Sympathomimetic Toxicity

Etiology

The etiology of acute sympathomimetic toxicity is exposure to a stimulant, with the most commonly encountered being amphetamines, cocaine, arylcyclohexylamines such as phencyclidine, and cathinones. Each of these drug classes exhibits different action mechanisms, though they all act as agonists at postsynaptic adrenergic receptors, whether due to catecholamine reuptake inhibition or increased presynaptic catecholamine release. Trends in stimulant use and misuse vary over time. Synthetic cathinones such as mephedrone and 3,4-methylenedioxy-N-methylamphetamine (MDMA) have recently gained popularity, while phencyclidine abuse is now considered less common in most places.

Epidemiology

Methamphetamine use in the United States is on the rise, with an estimated 2 million Americans aged 18 to 64 using this drug in 2019, compared to 1.4 million in 2015.[3] Cocaine use is most prevalent among male individuals aged 18 to 25, remaining stable between 2002 and 2018. However, mortality from cocaine overdose has tripled in the same period, possibly due to increasing contamination of the recreational drug supply.[4] These drugs know no socioeconomic boundary, are generally easy to obtain, and are considered inexpensive to manufacture in a clandestine setting.

Pathophysiology

The pathophysiology of acute sympathomimetic toxicity is related to increased binding of biogenic monoamines, including norepinephrine and dopamine, at their respective receptors, either by reuptake inhibition or increased presynaptic release. While the primary mechanism of action of cocaine is reuptake inhibition, amphetamines have multiple mechanisms of action, including reuptake inhibition, disruption of synaptic storage vesicles, and reversal of monoamine transporters.

Excess norepinephrine and dopamine in the synaptic cleft produce symptoms of increased sympathetic nervous system activity, including heightened alertness, mydriasis, tachycardia, hypertension, diaphoresis, psychomotor agitation, and hallucinations. Dangerous manifestations that occur with the progression of sympathetic effects from these drugs include autonomic instability, seizures, rhabdomyolysis leading to renal injury, coronary or cerebral ischemia, acidosis, hyperthermia, intracranial hemorrhage, and cardiovascular collapse.

Toxicokinetics

Toxicity from sympathomimetic agents occurs when one is taken excessively or multiple drugs are used in combination. The effects of these agents occur within minutes after inhalation, insufflation, or intravenous administration. Symptoms may be delayed after ingestion. Amphetamine, cocaine, and ketamine may all be used by inhalation, insufflation, or intravenous injection. MDMA is most commonly ingested.

The elimination half-life of methamphetamine is estimated to be 11 to 12 hours.[5] In contrast, cocaine has an elimination half-life of only about 1 hour, as it is rapidly metabolized by plasma esterases.[6] Clinicians should note that the elimination of many drugs shifts from 1st- to 0-order kinetics at high doses, which prolongs their duration of action and the time required for their complete elimination.

While methamphetamine is excreted as a combination of both amphetamine and the parent compound, cocaine is primarily excreted as benzoylecgonine. These metabolism and excretion patterns have important implications for urine drug testing. While low urinary pH is thought to increase the elimination of amphetamines, urine acidification is not recommended due to the risk of worsening rhabdomyolysis-induced renal injury.

History and Physical

Both the history and physical examination are of paramount importance when evaluating any poisoned patient. In many cases, encephalopathy or comorbid clinical conditions may limit the clinicians' ability to take the patient's history. The patient's knowledge of the substance they used may also be confounded by contamination and adulteration in the recreational drug supply. In such cases, identifying the toxidrome during the physical examination serves as the gold standard for diagnosing poisoning clinically.

The early signs of sympathomimetic toxicity include tachycardia, mydriasis, hypertension, increased arousal or psychomotor agitation, and diaphoresis. As toxicity progresses, patients may develop increased muscle tone, hyperreflexia, delirium, hallucinations, and hyperthermia. Severe end-organ effects may include myocardial or cerebrovascular ischemia, intracranial hemorrhage, rhabdomyolysis, renal failure, coagulopathy, seizures, metabolic acidosis, and cardiovascular collapse. Thus, besides a thorough evaluation of cardiovascular and renal symptoms, the physical examination should also assess for neurologic damage that may manifest as abnormal mental status, pupil size, muscle tone, and reflexes.

Evaluation

The history and physical examination are the primary methods of diagnosing sympathomimetic toxicity. Diagnostic tests are often appropriate only for evaluating potential complications. Clinicians should not rely on a urine drug test to diagnose acute sympathomimetic toxicity. A urine drug test never gives reliable information regarding active intoxication. However, serum concentrations of certain substances may be obtained in some cases to determine active intoxication, though this measure is less clinically feasible.

