Basics
Description
- Excess autonomic stimulation by adrenergic agents produces the clinical syndrome typically described as "sympathomimetic. "
- Overdose from sympathomimetic agents occurs secondary to the use of prescription drugs, nonprescription drugs such as OTC cold medicine (e.g., pseudoephedrine), dietary supplements (e.g., ephedra, synephrine), and illicit drugs such as cocaine, amphetamine, and methamphetamine.
- A more recent trend is the use of mephedrone and methylenedioxypyrovalerone (MDPV) among others are sold legally under the guise of "bath salts. "
- The sequelae of sympathomimetic overdose are generally related to the neurologic and cardiovascular systems.
- Severe problems may include agitation-induced hyperthermia, cardiac dysrhythmia, hypertension, myocardial ischemia, and infarction; CVA; seizure; and cardiovascular collapse.
- Bath salts appear to be associated with a much higher incidence of psychotic events than other sympathomimetics.
- A number of potent amphetamine analogs, such as paramethoxymethamphetamine (PMA), which have a high incidence of morbidity and mortality, are increasingly common components of tablets sold as MDMA.
Epidemiology
- Cocaine, methamphetamine, and MDMA (commonly called "Molly " or "ecstasy " ) are the 3 most common illicit stimulant drugs causing emergency visits in the United States.
- Prescription stimulants such as methylphenidate and albuterol are often frequent causes of intentional as well as unintentional poisoning.
Pathophysiology
- Relevant pathophysiology is based on the adrenergic receptor type stimulated by the drug in question. The adrenergic receptors of relevance includeα1, ²1, and ²2 receptors.
- Ephedrine and pseudoephedrine stimulate bothα and ² receptors:
- Excessive cardiovascular stimulation results in symptoms qualitatively similar to those that occur with catecholamines.
- Ephedrine and pseudoephedrine have weaker penetration of the CNS relative to drugs of abuse.
- As a result, users may suffer from systemic complications of the relatively larger doses necessary to achieve the CNS "high " of other stimulants.
- Nonelective ²-adrenergic agonists
- Isoproterenol, rarely used, is the prototypical nonselective ²-agonist causing the following:
- Tachycardia, hypotension, tachydysrhythmia, myocardial ischemia, and flushing due to its cardiostimulatory and vasodilatory properties
- Commonly, CNS effects of anxiety, fear, and headache occur.
- Selective ²2 adrenergic agonists are commonly used, and these include albuterol, levalbuterol, salmeterol, terbutaline, and others.
- Common adverse effects include the following:
- Tachycardia, palpitations, and tremor
- Hypotension, often with widened pulse pressure
- Nausea, vomiting, and sometimes diarrhea
- Hyperglycemia and hypokalemia
- Elevation of CPK as well as troponin, although myocardial infarction is never expected to occur in otherwise healthy children with selective ²2 agonist exposure
- Anxiety, fear, and headache also may occur.
- α1 Selective agonists include phenylephrine and phenylpropanolamine, although the latter is no longer commercially produced in any meaningful quantity in the United States.
- Hypertension due to direct vasoconstrictive effects is the most common effect.
- Reflex bradycardia may occur, particularly with phenylpropanolamine.
- Headache due to elevated BP and even CVA may occur.
Etiology
Causative agents:
- Agents with combinedα- and ²-adrenergic activity: epinephrine, norepinephrine, dopamine, ephedrine, and pseudoephedrine
- α1-Adrenergic agonists: phenylephrine, phenylpropanolamine
- ²-adrenergic agonists: nonselective ²-agonist isoproterenol
- Selective ²1 agonists: dobutamine
- Selective ²2 agonists: albuterol, salmeterol, terbutaline, ritodrine
- OTC agents: ephedrine-containing cold medicine, ephedra, Ma Huang
- Illicit drugs: cocaine, amphetamine, methamphetamine, MDMA (ecstasy), MDPV (bath salts)
- Theophylline and caffeine may cause a clinical syndrome of sympathomimetic poisoning.
Commonly Associated Conditions
- Many sympathomimetic agents are capable of producing psychiatric symptoms, particularly psychosis.
- This psychosis is similar to or indistinguishable from schizophrenia.
- 2 rare results of MDMA use include serotonin syndrome and SIADH with symptomatic hyponatremia.
