Michael J. Lynch and Anthony F. Pizon
Sympathomimetic agents represent a wide range of legal and illegal drugs. As the name implies, the physiologic response to these medications is a result of stimulation of the sympathetic nervous system. In therapeutic doses, these medications are used as stimulants, appetite suppressants, attention-deficit hyperactivity disorder (ADHD) therapy, decongestants, and bronchodilators. However, in supratherapeutic ingestions, patients may suffer cardiovascular and central nervous system (CNS) toxicity.
Sympathomimetics are typically divided into direct- and indirect-acting drugs. Direct-acting sympathomimetics (e.g., albuterol) bind postsynaptic receptors, stimulating them directly. Indirect-acting sympathomimetics (e.g., methamphetamine and amphetamine) raise synaptic concentrations of biogenic amines (norepinephrine, epinephrine, dopamine, serotonin) by (a) enhancing transmitter release from presynaptic vesicles, (b) inhibiting neurotransmitter reuptake, and (c) decreasing transmitter degradation. Mixed-acting agents such as dopamine and pseudoephedrine stimulate receptors both directly and indirectly (1).
Several different neurotransmitters may be affected, leading to variation in clinical presentation, therapeutic use, and toxicity. Stimulation of α- and β-receptors by epinephrine and norepinephrine leads to tachycardia and vasoconstriction, and central norepinephrine release leads to anorexia and CNS excitation. Excess dopaminergic stimulation plays a role in the addictive nature of many of these drugs. Dopamine-mediated glutamate activity coupled with γ-aminobutyric acid (GABA) inhibition leads to seizures as well as “crack dancing,” choreoathetoid-movement disorders that occur with acute intoxication (1). Euphoria and altered perception have been attributed to increased serotonin.
“Stimulants and street drugs” were responsible for 65,856 human exposures reported to US poison centers in 2011 and was associated with nearly 6% of all fatalities reported (2). Abuse of both legal and illegal stimulants is a growing problem that will be encountered by emergency physicians.
DRUGS OF ABUSE
Amphetamines are phenylethylamine derivatives, structurally similar to catecholamines, with different enantiomers and chemical substitutions that account for the variety of clinical effects. Amphetamines are a class of drugs that should not be confused with the drug amphetamine, which has a very specific structure and function. Drugs in the class of amphetamines are all based on the phenylethylamine structure. Compared to amphetamine, methamphetamine causes more powerful cardiovascular and CNS stimulant effects and methylenedioxymethamphetamine (MDMA) also known as ecstasy, is a much more potent serotonergic drug. Amphetamine metabolites also weakly inhibit monoamine oxidase.
MDMA and several of its derivatives are available as oral formulations, and methamphetamine is typically ingested or injected (“crank” or “speed”). Methamphetamine may also be smoked when in its purest crystalline formulation (“ice” or “crystal meth”). Metabolism takes place primarily by the liver cytochrome p450 system with renal elimination. Amphetamines are bases, and the elimination half-life of the drug is dependent upon urine pH, with more rapid elimination in acidic urine. Half-lives range from roughly 5 to 10 hours for MDMA to 12 to 34 hours for methamphetamine (3). These drugs are manufactured illegally and may be significantly contaminated with impurities. Moreover, because of the volatile nature of the chemicals involved in production of methamphetamine, explosions occurring during their synthesis pose a significant chemical hazard to the public, law enforcement officers, and emergency medical service (EMS) providers.
Cathinone is the active ingredient in khat (Catha edulis), a plant that is chewed or brewed into tea in eastern and central Africa and the Middle East for its stimulant effect. In 2009, the United States experienced an explosion of cathinone-derived drugs sold as legal highs and marketed as “bath salts,” “plant food,” and “stain remover.” Though largely made illegal on either the state and/or federal level, cathinones are still widely abused with similar chemical structure to methamphetamine and MDMA. Commonly abused cathinone derivatives include mephedrone, methcathinone, and methylenedioxypyrovalerone (MDPV).
PHARMACEUTICALS
Prescription amphetamines used to treat ADHD, including methylphenidate and amphetamine/dextroamphetamine, are widely abused. Much of this abuse is related to the fourfold increase in amphetamine prescriptions since the late 1980s, leading to greater availability (4), so that 15% of 12th graders admit to their illicit use. These medications have effects and pharmacokinetics similar to those of methamphetamine but are significantly less potent. Selegilene, a monoamine-oxidase inhibitor (MAOI) used in the treatment of Parkinson disease, is metabolized to L-methamphetamine, but there are no reports of overdose.