Laboratory evaluation should include a metabolic profile to assess for acidosis, electrolyte derangements, and renal dysfunction. A serum creatine phosphokinase can rapidly diagnose rhabdomyolysis. Serum salicylate and acetaminophen levels should be obtained to assess for these coingestions. Serum lactic acid concentration may suggest bowel ischemia.

An electrocardiogram may reveal signs of coronary ischemia or changes in QRS or QTc intervals, which may suggest other drug ingestions. Any focal neurologic deficit warrants consideration of cerebral ischemia or hemorrhage and subsequent cross-sectional head imaging. If the patient is suspected to have ingested packaged substances for internal concealment, abdominal imaging may be employed to search for containers such as plastic bags, condoms, and balloons. Confirmation of the presence of such materials can help preempt or treat bowel ischemia or obstruction and possibly dictate decontamination measures.

Treatment / Management

Sympathomimetic toxicity is typically evaluated in the acute setting, where airway, breathing, and circulation management takes priority. Decontamination methods, such as administration of activated charcoal or whole bowel irrigation, have limited utility, though they may be considered with ingestions of packaged drugs. No specific antidotes are recommended for the treatment of sympathomimetic toxicity. Consequently, supportive care and management of complications are the mainstay of treatment. 

Benzodiazepines are the drug class most often considered first-line in managing sympathomimetic toxicity.[7] These agents increase the frequency of γ-aminobutyric acid (GABA) chloride channel opening, resulting in the hyperpolarization of postsynaptic neurons and decreasing the release of excitatory neurotransmitters. Consequently, the effects of excessive adrenergic stimulation caused by sympathomimetic drugs are mitigated, reducing tachycardia, hypertension, agitation, increased muscle tone, hyperthermia, and the risk of seizures.(A1)

The use of β-blockers in sympathomimetic toxicity management is controversial. While some authors have reported successful use of this class of drugs, some clinicians avoid them to reduce the risk of unopposed α-adrenergic receptor agonism that can worsen vasoconstriction.[8] This effect is of greater concern when cocaine is suspected to be the offending agent. If β-blockers are contemplated, short-acting drugs that may be titrated by infusion are preferable.[9](A1)

Antipsychotics may be considered in this setting when hallucinations or choreoathetosis is the predominant manifestation, suggesting excessive dopaminergic rather than adrenergic activity. The use of high-dose 2nd-generation antipsychotics may complicate the clinical picture by triggering anticholinergic delirium. Adjunctive medications such as the α2-receptor agonist dexmedetomidine may also be administered for persistent hypertension, tachycardia, and agitation.

Benzodiazepines should be titrated until autonomic instability and psychomotor agitation resolve. Intravenous administration is often preferred to avoid dose stacking, although oral benzodiazepines may be considered in milder cases. Rapid sequence intubation is occasionally required to protect the patient from severe sympathomimetic toxicity. Hyperthermia is a very poor prognostic indicator and predicts imminent clinical deterioration.[10] External cooling should thus be implemented. A long-acting paralytic administered after intubation may effectively treat refractory hyperthermia by reducing elevated muscle tone.

Seizures are a common manifestation of severe sympathomimetic poisoning. The mainstay of treatment is the administration of benzodiazepines and other GABA receptor agonists. Limited evidence supports the use of antiepileptic drugs, such as levetiracetam and phenytoin, in the management of drug-induced seizures. Meanwhile, GABA-receptor agonists are not only effective in controlling seizures but also reduce concomitant adrenergic hyperactivity. 

Rhabdomyolysis results from agitation or increased muscle tone. Besides renal protection with intravenous hydration, further muscle breakdown may be prevented by either calming the patient with benzodiazepines or initiating intubation and paralysis in severe cases.

Differential Diagnosis

The differential diagnosis of sympathomimetic toxicity should include other disease processes, toxidromes, and withdrawal syndromes that may result in delirium and autonomic instability, including but not limited to the following: 

• Delirium tremens
• Hypertensive emergencies
• Anticholinergic poisoning
• Neuroleptic malignant syndrome
• Serotonin syndrome
• Malignant hyperthermia
• Salicylate poisoning
• Benzodiazepine withdrawal
• Baclofen withdrawal
• Panic disorder
• Scorpion envenomation
• Thyrotoxicosis
• Sepsis

A thorough evaluation of these potential diagnoses is crucial for timely and appropriate management to optimize patient outcomes.

Prognosis

Chronic use of sympathomimetic drugs like amphetamines or cocaine can induce end-organ damage due to persistent hypertension and vasoconstriction. Prolonged or excessive use of these agents may cause myocardial infarction, heart failure, cardiac arrhythmias, stroke, and arterial dissections. Intravenous use of these drugs places patients at risk of endocarditis and viral infections such as HIV or Hepatitis C if injection equipment is shared. Hyperthermia is a key predictor of poor prognosis in patients with acute sympathomimetic poisoning and may lead to systemic effects such as disseminated intravascular coagulopathy and organ failure.