Clinical manifestations

Presentation and course

When poisoning is suspected, a careful history should be obtained. The history should focus on home medications, herbal supplements, and environmental disruptions. To aid in diagnosis, medical toxicologists have coined the term “toxidrome” to organize common clinical presentations. A thorough physical examination coupled with a detailed history may point toward a specific toxidrome.

Sympathomimetic. Sympathomimetic toxicity is characterized by hypertension, tachycardia, mydriasis, diaphoresis, agitation, and hyperactive bowel sounds. This pattern is frequently seen in adolescents and is associated with the use of cocaine, amphetamines, and, in younger children, with accidental exposure to stimulants. Sympathomimetic toxicity can produce strokes, seizures, and serious infectious complications.

There is a 1% to 2% incidence of seizures associated with cocaine use (48). Cocaine seizures are most commonly single tonic clonic events that resolve without specific intervention (32). However, patients who ingest massive amounts of cocaine (2 to 8 grams) may have refractory seizures and die. Sedation is the mainstay of therapy. Hypoglycemia is a critical symptom requiring treatment.

Patients who inject amphetamines or cocaine may develop endocarditis, which can generate septic emboli and brain abscesses. Permanent neuronal changes can produce psychosis (67).

Cocaine is responsible for most drug-induced strokes. Amphetamine, phenylpropanolamine, phencyclidine, ephedrine, and pseudoephedrine also have the potential to cause a stroke (57). Long-term exposure to adrenergics, including methamphetamine and ecstasy, may produce cardiomyopathy (33; 36).

Anticholinergic. Patients who are exposed to overdoses of anticholinergic agents can experience agitation (but are generally redirectable), mydriasis, tachycardia, dry and diffusely erythematous skin, and hypoactive bowel sounds (39). Numerous medications can produce anticholinergic toxicity (Table 1).

Table 1. Medications producing anticholinergic toxicity

Serotonergic. Serotonin syndrome may be caused by an overdose of proserotonergic drugs, drug interactions with other drugs or xenobiotics, or in the setting of therapeutic use of proserotonergic drugs. Although the definition of serotonin syndrome as an entity is relatively recent, the clinical syndrome has been recognized since the use of monoamine oxidase inhibitors in the 1960s (43). Serotonin syndrome is classically described as a triad of autonomic hyperactivity, alterations in mental status, and neuromuscular abnormalities (61; 55). Despite the classic triad, the syndrome is spectrum of clinical findings both benign and lethal.

Diagnosis is made based on clinical findings, often by fulfilling the Hunter Toxicity Criteria decision rules. There are other sets of diagnostic criteria, but the Hunter Criteria are most accurate. To fulfill the criteria, a patient must have taken a serotonergic agent and meet 1 of the following conditions: spontaneous clonus, inducible clonus plus agitation or diaphoresis, ocular clonus plus agitation or diaphoresis, tremor plus hyperreflexia, hypertonia plus temperature above 38 degrees celsius plus ocular clonus, or inducible clonus (08).

Severity is highly variable. Mild serotonin syndrome may present with tachycardia, shivering, diaphoresis, mydriasis, intermittent tremor, or myoclonus. Moderate cases are more likely to suffer from hyperthermia, more severe hyperreflexia or clonus, and mild agitation or confusion. Severe serotonin syndrome typically presents with hyperthermia, rigidity that is often greater in the lower extremities, and hypertension and tachycardia, which may rapidly deteriorate into a state of shock. Patients may develop renal failure, rhabdomyolysis, transaminitis, and disseminated intravascular coagulation. Much of this is the result of the primary issues of hyperthermia and muscular rigidity (09). Typically, patients with serotonin syndrome present within 6 hours of starting or adding a proseritonergic drug; however, patients with mild symptoms may have a chronic presentation.

Opiate. Opiate toxicity is characterized by sedation, miosis, respiratory depression, peripheral vasodilation, hypotension, and decreased bowel motility. Multiple opiates have no direct pupillary effects, and meperidine and propoxyphene produce mydriasis (41; 40). Flushing and bronchospasm may occur secondary to histamine release. Anoxia-associated acute leukoencephalopathy carries a 23% mortality rate (22).