Phentermine, diethylpropion, and mazindol are centrally acting stimulants that have direct anorectic effects. These drugs are available as schedule IV prescription weight loss drugs. Fen-Phen, which contained phentermine in combination with the serotonergic drug fenfluramine, was voluntarily taken off the market because of its association with valvular heart disease and primary pulmonary hypertension.
Oral and topical decongestants, as well as some weight loss drugs, act via direct and indirect effects at α- and/or β-adrenergic receptors to induce vasoconstriction and decreased localized edema. Phenylephrine is a potent direct α1,2-receptor agonist while phenylpropanolamine is a direct- and indirect-acting α1,2 agonist. Toxicity of these medications includes hypertension with reflex bradycardia caused by the lack of β-adrenergic stimulation. Ephedrine and its less potent d-isomer, pseudoephedrine, are both direct and indirect-acting α1,2- and β1,2-adrenergic–receptor agonists. Consequently, toxicity consists of both tachycardia and hypertension, as seen with other sympathomimetic stimulants. CNS stimulation and seizures are also reported with these classes of decongestants. Because of its association with intracranial hemorrhages, phenylpropanolamine was removed from the market by the FDA (5). The sale of ephedrine, although not illegal, has also been restricted in many states because of its abuse potential and reported toxicity.
Another class of decongestants is the imidazolines (oxymetazoline, tetrahydrozoline, and naphazoline). Typically, the imidazolines are used as topical decongestants in nasal sprays and eye drops, but they can cause systemic toxicity. These drugs are central and peripheral α2-agonists like clonidine and therefore lead to peripheral α-mediated adrenergic symptoms, including hypertension with reflex bradycardia, followed by centrally mediated sympatholysis, bradycardia, and hypotension. CNS and respiratory depression caused by central α-agonism can also occur. See Chapter 322.
Prescription sympathomimetics also include β2-agonists such as albuterol, salmeterol, and terbutaline. These medications are used to treat asthma and bronchospasm but are rarely abused. Nevertheless, in therapeutic and supratherapeutic doses, these drugs may lead to supraventricular or sinus tachycardia, increased inotropy, and hypotension secondary to β-agonism without α-agonism. Other toxic effects include hypokalemia, rhabdomyolysis, nausea, and vomiting. Clenbuterol, a long-acting β2-adrenergic agonist, is abused as a performance-enhancing drug as well as used as an adulterant in heroin (6). Heroin overdoses that present with tachycardia, hypotension, and hypokalemia are suggestive of clenbuterol exposure.
HERBAL SUPPLEMENTS
Herbal supplements are extremely popular adjuncts for weight loss regimens in the United States. Ma huang, a Chinese herbal supplement, contains ephedra alkaloids that comprise six different sympathomimetic amines, including ephedrine and pseudoephedrine. Because of the incidence of significant cardiovascular toxicity, including stroke, cardiac arrest, and MI, the sale of ephedra was banned in 2005 (7). As a result, many herbal supplements have been reformulated to include bitter orange extract (Citrus aurantium), which contains synephrine, an isomer of the direct-acting α-agonist phenylephrine. Cases of variant angina, cerebral ischemia, and compartment syndrome with rhabdomyolysis and renal failure have been reported in association with synephrine use (8). A careful history, including over-the-counter medications and herbal supplements, must be taken in patients with suspected sympathomimetic toxicity.
CLINICAL PRESENTATION
Patients presenting to the ED with acute sympathomimetic toxicity typically display tachycardia, hypertension, diaphoresis, and hyperactivity. Pupils may be normal or dilated. Some patients exhibit psychotic behavior. Tremor and hyperreflexia can progress to seizures. In cases of severe toxicity, hypertension can lead to cerebral ischemia or intracerebral hemorrhage (7). Because the hypertension is usually acute, it can cause neurologic injury at pressures lower than those typically seen in patients with chronic hypertension; this is presumably caused by the lack of autoregulatory mechanisms. Sustained increases in muscle activity and seizure may result in rhabdomyolysis with significant elevation in creatine kinase (CK) and myoglobinuric renal failure. Patients with continued untreated muscle activity are at risk for severe metabolic acidosis and hyperthermia. Hyperthermia is a late and ominous finding in patients suffering from sympathomimetic toxicity.
Common mental status changes include euphoria, agitation, psychosis, anxiety, and confusion. These changes are usually related to the expected drug effects, but other causes such as intracranial hemorrhage, ischemia, or cerebral edema must be considered. Hyponatremia related to markedly increased free water intake and elevated antidiuretic hormone (ADH) levels may be seen in patients who have been “clubbing” or “raving” (3). Bruxism, or jaw clenching and teeth grinding, occurs with MDMA (ecstasy) ingestion (3).
