoring and Prevention
Poisoned patients may require monitoring of vital signs, ventilatory adequacy (ie, blood gases and pulse oximetry), and chest radiographs to assess the degree of pulmonary edema or development of aspiration pneumonitis. Patients should also be monitored for the potential development of complications such as rhabdomyolysis, acute kidney injury, or seizures. Determination of a serum acetaminophen concentration is warranted to rule out the coincidental ingestion of acetaminophen with an opioid-acetaminophen combination product.89
The rising number of deaths from prescription opioid analgesics has been categorized as an epidemic by the Centers for Disease Control and Prevention. Multiple strategies have been implemented and proposed to prevent opioid-related deaths.97 A controlled substances monitoring database (also called a prescription drug monitoring program) has been implemented in nearly every state in order to identify individuals using frequent prescriptions of controlled substances from multiple prescribers (“doctor shopping”) or fraudulent prescriptions.98 Enforcement and implementation of laws on “doctor shopping,” indiscriminant prescribing of controlled substances without a medical evaluation by “pill mills,” and efforts to improve medical practice through educational programs and guidelines for the treatment of chronic pain are underway. The FDA has developed a Risk Evaluation and Mitigation Strategy for long-acting and extended-release opioids that involve prescriber training on appropriate prescribing practices. “Drug take-back” events to dispose of unneeded medications have been conducted in communities nationwide. Reducing the availability of medications, particularly opioids, in the home reduces the opportunity for stealing and diverting medications that can lead to overdoses and drug abuse. Most states have enacted laws to allow intranasal, intravenous, or intramuscular administration of naloxone by trained bystanders and law enforcement officers in the community to opioid-dependent individuals and heroin abusers at risk for life-threatening overdose in order to prevent death before an ambulance arrives.99 Education of the general public on the risks of opioid poisoning and appropriate use and storage of opioid analgesics should be a routine practice in the prescribing and dispensing of opioid analgesics.
Weapons of Mass Chemical Poisoning
Most chemicals used in warfare or terrorist attacks act immediately upon contact with the skin, mucous membranes or respiratory tract. The variety of potential agents has been generally categorized by the type of toxic action or target organ system (Table e9-14) that also reflects the anticipated signs and symptoms of poisoning. Typically clusters of victims have similar presentation, but the extent and onset of injury depends upon the person’s level of exposure, which is related to their proximity to the source of the chemical, the method of deployment (eg, vapor, liquid, gas, and aerosol explosive device) and the mechanism of toxicity of the chemical. Inhalational exposures to nerve agents or cyanide will produce symptoms and sometimes death within minutes of exposure; whereas, slower absorption with dermal contact will delay the onset. Agents such as sulfur mustard and phosgene may take 4 to 6 hours for onset of toxicity.7 Some toxins of biologic origin, such as ricin, often require days to weeks for characteristic symptoms to develop due to the mechanism of action. Nerve agents are highly potent anticholinesterases that have the same pathogenesis of toxicity (see Fig. e9-2) and produce the full spectrum of signs and symptoms of organophosphate insecticides (see Table e9-14).7,100 One of the several major differences between nerve agents and organophosphate insecticides is the hyperacute onset of life-threatening symptoms, such as fulminant respiratory failure within seconds to minutes with nerve agents.7 Another difference is the extreme oculogyric torsion with nerve agents that may require administration of tropicamide ophthalmic drops to relieve eye pain. Moderate to severe poisonings from chemical warfare or terrorist agents will typically require care in an intensive care unit.101
TABLE e9-14Categories of Chemicals of Mass Poisoning |Favorite Table|Download (.pdf) TABLE e9-14 Categories of Chemicals of Mass Poisoning
|Category and General Effects ||Examples* |
(variety of toxicities from plant or animal origin)
(severely blister the eyes, respiratory tract, and skin on contact)
|Mustards, sulfur mustard gas (H), lewisites (L), chloroarsine agents, phosgene oxime (CX) |
(interfere with the delivery and use of oxygen)
|Arsine (SA), carbon monoxide, cyanides, sodium monofluoroacetate |
(cause severe irritation or swelling of the respiratory tract)
|Ammonia, chlorine, hydrogen chloride, methyl isocyanate, phosgene (CG), phosphine |
Corrosives (Caustics, Acids)
(burn or corrode skin, eyes, and mucus membranes on contact)
|Hydrofluoric acid, hydrogen chloride, sulfuric acid |
(cause an altered state of cognition and consciousness or unconsciousness)
|Fentanyl analogs and other opioids, “QNB” 3-quinuclidinyl benzilate (BZ) |
(heavy metals that disrupt cellular function)
|Arsenic, mercury, thallium |
(anticholinesterases that affect normal functioning of peripheral and central nervous systems)
|Sarin (GB), soman (GD), tabun (GA), VX |
Riot Control Agents/Tear Gas