Complications of opiate abuse include endocarditis, cellulitis or abscesses of the extremities, epidural spinal abscesses, osteomyelitis, and myelopathy. Brain abscess may complicate intravenous drug use of any type (22). Abscesses may raise intracranial pressure or serve as an irritating focus, producing seizures or stroke. Patients that are immobile due to acute toxicity are at risk for compartment syndrome, rhabdomyolysis, and peripheral nerve compression. Heroin use in particular is linked to the development of transverse myelopathy, neuropathy, spongiform leukoencephalopathy, seizures, and stroke (12).

Certain clinical manifestations warrant special mention. Propoxyphene causes cardiac sodium channel antagonism, leading to EKG changes mirroring those of tricyclic antidepressants. Seizures may occur secondary to hypoxia in the setting of overdose of any opioid, but are direct effects of meperidine, propoxyphene, and tramadol. Muscular rigidity has been reported with rapid administration of fentanyl.

Cholinergic. Cholinergic toxicity is caused by acetylcholinesterase inhibitors (14). Organophosphates are typically irreversible, whereas carbamates are generally reversible. Organophosphates are typically used in industrial settings as chemical warfare agents or as pesticides, whereas carbamates include various pharmaceuticals including physostigmine, neostigmine, rivastigmine, meprobamate, and carisoprodol (60). Worldwide, nearly 3,000,000 people are exposed to organophosphate or carbamate agents each year, and up to 300,000 people die from poisoning annually (15).

Cholinergic toxicity is characterized by the presence of excessive muscarinic stimulation, including miosis, bradycardia, bronchorrhea, urinary and fecal incontinence, and seizures. Profound airway secretions, bronchospasm, and respiratory muscle weakness lead precipitously to death (42; 11). Nicotonic symptoms may be present as well, including weakness, which may progress to fasciculations and paralysis. Central nervous system toxicity includes rapid loss of consciousness, seizures, and inhibition of the medullary respiratory center (42).

Ten percent to 40% of patients with organophosphorus poisoning develop a distinct neurologic disorder 24 to 96 hours after exposure and resolution of cholinergic excess, called the “intermediate syndrome.” It is characterized by decreased deep tendon reflexes, cranial nerve abnormalities, proximal muscle weakness, weak neck flexors, and respiratory failure. Nerve conduction studies on patients with intermediate syndrome show unique postsynaptic abnormalities that differentiate the syndrome from delayed neurotoxicity. With adequate supportive care, which can involve prolonged mechanical ventilation, most patients have complete resolution of neurologic dysfunction within 2 to 3 weeks (07). Etiology has not been elucidated but may be reflected in ineffective acetylcholinesterase reactivation (14).

Chronic toxicity may occur in patients in regular contact with organophosphates. Chronic toxicity presents with similar clinical findings (14).

Finally, several organophosphates also affect neuropathy target esterase. Inhibition of neuropathy target esterase produces breakdown of the myelin lining of nerve fibers generating polyneuropathy (59).

Lead poisoning. Lead remains a common environmental toxin affecting children. Any detectable lead level is abnormal. Evidence shows that blood lead levels (BLL) below 10 µg/dL are associated with adverse effects in infants and children, although the U.S. Centers for Disease Control and Prevention (CDC) reference value was lowered to 5 µg/dL in 2012 (21). Of the 32 jurisdictions that reported data to the CDC in 2014, prevalence data indicate that 76,680 U.S. children under 5 years of age had blood lead levels 5 to 9 ug/dL (Raymond and Brown 2014).

Older children and adolescents experience fatigue, abdominal pain, back pain, myalgias, and paresthesias (30; 17). Younger children exhibit problems with concentration, memory, and learning. Several metaanalyses have demonstrated that childrens’ IQ scores drop 2 to 3 points for every 10 ug/dL increase in blood lead level (70). Deficits in reading, mathematics, memory, language development, and motor skills are all documented sequelae of lead exposure (70). Typically, these sequelae are irreversible. Physical examination is not generally revealing; however, bluish-black lines at the gingiva may be present (68).

