Sympathomimetic intoxication (2024)

CONTENTS

• Overview
• Clinical presentation
• Evaluation
• Management
  • Serotonergic medications to avoid
  • Agitation
  • Seizures
  • Hyperthermia
  • Hypertension
  • Arrhythmia
    • Atrial fibrillation
    • Monomorphic ventricular tachycardia
  • Hepatic failure
  • Respiratory complications
  • Rhabdomyolysis
  • Hyponatremia
• Podcast
• Pitfalls

overview

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common sympathomimetic intoxications:

• Cocaine.
• Methamphetamine:
  • Illicit “crystal meth.”
  • Medicinally prescribed methamphetamine, used for attention deficit hyperactivity disorder (ADHD) and obesity (tradename DESOXYN).
• Medicinal amphetamines used for ADHD:
  • Amphetamine (ADDERALL).
  • Lisdexamfetamine (VYVANSE).
• MDMA (3-4 methylenedioxymethamphetamine, a.k.a. “ecstasy” or “molly”).
• Symthetic cathinones (“bath salts”).

why one combined chapter on sympathomimetics?

• The clinical presentation of these different agents is largely indistinguishable, especially initially.
• Even if the patient is able to provide a history of which agent was taken, street sympathomimetics are often labeled incorrectly (e.g., a tablet marketed as “MDMA” might actually contain various cathinones).
• The treatment of sympathomimetic intoxication is generally the same across different agents.

clinical presentation

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sympathomimetic toxidrome

• Hypertension, tachycardia.
• Pupillary dilation.
• Diaphoresis, hyperthermia.
• Hyperreflexia, clonus.
• Agitated delirium, which eventually may progress to coma.

patients can also present with one or more complications of substance use:

• Cardiovascular:
  • Chest pain, MI.
  • Aortic dissection.
  • Cardiomyopathy: takotsubo cardiomyopathy (acute), nonischemic cardiomyopathy (chronic sympathomimetic use).
  • Cocaine causes sodium channel blockade, causing cardiotoxicity similar to tricyclic antidepressants.
  • Arrhythmias (e.g., atrial fibrillation, ventricular tachycardia).
  • Endocarditis (due to IV drug use).
• Pulmonary:
  • Aspiration pneumonia.
  • Pulmonary edema (cardiogenic or noncardiogenic).
  • Smoking crack or crystal meth may cause pneumothorax, pneumomediastinum, severe asthma exacerbation, or diffuse alveolar hemorrhage (“crack lung” – see below).
  • Tricuspid endocarditis due to IV drug use (IVDU) may lead to septic pulmonary embolization.
• Gastrointestinal:
  • Ischemia: Colonic ischemia, acute mesenteric ischemia.
  • Fulminant liver failure (especially following hyperthermia or MDMA use).
• Renal:
  • Rhabdomyolysis (especially following hyperthermia, overexertion, or seizures).
  • Renal infarction can occur.
• Neurologic:
  • Agitated delirium.
  • Seizures.
  • CVA (ischemic stroke, intraparenchymal hemorrhage, subarachnoid hemorrhage).
  • Acute angle-closure glaucoma may result from aggressive pupil dilation.

evaluation

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The exact evaluation will be tailored to the clinical context. Investigations to consider may include:

vital signs, especially temperature

• If there is any concern for possible hyperthermia, core temperature is ideal (e.g., rectal temperature).
• If the patient is hyperthermic (e.g., >104F or >40C), this mandates emergent management (more on this below).

laboratory studies

• Fingerstick glucose, if mental status is altered.
• Electrolytes (including Mg & Phos), complete blood count with differential, coagulation studies.
• Creatinine kinase (also consider repeating this if there is high risk for rhabdomyolysis).
• Liver function tests, especially if hyperthermic.
• Blood cultures (if there is intravenous drug use and concern for endocarditis).
• Troponin (if, based on EKG and symptoms, there is concern for myocardial ischemia).
• Acetaminophen and salicylate levels.
• Pregnancy test if appropriate.
• Toxicology screening has unclear clinical value:
  • Positive screening may prove exposure to certain substances (e.g., cocaine). However, a positive toxicology screen doesn't exclude simultaneous pathology (e.g., endocarditis or intracranial hematoma). Additionally, some tests may be positive for days following exposure, so a positive result doesn't prove acute intoxication.
  • Negative screening does not exclude sympathomimetic exposure (there are numerous “designer” sympathomimetics which will not be detected by standard screens).