Diagnosis
Signs and Symptoms
- The clinical effects of these agents ' overdose vary based on their receptor selectivity.
- Most agents have some degree of combinedα- and ²-adrenergic activity (ephedrine, pseudoephedrine).
- Hypertension, tachycardia, dysrhythmia, acute coronary syndromes, pulmonary edema and cerebrovascular injury, anxiety, a sense of impending doom, apprehension, fear, and headache may occur.
- At very high doses, agents cross the blood " brain barrier, which results in CNS symptoms, such as headache, seizures, and intracranial hemorrhage.
History
- History of exposure may be helpful but is often unavailable or deliberately concealed, particularly use of illicit drugs such as cocaine, methamphetamine, and ecstasy.
- Use of OTC medicines, such as multisymptom cold preparations or dietary supplements
- High suspicion of sympathomimetic overdose especially in patients with the sympathomimetic toxidrome
- The onset of symptoms usually occurs within 1 hour.
- Typically, prescription and OTC sympathomimetic agents are inhaled or orally administered.
- Inhalation or injection results in immediate symptoms.
- Cocaine, amphetamine, and methamphetamine or the sympathomimetics are most commonly used in this manner.
- Sympathomimetic toxicity following ingestion typically peaks 1 " 4 hours and last 4 " 8 hours, but sustained-release preparations may alter this time course.
- Chest pain due to dysrhythmia, myocardial ischemia, infarction, etc. may be a complaint.
- Headache, visual changes, epistaxis
Physical Exam
Sympathomimetic toxicity is a clinical diagnosis.
- Vital sign derangement is the most common and most reliable indicator of toxicity.
- Mental status changes are also common although less reliable as they do not occur with the same regularity and may be the result of toxicologic or psychiatric phenomenon.
- The patient 's general appearance (e.g., agitation, diaphoretic, delirium, psychotic) is often suggestive of toxicity.
- HEENT: mydriasis, visual changes, epistaxis, poor dentition
- Tachycardia and hypertension are the most common vital sign abnormalities.
- Skin: diaphoresis, flushing, the track marks associated with IV drug use
- CNS: Focal neurologic findings may occur. Focal cranial nerve abnormalities are particularly concerning for the possibility of CVA. CNS stimulation or agitation is very common.
Diagnostic Tests & Interpretation
- Sympathomimetic overdose is a clinical diagnosis and assays are only adjunctive.
- Unless there are specific forensic indications, such as malicious poisoning or child abuse, drugs of abuse screening is not recommended and is not useful.
- Serum acetaminophen level should be considered in patients with ingestion with intent of self-harm.
- The measurement of electrolytes, BUN, creatinine, and blood sugar may be useful.
- Cardiac markers (e.g., CPK-MB, troponin) are appropriate to screen for cardiac injury.
- An EKG should be obtained to assess for ischemia as well as dysrhythmias.
Imaging
A noncontrast head CT should be obtained in unresponsive patients or those with focal neurologic deficits.
Differential Diagnosis
- Hyperthyroidism/thyroid storm
- Anticholinergic syndrome
- Pheochromocytoma
- Withdrawal syndromes
- Mania
- Subarachnoid hemorrhage
- Serotonin syndrome
- Neuroleptic malignant syndrome
- Other situations of increased endogenous catecholamine release
Treatment
Initial Stabilization
Managing ABCs should be addressed first, but sympathomimetic toxicity usually does not result in illness requiring any specific airway, breathing, or circulation issues.
General Measures
Maintaining vital signs within acceptable limits and controlling patient agitation are commonly required.
- Managing ABCs is paramount.
- If protocol permits, sedation of agitated patients with a benzodiazepine may be appropriate.
- Use of benzodiazepines is helpful to address both cardiovascular stimulation as well as psychomotor agitation.
- Use of specific cardiovascular medications may be needed.
- Use of antipsychotics, such as haloperidol or droperidol, is relatively contraindicated both because these medications may lower seizure threshold, impair heat dissipation, and increase risk of cardiac dysrhythmia.
Special Therapy
- Severe hyperthermia should be treated with active cooling.
- Patients with core temperature of ≥107 °F should be placed in an ice bath and have core temperature monitored.