Acute lead poisoning in children may be secondary to ingestion or inhalation of volatilized lead. Symptoms of acute exposure include vomiting; apathy; bizarre behavior; loss of recently acquired developmental skills; ataxia, which is followed by seizures; delirium; and coma. Patients may develop devastating cerebral edema. It is important to note that “acute” presentations may be the culmination of increasing body burden of lead secondary to ongoing exposure. Typically, children will have venous levels between 70 and 100 micrograms per deciliter when acute symptoms are present.

Lead alters very basic nervous system functions, including calcium-modulated signaling, even in very low concentrations. Children exposed to lead are usually at a developmental age at which, normally, dendritic pruning occurs, along with other crucial developmental events.

Lead also has effects outside of the neurodevelopmental area. Kidneys are common targets; hypertension is a frequent consequence. Delayed growth can also be a systemic consequence of lead exposure.

Imaging studies of adults who had elevated blood lead levels in childhood show region-specific reductions in brain volume and changes in the microstructure of the brain.

The risk of exposure from lead continues to be a major childhood hazard. Lead is in household dust, the soil, lead pipes in some cities’ water supply, as well as lead paint and some ceramics. There is no safe level of lead (31; American Association of Poison Control Centers 2014; 02).

Prognosis and complications

Sympathomimetic. In the acute setting, the prognosis is usually excellent with adequate supportive care and absent serious complications, such as stroke.

Anticholinergic. Morbidity and mortality result from cardiotoxicity, rhabdomyolysis, and status epilepticus. Most patients will recover fully, however, with rapid identification and aggressive therapy.

Serotonergic. Successful treatment portends an excellent prognosis for full recovery. However, failure to recognize and adequately address the clinical needs of patients with serotonin syndrome may lead to further autonomic instability and death.

Opiate. With good supportive care, the prognosis for acute intoxication is primarily dependent on the sequelae of toxicity/abuse.

Cholinergic. The prognosis for patients exposed to organophosphates is guarded. They may have long-term deficits in memory and concentration, for example, and may also have problems with gait and color vision (13; 26). Personality changes, affect, and cognition may also be affected (26). There are some clinical scoring systems that may be used to determine prognosis, but only for those specific organophosphate pesticides that were included in the relevant study: International Program on Chemical Safety Poison Severity Score (IPCS PSS); Acute Physiology and Chronic Health Evaluation II (APACHE-II); Simplified Acute Physiology Score II (SAPS-II); Mortality Prediction Model II (MPM-II) scoring systems (07).

Lead poisoning. Lead-exposed patients are at long-term risk for hypertension and renal disease (05; 28). The precise mechanism behind lead-related hypertension may be related to lead’s effects on hormone metabolism, renal tubular function, or vasoconstriction (53).

Biological basis

Sympathomimetic. Sympathomimetics work by increasing adrenergic tone. There are 2 classes of sympathomimetics: direct- and indirect-acting. Indirect agents rely on the generation of high cytoplasmic norepinephrine concentrations. Agents such as methamphetamines, phencyclidine, and monoamine oxidase inhibitors work through this mechanism (40).

Indirect agents move into the neuron by diffusion and concentrate in neurotransmitter-containing vesicles altering their pH, resulting in norepinephrine release into the cytoplasm. High cytosolic concentrations of norepinephrine are reverse-transported out of the cell and into the synapse where they can activate postsynaptic sites (50). Inhibition of reuptake of norepinephrine in the central nervous system (CNS) and peripheral nervous system (PNS) can produce sudden increases in blood pressure, resulting in vascular injury (44; 25).

The causes of cocaine-induced stroke are multifactorial and include vasospasm, acute elevations in blood pressure, early cocaine-related vascular endothelial damage, vasculitis, and cardiac dysrhythmias (27).

Autopsy studies demonstrate premature coronary atherosclerosis and thrombosis among cocaine users (34). Animal studies demonstrate endothelial low-density lipoprotein permeability (47). Cocaine has also been shown to increase aortic sudanophilia, a precursor for atherosclerosis development.

Sekine and colleagues found decreased dopamine transporter density in the orbitofrontal and dorsolateral prefrontal cortex of patients using methamphetamine chronically; a time-dependent decrement in these areas was associated with worsened psychosis (58).