Amphetamine and other sympathomimetics have been associated with acute myocardial infarction (MI), supraventricular and ventricular tachydysrhythmias, and cardiomyopathy with heart failure in a variety of age groups (3,7). Myocardial ischemia is thought to be related to vasospasm rather than occlusive disease. Chronic use of sympathomimetic drugs, even in therapeutic doses, has led to elevations in blood pressure and heart rate. Long-standing amphetamine abuse has also been associated with vasculitis that is responsive to treatment with immunosuppressants.
Sympathomimetic drug use and abuse can cause significant toxicity, disability, and death. Recognition of the disease process and rapid and aggressive treatment are necessary to prevent progression of symptoms.
DIFFERENTIAL DIAGNOSIS
Sympathomimetic toxicity should be considered in any patient with some or all of the clinical findings described previously. In particular, young patients with intracerebral hemorrhage, myocardial ischemia/infarction, arrhythmia, severe hypertension, or altered mental status should be interviewed with particular emphasis on legal and illegal drug use. However, a variety of toxicologic and organic disease processes may produce similar signs and symptoms. Toxicity from anticholinergic agents, cocaine, phencyclidine, MAOI interactions, and serotonin syndrome may produce a similar clinical picture. Classically, anticholinergic toxicity has dry skin while the skin with sympathomimetic symptoms should be clammy. Withdrawal syndromes, as seen with alcohol, clonidine, γ-hydroxybutyrate (GHB), or sedative–hypnotics, should also be considered.
The differential diagnosis of sympathomimetic toxicity also includes thyroid storm, pheochromocytoma, infection, nondrug-induced intracerebral hemorrhage, ischemic stroke or seizure, brain tumor, MI, aortic dissection, and psychiatric disease.
ED EVALUATION
The initial evaluation should focus on the vital signs. The sympathomimetic poisoned patient develops tachycardia, hypertension, and hyperthermia. Hyperthermia is the most important determinant of mortality, and accurate temperature measurement should be a priority. An axillary temperature is not adequate for these patients, and a rectal or esophageal measurement is best. Once the vital signs have been addressed, a neurologic assessment is paramount. Hallucinations, agitation, dystonias, and seizures are noted in some patients. Choreoathetosis from excessive dopamine stimulation in the basal ganglia is often referred to as “crack dancing” but is seen with other sympathomimetic drugs. “Bath salts” commonly present with agitation and aggression, and symptoms may be prolonged after the abuse of long-acting cathinone derivatives like MDPV. The exact constellation of findings depends upon the specific sympathomimetic drug involved.
Laboratory testing includes electrolytes, blood urea nitrogen (BUN), creatinine, total CK, and urinalysis. These tests are important for the assessment of hydration, hyponatremia from excessive hypotonic water intake during periods of excessive drug abuse, rhabdomyolysis, and signs of acute kidney injury from myoglobinuria. An electrocardiogram (ECG) and troponin may be helpful with chest pain, to measure QRS and QTc intervals for potential ventricular dysrhythmias and along with continuous monitoring, to monitor response to treatment. Additionally, QRS and QTc interval evaluation is critical to identifying potential for ventricular dysrhythmias and response to treatment. A head computed tomography (CT) scan may be helpful, if there are signs of trauma or intracranial hemorrhage, but is likely to be of low yield in most patients. A urine drug screen (e.g., EMIT assay) is not considered a useful diagnostic test. A negative amphetamine screen on an EMIT assay does not eliminate a sympathomimetic as the cause of symptoms, because many sympathomimetic drugs do not produce positive tests. Similarly, a positive test does not mean the patient took an amphetamine or amphetamine-like drug immediately prior to arrival, because an amphetamine screen may remain positive for days after drug use. Clinical suspicion for sympathomimetic poisoning should be based on history and physical examination.
KEY TESTING
• Immediately obtain vital signs with an emphasis on an accurate temperature.
• Electrolytes, BUN, creatinine, and total CK are used to evaluate for hyponatremia, dehydration, acute kidney injury, and rhabdomyalysis.
• An EKG is useful for the evaluation of dysrhythmias or cardiac ischemia.
ED MANAGEMENT
The initial management of sympathomimetic poisoning should focus on treatment of the vital signs. Because hyperthermia is the most important determinant of mortality, aggressive cooling should be initiated early. Any elevation in temperature should be taken seriously, and a reasonable goal is to reduce temperature to below 38°C. Because hyperthermia is a result of excessive muscle contraction or shivering, sedation or even paralysis should precede cooling measures for cooling to be more effective (see Chapter 360).