imaging

• EKG.
• CXR (if fever or hypoxemia, leading to concerns for aspiration or pneumonia).
• CT head (if altered mental status, focal neurologic findings, or head trauma).
• POCUS:
  • Evaluate for cardiomyopathy, valvular regurgitation, aortic root dilation.
  • Thoracic ultrasonography if hypoxemia or respiratory symptoms.
  • (Formal echo as needed to further characterize subtle abnormalities, especially valvular pathology.)

serotonergic medications to avoid

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serotonin syndrome and sympathomimetic intoxication

• Many sympathomimetics increase serotonergic neurotransmission. Consequently, many of these agents have been implicated in causing serotonin syndrome (e.g., cocaine, amphetamine, methamphetamine, and especially MDMA).
• Whether or not the patient has “serotonin syndrome” is often debatable. This doesn't matter very much, because the treatment is largely supportive regardless (more on the treatment of serotonin syndrome here).
  • If there is marked ankle clonus, the patient probably meets the Hunter Criteria for serotonin syndrome.
• The main clinical implication here is that medications which increase serotonin signaling should probably be avoided (within the context of sympathomimetic intoxication these could either cause or exacerbate serotonin syndrome).

serotonergic medications to avoid

• SSRIs, SNRIs, cyclic antidepressants, MAO inhibitors.
• Buspirone.
• Opioids: meperidine, fentanyl, tramadol, dextromethorphan, methadone, possibly oxycodone.(29916050)
• Linezolid. (discussed further in the antibiotics chapter)
• Triptans.
• Methylene blue.
• Antiepileptics (carbamazepine, valproate).
• Antiemetics (ondansetron, granisetron, metoclopramide).
• Chlorpheniramine (an over-the-counter antihistamine).

agitation

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The differential diagnosis of agitation is broad (with a full differential of delirium here). More notable considerations in this clinical context include:

• Sympathomimetic intoxication and/or serotonin syndrome.
• Hypoglycemia.
• Hyponatremia or hypernatremia.
• Hypoxemia.
• Hyperthermia.
• Intracranial hemorrhage (intraparenchymal hematoma, trauma-induced hematoma, subarachnoid hemorrhage).
• Ischemic stroke.
• Nonconvulsive status epilepticus.
• CNS infection (e.g., HSV encephalitis, endocarditis with septic embolization to the brain).
• Posterior reversible encephalopathy syndrome (PRES).

further investigation?

• Fingerstick glucose and vital signs should immediately exclude hypoglycemia, hypoxemia, or hyperthermia. Urgent laboratory tests will subsequently exclude sodium abnormalities.
• Additional evaluation may vary, depending on clinical course and neurological examinations.