(cause significant irritation of the eyes, skin, and airway)
|Bromobenzylcyanide (CA), chloroacetophenone (CN), chlorobenzylidenemalononitrile (CS), chloropicrin (PS), dibenzoxazepine (CR) |
(cause severe nausea and vomiting)
|Adamsite (DM) |
There is no single unifying mechanism of toxicity of the chemicals used for warfare or terrorism because of the variety of different agents involved (see Table e9-14). The mechanism for nerve agents is well characterized by its anticholinesterase action (see earlier section on Anticholinesterase Insecticides).61,100 Some agents act by an extreme exaggeration of their pharmacologic actions such as BZ producing extreme anticholinergic CNS effects and fentanyl analogs producing extreme opioid toxicity (see CLINICAL PRESENTATION BOX for acute opioid poisoning). Vessicants, such as sulfur mustard, irreversibly alkylate DNA, RNA and proteins and produce burns, blisters, and tissue destruction.100 Blood agents act in several ways, but ultimately interfere with the transport or utilization of oxygen by cells. Cyanide, for example, is a potent competitive inhibitor of cytochrome oxidase and other enzymes and stops cellular respiration throughout the body.7,100 Pulmonary agents, such as chlorine or phosgene, both react with water to produce hydrochloric acid, which produces severe irritation and destruction to mucosal tissue, ocular surfaces, the airway and lungs.100
Many different chemicals have been used or have been recognized for their potential for terrorism or warfare (see Table e9-14). Adaptation of other commercial chemicals, synthesis of analogs of existing toxins, or creation of novel chemicals may introduce additional hazards in the future.
The use of chemical weapons during the past century has been documented in numerous warfare and terrorism settings that produced mass casualties. For example, during World War I, 100,000 deaths and 1.2 million casualties were attributed to attacks with chlorine, phosgene or mustard.102 In 1995, terrorists released sarin in the Tokyo subway system, leading to 11 deaths and 5,510 people seeking medical attention including many first-responders.103,104
Assessment of injuries at the scene, triage stations, and healthcare facilities should identify victims at greatest risk and priority for treatment. The acute onset of serious symptoms in many victims without signs of trauma suggests a mass chemical exposure. Patients with typical clusters of symptoms, such as those associated with anticholinesterase agents, may provide clues to the type of chemical and guide treatment.7,105
High priorities for managing exposures to chemical warfare or terrorism agents are to evacuate victims from the contaminated area, decontaminate any exposed surfaces with first aid measures (see Table e9-5), and removal of contaminated clothing.105 First-responders should guard against being poisoned by wearing personal protective equipment, such as body suits, gloves, boots and air supply, as appropriate for the situation. Supportive and symptomatic care with attention to airway, breathing and circulation are critical for all types of exposures and may be the extent of treatment options useful for a toxin.7,101,105,106 Most chemicals associated with mass poisoning exposures do not have a specific therapy or antidote. Several toxins, such as nerve agents, opioids, and cyanides, do have specific antidotes that may be life-saving (see Table e9-9). The sooner therapy can be instituted in the field, as in carrying atropine, pralidoxime, and diazepam autoinjectors in an area where a nerve agent attack is anticipated, generally the better the outcome will be. Depending upon the conditions, additional decontamination before a victim enters a healthcare facility may be necessary to avoid contaminating healthcare workers and other patients in the treatment area. Guidance on treatment for a specific chemical exposure is available at several websites of the Centers for Disease Control and Prevention (CDC) (http://emergency.cdc.gov/chemical/index.asp; www.cdc.gov/NIOSH/ershdb/default.html; www.atsdr.cdc.gov).
Monitoring and Prevention
Survivors of a chemical attack may develop long-term effects or life-long disabilities.107 For example, vesicants have been associated with cancer, severe burns, and scars; pulmonary agents may produce permanent respiratory conditions; and nerve agents may lead to short- and long-term neuromuscular disabilities. Victims of any mass poisoning are at risk for developing psychological distress after the attack and warrant follow-up once the acute medical condition is stabilized.
Prevention of chemical attacks is beyond the scope of healthcare providers’ standard responsibilities; however, preparation for mass chemical emergencies is a vital element of mass casualty preparedness. Working with local health department representatives, safety officials and other healthcare providers to develop a community plan is important because no single site can likely provide the necessary resources to treat the number of victims. The CDC has resources that provide guidance on medical management of chemical hazards (http://emergency.cdc.gov/agent/agentlistchem.asp), emergency healthcare preparedness (http://www.cdc.gov/phpr/healthcare/index.htm), and access to the Strategic National Stockpile (http://www.cdc.gov/phpr/stockpile/stockpile.htm) among other areas of interest.