Anticholinergic. The primary cause of the anticholinergic toxidrome is antagonism of muscarinic receptors. There are at least 5 muscarinic receptors linked to G-protein systems. In the myocardium, agonism at the M2 site produces potassium efflux and cell hyperpolarization, producing bradycardia. By contrast, muscarinic antagonism produces tachycardia (40).

Patients with anticholinergic toxicity are at risk for seizure, although the mechanism is unclear.

Serotonergic. Serotonin is produced by decarboxylation and hydroxylation of l tryptophan in the presynaptic neuron. Excessive stimulation of 5-HT2A and 5-HT1A postsynaptic receptors is the cause of serotonin syndrome. Serotonin is metabolized in the presynaptic neuron by monoamine oxidase. Exocytosis onto the synapse and reuptake is regulated by presynaptic serotonin receptors. The serotonergic system is involved in the regulation of wakefulness, thermoregulation, and vascular tone (37). Excess serotonin levels may be caused by inhibition of uptake as well as inhibition of metabolism by monoamine oxidase inhibitors (09).

Opiate. Three major and several minor classes of opiate receptors have been identified: mu, kappa, and delta (major) and nociception, sigma, epsilon, and zeta (minor). The majority of toxidromic effects are mediated by opiate activity at mu receptors and kappa receptors. All opiate receptors are members of the superfamily of G protein-coupled receptors.

Mu 2 receptors (OP3B) are localized to the periaqueductal gray matter, nucleus raphe magnus, medial thalamus, and medulla and are responsible for body analgesia as well as respiratory depression. Mu 2 activation diminishes chemoreceptor sensitivity to hypercapnia and decreases response to hypoxia, which may produce seizures (40).

Opiate kappa receptor activation is linked to miosis, a familiar part of the prototypic opiate presentation. The relative hypotension that opiate-intoxicated patients experience is thought to be mediated via histamine release (40).

Cholinergic. Organophosphates and carbamates bind to and disable synaptic acetylcholinesterase, leading to excess synaptic acetylcholine. Toxicity results from excessive postsynaptic stimulation.

Lead poisoning. Lead is toxic to virtually all systems in the body. The organ systems most at risk include the CNS, kidney, and hematopoietic system (16).

CNS effects are multiple. Lead affects synaptic pruning, resulting in flawed cortical architecture. The hippocampus is targeted, and learning and memory function are significantly inhibited. Furthermore, lead exposure is responsible for peripheral neuropathy, which is thought to be related to Schwann cell dysfunction (Nelson and Olsen).

Hematologic effects include red cell fragility and lysis. Lead interferes with both ferrochelatase and delta amino levulinic acid, interfering with heme synthesis and causing anemia (70). Further, lead can interfere with vitamin D activation.

Renal damage may result from hyperuricemic states that happen as a result of impaired uric acid excretion. Long-term high-dose exposure may produce interstitial fibrosis (29).

Lead is cardiotoxic and is linked to hypertension. Lead-poisoned patients may have elevated plasma renin levels as well as interference with nitrous oxide-induced vasodilation. Lead also exhibits significant endocrine toxicity manifest by male and female reproductive failure, impaired bone growth, and thyroid dysfunction (40).

Lead interferes with osteoblast activity, translating into weakened bones and poor fracture healing. Lead inhibits bone vascularization and affects mineralization of cartilage (70).

Differential diagnosis

Sympathomimetic. Thyroid storm, pheochromocytoma, and other toxicities and adverse drug reactions, including alcohol withdrawal, neuroleptic malignant syndrome, serotonin syndrome, and malignant hyperthermia should be considered in the differential diagnosis of sympathomimetic toxicity.

Anticholinergic. Thyrotoxicosis, pheochromocytoma, CNS infection, heat stroke, hypoglycemia, and other toxins, including adrenergics, neuroleptic malignant syndrome, serotonin syndrome, salicylate poisoning, lithium poisoning, and steroid psychosis should be considered in the differential diagnosis.