antipsychotics vs. benzodiazepines – a brief history of the grudge match

• Traditionally, antipsychotics have been feared due to the potential of promoting hyperthermia or seizures. This led to a strategy of treating patients with large doses of benzodiazepines (e.g., diazepam 10 mg every 5 minutes PRN, up to cumulative doses as high as ~100 mg). This strategy may be effective in the hands of practitioners who are highly experienced at titrating diazepam, and who have the resources to administer 5-10 doses of IV diazepam within a couple of hours.
• However, available evidence suggests that antipsychotics are safe and effective.(25724076, 30639129, 31088749) Since sympathomimetic intoxication increases brain dopamine activity, using antipsychotics to antagonize dopamine signaling may be a rational strategy. Additionally, antipsychotics have an extensive track record for the treatment of agitated delirium. Although most studies of agitated patients haven't teased out exactly which patients had sympathomimetic intoxication, many patients included in studies of agitated delirium were undoubtedly intoxicated.
• In one RCT comparing lorazepam versus droperidol in emergency department patients with agitation due to methamphetamine, droperidol was found to be more effective.(9426992) A more recent case series of emergency department patients with methamphetamine found that droperidol 10 mg IM was very effective (repeated once if needed in ~20% of patients, for a cumulative dose of 10-20 mg droperidol).(30592564)
• Perhaps the best evidence is an RCT involving 92 emergency department patients with methamphetamine-related agitation, who were randomized to treatment with 10 mg droperidol, 10 mg olanzapine, or a combination of 5 mg droperidol plus 5 mg midazolam (all administered intravenously). The droperidol/midazolam combination therapy was more rapidly effective. However, there were more adverse events in the combination therapy group (although they were generally minor).(28160494)
• Below is an editorial on this controversy, which merits reproduction based on both its educational and comedic value.

antipsychotic monotherapy strategy

• Most patients can be treated adequately with an antipsychotic alone. Typical dosing would be 10 mg of droperidol or olanzapine, followed by an additional 5-10 mg as needed. These agents can be given intravenously or intramuscularly.
• Haloperidol might work as well, but haloperidol is about half as potent as droperidol/olanzapine. So this would require higher doses of haloperidol to be effective. For patients being treated via an intramuscular route, haloperidol has a more sluggish onset than droperidol or olanzapine.
• Antipsychotic monotherapy carries a relatively low risk of respiratory suppression, since antipsychotics don't suppress respiration. However, this approach may take longer to work than a combination strategy including benzodiazepines.

antipsychotic/benzodiazepine combination strategy

• The combination of antipsychotic plus benzodiazepine may be used to achieve more rapid control of agitation. Yap et al. utilized 5 mg droperidol plus 5 mg midazolam intravenously.(28160494) If droperidol isn't available, similar results could likely be achieved using 10 mg haloperidol plus 5 mg midazolam intravenously (haloperidol is half as potent as droperidol, with similar kinetics when administered intravenously).
  • Lorazepam should be avoided here due to a slow onset of action.
• Combination therapy carries a higher risk of respiratory suppression but works faster, making it more suitable for patients with more severe agitation.

other treatment options

• Ketamine is an option for patients with extreme violence and agitation, who require immediate tranquilization. Theoretically ketamine could increase the blood pressure, but lysis of agitation will often have the opposite effect. If ketamine is used, vital signs must be carefully monitored subsequently and managed appropriately.
• Opioids may be useful if pain is contributing to the agitation. Avoid using fentanyl, as this could increase serotonin levels and promote serotonin syndrome. IV morphine or hydromorphone may be preferable.
• Dexmedetomidine
  • This might be an option for challenging cases, based on its sympatholytic, sedative, and analgesic properties. Since dexmedetomidine is titratable and doesn't suppress respiration, adding dexmedetomidine could help achieve sedation targets without impairing ventilation. However, current evidence supporting dexmedetomidine remains scant.(26919414, 25724076)
  • Dexmedetomidine takes a while to take effect, so it's not useful for immediate control of agitation. Since the onset of action is gradual, it may be reasonable to start dexmedetomidine sooner rather than later. One approach would be to start an infusion at a relatively high rate without a loading bolus (e.g., 1-1.4 mcg/kg/hour). This will gradually take effect over about an hour, after which it may be down-titrated. The patient's vitals and mental status should be followed carefully during this period. Sympatholysis may unmask occult hypovolemia, causing hypotension which responds to fluid resuscitation.
• Intubation
  • Intubation is a uniformly effective strategy, but ideally intubation shouldn't be required solely for the purpose of controlling agitation (given numerous options for treatment of agitation, as outlined above).
  • Intubation may be necessary to emergently control hyperthermia or facilitate obtaining diagnostic studies (e.g., CT scans or lumbar puncture).
  • ⚠️ Avoid succinylcholine (given that patients may have hyperkalemia). Once patients are intubated, propofol may be a good sedative choice (given its antiepileptic properties and rapid onset/offset).