Chemical sedation treats hyperthermia and is also an effective treatment of other vital-sign abnormalities (e.g., tachycardia and hypertension) and agitation. Benzodiazepines are the best first-line agents in these cases. Benzodiazepines should be quickly titrated to the point of making the patient noticeably comfortable; when used by themselves, they rarely result in airway compromise. In addition, benzodiazepines treat possible seizures and other syndromes that may be included in the differential diagnosis (e.g., GABA-agonist withdrawal or other drug-induced delirium). Reasonable intravenous (IV) adult starting doses are diazepam 5 to 10 mg or lorazepam 2 to 4 mg every 5 to 10 minutes. Besides benzodiazepines, sympathomimetic-induced delirium may also benefit from haloperidol (9). Antipsychotics like haloperidol or droperidol antagonize central dopamine receptors and may offer additional benefit by a mechanism distinct from that of benzodiazepines. In particular, choreoathetosis associated with sympathomimetic poisoning will disappear after antipsychotic administration. Antipsychotics should be used with caution, because they can lower the seizure threshold, can lead to dysrhythmias from QT prolongation, and may alter temperature regulation. Haloperidol 5 mg IV, with increasing doses every 20 minutes, can be an effective addition to benzodiazepines.
At times, agitation and aggression may be prolonged and difficult to manage with benzodiazepines and antipsychotics. This is most commonly observed in patients who abuse “bath salts.” In these circumstances, pharmacotherapy should be rapidly titrated but under these extreme presentations, appropriate management includes intubation and use of general anesthetics like propofol (Diprivan).
Hypertension is usually controlled by sedatives alone. However, when additional treatment is needed, nitroglycerin (5 to 400 μg/min IV), phentolamine (5 to 15 mg IV every 20 minutes), and nitroprusside (0.25 to 10 μg/kg/min) are good adjuncts. It is difficult to specify a target blood pressure for treatment, but a pressure <180/110 mm Hg is generally recognized as a reasonable goal while avoiding overtreatment. If there is evidence of hypertensive encephalopathy or intracranial hemorrhage, more aggressive treatment may be necessary. β -Blockers should be avoided. Paradoxical hypertension may result from blockade of β2-mediated vasodilation and unopposed α1-adrenergic vasoconstriction. Coronary artery vasospasm has been noted when propranolol is used after cocaine administration in human volunteers (10).
Rhabdomyolysis requires aggressive fluid resuscitation, with a target urine output of 1 to 2 mL/kg/hr. Sympathomimetic-poisoned patients are often volume depleted, and routine fluid administration is good practice in this population.
Gastrointestinal (GI) decontamination is rarely of benefit. In patients who present after the onset of symptoms, activated charcoal administration is not expected to be helpful. The exception is in “body stuffers.” Patients who have ingested poorly packaged stimulants to hide contraband from the police may benefit from activated charcoal because they may be subject to absorption (often erratic) of the drug. Body stuffers who present before the onset of symptoms should routinely receive activated charcoal. Other forms of GI decontamination are not routinely recommended for this patient population. “Body packers” are smuggling well-packaged stimulants and are treated differently.
CRITICAL INTERVENTIONS
• Measure the temperature in a timely manner in patients with agitation, hyperactivity, seizures, and abnormalities of other vital signs.
• Rapidly sedate and cool patients with hyperthermia while instituting core body temperature monitoring.
• Use benzodiazepines to treat hyperthermia, hypertension, and tachycardia from sympathomimetic poisoning.
DISPOSITION
Because the duration of toxicity is often brief, patients with mild signs or symptoms may be monitored in the ED. Observation and monitoring of vital signs is advised for a minimum of 6 hours or until symptoms abate. Patients with persistent headache or neurologic signs may require a head CT scan. Patients with persistent CNS stimulation or vital-sign abnormalities should be admitted to an intensive care unit. The most ill patients, who present with hyperthermia, often require prolonged hospitalization for treatment of rhabdomyolysis and the associated renal failure. However, most cases require only short hospital stays for benzodiazepines, IV fluids, and monitoring of vital signs.
Common Pitfalls
• Failure to consider sympathomimetic toxicity in the differential diagnosis of tachycardia, hypertension, intracranial hemorrhage, and cerebral or myocardial ischemia.
• Failure to appreciate that headache, even without focal neurologic signs, may be the result of intracerebral hemorrhage.
• Failure to identify hyponatremia as a cause of cerebral edema and altered mental status.
• Failure to obtain a CK to check for rhabdomyolysis in patients with agitation and hyperthermia.
• Failure to appreciate that bradycardia in patients with hypertension as a result of sympathomimetic abuse is a normal reflex response. Treating bradycardia with atropine in this situation could aggravate hypertension.
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