IV Fluids
- Unless there is a contraindication, at least maintenance IV fluid should be administered.
- IV fluids may protect against rhabdomyolysis as well as potential dehydration that may occur with stimulant exposure.
Medication
Agitation, vasoconstrictive effects, chronotropic and inotropic effects, and psychomotor agitation are the most common issues requiring mediation therapy for sympathomimetic toxicity.
First Line
- Psychomotor agitation may be managed with benzodiazepines.
- The quantity of benzodiazepine required will directly depend on degree of adrenergic stimulation.
- In some cases, large doses may be required for sedation.
- Lorazepam in doses of 0.1 mg/kg IV q15min titrated to effect is preferred due to predictable duration of action.
- Diazepam 0.1 mg/kg IV q15min titrated to effect may also be used.
- Vasoconstrictive effects may be managed with a variety of medications.
- Phentolamine 0.1 mg/kg/dose (up to 5 mg/dose) IV repeated q10min PRN
- A dihydropyridine calcium channel blocker, such as nifedipine or amlodipine, may be used.
- Sodium nitroprusside 0.3 " 10 mcg/kg/min IV, titrated to effect
- Chronotropic and inotropic effects may be managed with conduction-modulating calcium channel blockers such as diltiazem or verapamil.
Second Line
- A ²-blocker may be used only if anα-adrenergic antagonist is concomitantly administered.
- Use of a ²-blocker withoutα-adrenergic blockade may result in paradoxical increase in BP and death.
- Labetalol has someα-adrenergic blockade and may be used alone as a 2nd-line agent: 0.2 " 0.5 mg/kg/dose IV, maximal dose 20 mg, followed by infusion of 0.25 " 1 mg/kg/h
- Esmolol 500 mcg/kg IV bolus over 1 minute followed by infusion 50 mcg/kg/min titrated to effect up to 500 mcg/kg/min
- Severe cardiovascular symptoms resulting from ²-agonists or methylxanthines such as theophylline or caffeine may be treated with a ²-blocker.
- This treatment may seem counterintuitive in the management of hypotension.
- Severe ²2 agonist effects resulting in hypotension may be counteracted by using a ²-blocker.
- Such therapy should only be undertaken under the direction of a medical toxicologist, intensivist, or other clinician familiar with and experienced with use of such cardiovascular medications.
Ongoing Care
Admission Criteria
Any patient with severely deranged vital signs, end organ manifestations such as chest pain, severe headache, focal neurologic deficit, or agitation should be admitted.
Discharge Criteria
Any patient with vital signs within safe limits, normal mental status, and no evidence of end organ damage or manifestations may be discharged from the emergency department or inpatient unit.
Prognosis
If end organ damage such as myocardial infarction or CVA are prevented, prognosis for full recovery to premorbid status is excellent.
Complications
The most common catastrophic complications are cardiovascular, including dysrhythmia, myocardial infarction, and CVA.
Additional Reading
- Carr BC. Efficacy, abuse, and toxicity of over-the-counter cough and cold medicines in the pediatric population. Curr Opin Pediatr. 2006;18(2):184 " 188. [View Abstract]
- Haller CA, Meier KH, Olson KR. Seizures reported in association with use of dietary supplements. Clin Toxicol. 2005;43(1):23 " 30. [View Abstract]
- Haynes JF Jr. Medical management of adolescent drug overdoses. Adolesc Med Clin. 2006;17(2):353 " 379. [View Abstract]
- Kuehn BM. Citing serious risks, FDA recommends no cold and cough medicines for infants. JAMA. 2008;299(8):887 " 888. [View Abstract]
- Thirthalli J, Benegal V. Psychosis among substance users. Curr Opin Psychiatry. 2006;19(3):239 " 245.
Codes
ICD09
- 971.2 Poisoning by sympathomimetics [adrenergics]
ICD10
- T44.901A Poisn by unsp drugs aff the autonm nervous sys, acc, init
- T44.991A Poisoning by oth drug aff the autonm nervous sys, acc, init
- T48.5X1A Poisoning by oth anti-cmn-cold drugs, accidental, init
SNOMED
- 45536007 poisoning by sympathomimetic drug (disorder)
- 291299006 Alpha-adrenoceptor agonist poisoning (disorder)
- 54561008 Poisoning by epinephrine (disorder)