⚠️ avoid physical restraints

• Physical restraints may promote the development of hyperthermia and rhabdomyolysis.
• Restraints may be necessary initially to ensure the safety of the patient and staff, but the primary goal should always be to calm the patient chemically.

some patients may require ongoing antipsychotic therapy

• Patients with synthetic cathinone intoxication may develop agitated delirium and psychotic features lasting days to weeks. Additionally, many patients with chronic amphetamine use may eventually develop chronic psychosis.
• Ongoing therapy with sedating atypical antipsychotics may be required to help transition patients out of the ICU, until they may gradually recover (e.g., use of quetiapine or olanzapine).

seizures

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causes of seizure & diagnostic investigation

• Aside from intoxication itself, other neurologic complications may lead to seizure.
• Common causes of seizure are the same as the causes of agitation, listed above.
• Immediate investigation involves checking a fingerstick glucose, electrolytes, and temperature. Additional investigations will depend on the context (e.g., video EEG, neuroimaging, and possibly lumbar puncture).

treatment

• Front-line therapy is benzodiazepines (e.g., 10 mg IM midazolam, or 0.1 mg/kg lorazepam IV).
• For these patients with status epilepticus, early intubation and propofol sedation should be strongly considered (to avoid a vicious cycle of ongoing hyperthermia, which leads to worsening seizures, to more hyperthermia, to more seizures, and ultimately culminates with death).
• Maintenance antiepileptic agent:
  • Levetiracetam is the preferred maintenance antiepileptic agent in this context.
  • ⚠️ Phenytoin is contraindicated in toxicological seizures (it has sodium channel blocking properties, which could aggravate cocaine intoxication).
  • ⚠️ Valproic acid may increase serotonin levels, which could theoretically promote development of serotonin syndrome.
• More on the treatment of status epilepticus here.

hyperthermia

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🚨 hyperthermia is an emergency🚨

• Hyperthermia may be defined roughly as a temperature above ~104 F/40 C in this context.
• Hyperthermia is an immediate threat to life (may cause brain injury, rhabdomyolysis, and disseminated intravascular coagulation).
• ⚠️ Hyperthermia is due to excessive thermal generation from muscle activity, not to hypothalamic changes in the set point. Therefore, antipyretics (e.g., acetaminophen) will fail to work.

agitation control is essential

• For agitated patients, immediate control of agitation is essential. This may be achieved using treatments described above.
  • Muscle exertion due to psychomotor agitation is a substantial driver of hyperthermia.
  • Control of agitation may be required to allow institution of physical cooling methods (see below).
• In the context of hyperthermia, if there is difficulty in controlling agitation then early intubation may be considered (as a strategy to achieve definitive control of agitation and temperature – deep sedation will stop heat generation by muscles).

physical cooling

• Several physical cooling methods should be immediately deployed, for example:
  • Chilled IV fluids.
  • Laying the patient on a cooling blanket.
  • Evaporative cooling, an immersive ice bath, or application of ice packs.
• More on physical cooling techniques for hyperthermia here.

hypertension

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the first step is control of pain and agitation (as described above)

• (1) Treatment of agitation will reduce the blood pressure.
• (2) Some agents used to treat agitation (especially dexmedetomidine) will particularly reduce the blood pressure.

titratable antihypertensive infusions

• An IV titratable infusion may be indicated for severe hypertension (e.g., mean arterial pressure over ~130 mm) with concern for hypertensive emergency, including end-organ damage (e.g., flash pulmonary edema or concern for posterior reversible encephalopathy syndrome). In this situation, the goal is to reduce the mean arterial pressure by ~20% initially (more on hypertensive emergency 📖).
• Nitroglycerine infusion 💉 may be useful, especially for patients with cardiopulmonary complications from hypertension:
  • Nitroglycerine is very easily titratable.
  • Nitroglycerine is the agent of choice for sympathetic crashing acute pulmonary edema (SCAPE). It also exerts favorable effects on myocardial perfusion, which may be beneficial among patients with ischemic chest pain.
  • Reflex tachycardia may occur, so hemodynamics should be followed closely.(26919414)
• Nicardipine infusion 💉 is another good choice:
  • Nicardipine may be more powerful than nitroglycerine.
  • Nicardipine might be preferred in patients with neurological target organ damage (e.g., posterior reversible encephalopathy syndrome or intracranial hemorrhage).