Serotonergic. Notable in the differential diagnosis of serotonin syndrome is neuroleptic malignant syndrome given the many overlapping features, including autonomic instability, hyperthermia, and increased muscular tone. However, the implicated agents and mechanisms are distinct. Neuroleptic malignant syndrome is characteristically associated with agents that interfere with dopaminergic activity. Neuroleptic malignant syndrome is associated with bradykinesia and hyporeflexia; it does not have the lower extremity predominance of neuromuscular symptoms, is not associated with diaphoresis and agitation, and is generally of slower onset (18; 09). Malignant hyperthermia may be confused with serotonin syndrome as well; however, this is less likely given the clear association with inhalational agents. Other conditions on the differential include: anticholinergic toxicity, intoxication from sympathomimetic agents, sedative-hypnotic withdrawal, meningitis, and encephalitis (08).

Opiate. Sedative-hypnotics, clonidine exposures, and sepsis form the primary differential diagnosis.

Cholinergic. Misdiagnoses attributed to children and infants with acetylcholinesterase inhibitor toxicity include pneumonia, diabetic ketoacidosis, encephalopathy, head trauma, hydrocarbon pneumonitis, bronchitis, respiratory syncytial virus pneumonia, seizure disorder, and shigellosis (72).

Lead poisoning. Attention deficit hyperactivity disorder (ADHD) may closely resemble pediatric lead poisoning (64). A causal connection between prenatal lead exposure and ADHD development may exist (35).

Diagnostic workup

Sympathomimetic. History and characteristic clinical findings are key to rapid diagnosis. Urine drugs of abuse screens typically have an amphetamine screen; however, positive screens may be misleading. Patients receiving brompheniramine, phenylpropanolamine, bupropion, chlorpromazine, promethazine, and even ranitidine may test falsely positive on amphetamine screens (10). The cocaine metabolite benzoylecgonine is generally assayed as well. This is a more reliable assay with fewer false positives and negatives.

Anticholinergic. Many agents that produce anticholinergic poisoning also poison voltage-gated sodium and potassium channels predisposing to arrhythmia. Thus, rapid assessment of the QRS and QTc interval is essential. Many anticholinergic agents share structural homology with tricyclic antidepressants and may produce false positive results on drug screens. Acetaminophen and salicylate are frequently combined with anticholinergic agents; thus, these plasma levels should be obtained. In cases where the diagnosis is unclear and there is no contraindication, the patient’s response to administration of physostigmine may be helpful with diagnosis. If the patient develops signs and symptoms of cholinergic excess, then the patient does not have anticholinergic poisoning (63).

Serotonergic. The diagnosis is made on the basis of the aforementioned clinical findings/criteria. Careful history taking regarding medication changes is essential, as is a high index of suspicion.

Opiate. The diagnosis is made based on the clinical presentation and any associated supporting history. Opiate drug screens are readily available; however, numerous compounds interfere with opiate assays. Rifampin, rifampicin, and fluoroquinolones all produce false positivity on general opiate assays. Diphenhydramine may interfere with methadone assays (51). Fentanyl and oxycodone are generally not detected. The response to opiate receptor antagonism with naloxone strongly suggests opiate toxicity (46).

Cholinergic. History of exposure and appreciation of physical findings are the keys to diagnosis. Many organophosphorus agents have a characteristic petroleum or garlic-like odor, which may be helpful in establishing the diagnosis. Diagnostic workup is rarely helpful in the acute setting. Reference ranges of organophosphates and nerve agents are not established, and assays for organophosphates or carbamates are not generally available. If doubt exists as to whether an organophosphate or carbamate has been ingested, a trial of 1 mg atropine in adults and 0.01 to 0.02 mg/kg in children may be given. The absence of signs or symptoms of anticholinergic effects following the atropine challenge supports the diagnosis of poisoning with an acetylcholinesterase inhibitor.

Red blood cell acetylcholinesterase (RBC AChE) activity provides a measure of the degree of toxicity. Sequential measurement of red blood cell acetylcholinesterase activity can be used to determine effectiveness of oxime therapy in regeneration of the enzyme. The red blood cell acetylcholinesterase activity can also help evaluate chronic or occupational exposure. Most hospitals are unable to perform this test. A more feasible alternative is an assay for plasma (or pseudo-) cholinesterase activity, but it does not correlate well with severity of poisoning and should not be used to guide therapy (07).

Finally, electromyographic studies may be helpful in assaying for acetylcholinesterase inhibition. A single nerve stimulation that produces repetitive potentials suggests persistent acetylcholinesterase inhibition. Thus, monitoring for train dissipation is an index of cholinesterase recovery (06; 24).