other agents to control blood pressure

• Diltiazem may be useful for the management of tachycardia and moderate hypertension.
• Clonidine 💉 could be a useful option to reduce blood pressure, while exerting sympatholytic effects.
• ⚠️ Beta-blockers are generally not preferred, due to concerns that beta-blockade could increase systemic vascular resistance and cause sympathomimetics to exert “unopposed alpha agonist” effects. The extent to which this is a real phenomenon is debatable (especially if alpha/beta blockers such as labetalol are used). During acute sympathomimetic intoxication, avoiding beta-blockers seems reasonable. However, once the acute intoxication subsides, beta-blockade should be safe.
• ⚠️ Avoid overly aggressive dosing of long-acting agents, because once the intoxication subsides the hypertension will often improve substantially.

rebound hypotension

• ⚠️ Patients are often hypovolemic due to insensible fluid loss (e.g., profuse sweating).
• Initial hypertension is caused by vasoconstriction. After vasoconstriction is controlled, this may unmask hypovolemia, leading to hypotension.
• If hypotension occurs, evaluate volume status with echocardiography and provide volume resuscitation if hypovolemic.

chest pain & acute coronary syndrome

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the differential diagnosis of chest pain in these patients includes:

• Demand ischemia (Type II MI) due to hypertension and physiological stress.
• Plaque rupture MI (Type I MI).
• Aortic dissection.
• Pneumothorax and/or pneumomediastinum.
• Crack lung.
• Septic pulmonary embolization following tricuspid endocarditis.
• Chest trauma.

evaluation

• EKG.
• Chest X-ray and thoracic ultrasonography.
• CT scan (if concern for aortic dissection).
• Troponin (if concern for myocardial ischemia).

management of acute coronary syndrome 2/2 sympathomimetics

• #1: Acute stabilization
  • Control psychomotor agitation if present, as described above.
  • Control hypertension if present, using agents described above.
  • Control hyperthermia if present, as described above.
  • Aspirin should be administered if no contraindication.
• #2: Repeat the EKG once blood pressure and agitation are controlled.
  • If EKG changes are substantially improved, then ischemia was likely due to physiological stress (i.e., demand ischemia).
  • If EKG changes are persistent or worse, this increases the likelihood of plaque rupture.
  • STAT echocardiography may also help sort out demand ischemia versus plaque rupture. For example, if the ventricle is hyperkinetic and without wall motion abnormalities, this argues strongly against occlusive myocardial ischemia.
  • The decision to pursue cardiac catheterization depends on consideration of serial EKGs, echocardiography, and the overall clinical picture. For example, if the patient is unlikely to adhere to dual antiplatelet therapy, then placement of a coronary stent could pose a hazard to the patient (in-stent thrombosis is a highly morbid event).

atrial fibrillation

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• Front-line treatments:
  • Diltiazem is often beneficial (to reduce the heart rate and blood pressure).
  • IV magnesium can be helpful.
• Cardioversion unlikely to be successful during the acute intoxication. Given the high degree of sympathetic tone, there is a high rate of reversion back into atrial fibrillation.
• More on the management of atrial fibrillation here.

monomorphic ventricular tachycardia

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• Cocaine can have sodium channel blocking effects, which may prolong the QRS duration and cause ventricular tachycardia. The treatment for this is similar to that of tricyclic intoxication, with hypertonic bicarbonate as a first-line therapy and lidocaine as second-line.
• Ventricular tachycardia can also be a manifestation of ischemia, so evaluate & treat this as needed (see section above on acute coronary syndromes).