Lead poisoning. Careful history for exposure should be taken. Immigrant children, children exposed to certain ethnic remedies, and children living in poorly maintained older housing all face increased risk of significant lead exposure (70). Imported toys, curtain weights, imported clothing accessories, charm bracelets, and bullets all are sources of exposure (52). Lead may be excreted in breast milk and, thus, sibling involvement may clue the physician to the diagnosis (66).

Elevation of whole blood lead level confirms the diagnosis. There is no safe or normal level of blood lead, and the CDC uses a blood level of 5 µg/dL as the reference value (21).

Patients may be anemic and may demonstrate basophilic stippling and hypochromic, microcytic cells on examination of the peripheral blood smear (70). Radiographs may reveal bands of calcification, typically in the knees, called “lead lines”; opacities may be observed in the gastroenterology tract following acute ingestion (23).

Management

Sympathomimetic. Patients should be placed in a calm atmosphere. Hyperthermic patients require aggressive cooling using ice packs and convectional cooling measures. Patients with focal neurologic deficits require imaging. Physical restraints predispose to metabolic acidosis and rhabdomyolysis and should be avoided. Haloperidol interferes with heat dissipation and lowers seizure threshold; therefore, it should also be avoided (01; 20). Benzodiazepines are the first-line agent. Although controversial, beta blockers should also be avoided for fear of unopposed alpha-agonist effects. There is no antidotal therapy for sympathomimetic exposure.

Anticholinergic. Supportive care and benzodiazepines are indicated for mild to moderate toxicity. As with sympathomimetic agents, haloperidol should be avoided (62).

Physostigmine is indicated for patients who have both peripheral and moderate central anticholinergic toxicity, ie, moderate to severe agitation/delirium. It should not be given if a condition other than a pure anticholinergic poisoning is suspected, ie, tricyclic antidepressant overdose (63). Physostigmine should be administered in a monitored setting. Physostigmine may produce secretions, inhibition of vascular smooth muscle, fasciculations, weakness, and paralysis (62).

The dose of physostigmine is 0.5 to 2 mg in adolescents/adults and 0.02 mg/kg in children up to a maximum of 0.5 mg per dose. Atropine should be available. Physostigmine should be infused over the course of 5 minutes. Overly rapid administration may result in cholinergic symptoms or seizures. Given the brief duration of action (half-life is approximately 15 minutes), repeat dosing is often necessary (63).

Serotonergic. Initial management requires identification and withdrawal of the offending agent. Mild or moderate serotonin syndrome will typically resolve in 24 hours. More severe cases will require administration of intravenous fluids and administration of benzodiazepines to control agitation. Correction of hypotension/hypertension should be achieved with short-acting agents given the characteristic autonomic instability (04). Dopamine is metabolized to epinephrine and norepinephrine by monoamine oxidase and, therefore, should be avoided. Hyperthermia and rigidity not readily controlled with cooling and sedation will require intubation and pharmacologic paralysis. Succinylcholine should be avoided given risk of hyperkalemia. Typically, hyperthermia resolves rapidly following paralysis.

Specific antidotal therapy includes cyproheptadine, which is a histamine-1 receptor antagonist with nonspecific 5-HT1A and 5-HT2A antagonistic properties, with weak anticholinergic activity. Cyproheptadine is indicated if benzodiazepines and supportive care fail to improve agitation and normalize vital signs. Initial recommended dose is 12 mg, followed by 2 mg every 2 hours until symptoms are controlled. Cyproheptadine is not available in a parenteral form; the oral form may be crushed and given through a nasogastric or orogastric tube if necessary. Antipsychotic agents such as olanzapine and chlorpromazine have been considered for antidotal treatment; however, given their unproven efficacy, their use is not recommended (08).

Opiate. For mild cases, supportive care may suffice. Patients who are exhibiting significant respiratory depression require opiate antagonism with naloxone. Naloxone is an opiate receptor antagonist with rapid onset of action. Children and adolescents with suspected opioid toxicity should receive naloxone rather than supportive care alone. Children under 20 kg should receive a dose of 0.1 mg/kg up to a maximum of 2 g per dose. Children over 20 kg can receive a dose of 2 g. Adolescents with suspected opioid addiction should receive lower doses of naloxone, similar to the adult treatment strategy, to avoid precipitating opioid withdrawal (71). Careful investigation of the chronic sequelae of opiate abuse should occur, and infectious or other complications may be addressed as they are identified (69).

Cholinergic. Patients with environmental exposure to organophosphates require aggressive decontamination, including full removal of clothing and vigorous washing of the body with soap and water (11). Water itself can help deactivate some nerve agents. If less than 1 hour has passed following ingestion, activated charcoal can be given (1 g/kg with a maximum dose of 50 g). Patients with markedly depressed mental status require 100% oxygen and immediate endotracheal intubation (07).

Atropine antagonizes the effect of acetylcholine. Atropine is indicated in the setting of any clinical signs of toxicity (0.05 mg/kg boluses in children, or 1 mg boluses in adolescents). Patients with mild toxicity may require only 1 to 2 mg, whereas more severe cases may require hundreds of milligrams over the course of several days. Boluses may be repeated every 3 to 5 minutes until pulmonary muscarinic signs and symptoms are alleviated (07).

Pralidoxime and other oximes are cholinesterase reactivating agents that are effective intreating both muscarinic and nicotinic symptoms. It must be administered concurrently with atropine to prevent worsening symptoms due to transient oxime-induced acetylcholinesterase inhibition. Pralidoxime can be given to patients with evidence of cholinergic toxicity, neuromuscular dysfunction, or with exposures to organophosphorus agents known to cause delayed neurotoxicity. Children can be given 25 to 50 mg/kg boluses based on severity of treatment. It should be administered slowly over 30 minutes. Rapid administration has been associated with cardiac arrest. A continuous infusion of 10 to 20 mg/kg/hr for children can be given after the bolus dose (07).

Seizure activity may be effectively managed with benzodiazepines (45).

Lead poisoning. The reference blood lead level of 5 µg/dL set by the CDC is not necessarily a level at which specific action is taken, but it documents the level at which the majority of U.S. children who have been tested for lead exposure fall. Because there is no safe blood lead level, all children with a detectable lead level warrant education and an environmental investigation (54). Initial management requires identification of the lead source and removal of the child from the exposure. When it is not obvious, certified home inspectors may help identify relevant lead sources (70). Once the source has been identified, thorough abatement must be performed.

Venous blood levels are used to determine the necessity of chelation therapy. Chelation is not routinely recommended for children with blood lead levels less than 45 µg/dL. Although chelation with oral agents has been shown to transiently reduce blood lead level, limited evidence including 1 randomized controlled trial has not found improved neurodevelopmental outcomes in children with blood lead levels less than 45 µg/dL who receive chelation. Even with chelation, the primary treatment for lead poisoning is removing the child from further lead exposure.

Asymptomatic children with blood lead level greater than or equal to 45 µg/dL should receive chelation therapy as soon as the blood lead level is confirmed with a venous lead level and only when the child is in a lead-safe environment (which may indicate hospitalization). The agent of choice is oral succimer. If the child cannot for whatever reason take succimer, then continuous infusion of calcium disodium edetate is suggested. Chelation should be performed in consultation with a toxicologist or other clinician experienced with chelating agents.

Symptomatic children without encephalopathy whose blood lead level is greater than or equal to 45 µg/dL should receive dimercaprol for 3 to 5 days and calcium disodium edetate for 5 days in order to avoid mobilization of lead into the brain. Symptomatic children with lead encephalopathy should be admitted to a pediatric intensive care unit to receive combined chelation therapy with dimercaprol and calcium disodium edetate. When inpatient chelation is complete, the child may be discharged if clinical status has improved and blood lead level is below 25 µg/dL. The child must be discharged to a lead-free environment and the caretaker must have the discharge medication such as succimer and demonstrate knowledge of its administration. Close follow-up is necessary (54).

Special considerations

Pregnancy

The diagnosis of pregnancy generally does not affect management of acute poisoning. Chronic exposures may pose risk to the fetus, depending on the agent involved.

Anesthesia

Acute poisonings rarely require any sort of operative intervention; consequently, interactions with anesthetics rarely pose any complications.