QT prolongation & torsade de pointes

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• Cocaine may cause QT prolongation and torsade de pointes.
  • “Primary prevention” – for patients with QT prolongation, aggressive electrolyte repletion may reduce the risk of torsade (targeting Mg >3 mg/dL and K>4 mM).
  • “Secondary prevention” – for a patient who has had an episode of torsade, consider a magnesium infusion as discussed here.

hepatic failure

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• Hepatic failure can occur in the context of hyperthermia, especially due to MDMA (even without hyperthermia). However, remote or concurrent acetaminophen ingestion may be another possibility. These patients are often also at increased risk of acute or chronic viral hepatitis.
• If acute liver failure does occur (e.g., massive elevation of transaminases with an INR elevation >1.5), IV acetylcysteine should be considered. More on acute hepatic failure here.

respiratory complications

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asthma exacerbation

• Snorting or smoking particulate matter may cause particularly severe asthma exacerbations.
• Asthma exacerbation may require steroid and rarely intubation (more on the treatment of asthma here).

“crack lung”

• Crack lung is roughly defined as acute pulmonary symptoms with radiologic evidence of alveolitis occurring within ~2 days of smoking cocaine. The pathophysiology isn't clear (with possible mechanisms including diffuse alveolar hemorrhage, eosinophilic pneumonia, or possibly even transient left ventricular dysfunction). Although termed “crack lung,” it's probable that a similar phenomenon could result from smoking other sympathomimetics (e.g., crystal meth).(33717751)
• Symptoms are usually mild to moderate, and may include:
  • Fever.
  • Cough and dyspnea.
  • Hemoptysis or melanoptysis (production of black sputum).
  • Pleuritic chest pain is very common.
• Diagnosis:
  • Toxicology studies may help establish exposure to cocaine (if this is unclear).
  • CT scan often shows a characteristic inhalational distribution, with sparing of the peripheral lung (figure below).
  • Bronchoscopy is usually unnecessary. If performed, bronchoscopy may demonstrate high levels of eosinophils (>25%), diffuse alveolar hemorrhage, and/or black soot within the bronchi.
• Treatment
  • The mainstay of therapy is supportive care and cessation of crack smoking.
  • In severe cases, steroid may be considered (especially if there is a possibility of acute eosinophilic pneumonia).

rhabdomyolysis

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• Rhabdomyolysis may be especially likely in the following situations:
  • Hyperthermia.
  • Seizure.
  • Marked psychomotor agitation.
  • Patients found down, who may have ischemic pressure necrosis. (Be sure to examine these patients for physical signs of compartment syndrome.)
• For patients at higher risk for rhabdomyolysis, consider repeating a creatinine kinase level.
  • More on rhabdomyolysis here.

hyponatremia

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Acute hyponatremia may occur with MDMA and some synthetic cathinones (e.g., mephedrone). This may cause cerebral edema and elevated intracranial pressure. The presence of true hypoosmolar hyponatremia should ideally be confirmed by measurement of serum osmolality, but this shouldn't delay treatment if the clinical picture is consistent with symptomatic hyponatremia.

why hyponatremia can be dangerous

• (1) Acute hyponatremia may be especially dangerous in younger people who have little intracranial space to accommodate cerebral edema (e.g., fatal hyponatremia is reported in young women with acute hyponatremia and sodium levels in the 120-128 mM range).
• (2) The physiology involves excess ADH production. If these patients are given isotonic fluids, they will tend to retain the free water while excreting the salt (a process known as “desalination”) – causing hyponatremia to get worse.
  • Without active treatment of the hyponatremia, it may initially get worse.

treatment

• Restrict oral fluid intake and avoid IV fluid administration (as able, at least until the sodium has been pushed into a safe range).
• The acuity of hyponatremia makes it a bit safer to reverse this more aggressively.
• Hypertonic therapy should be used initially if there are symptoms of hyponatremia, with a goal of raising the sodium by ~3-4 mM rapidly.
  • The fastest way to accomplish this is often slow administration of two ampules of hypertonic sodium bicarbonate (each ampule contains 50 ml of 1 mEq/ml sodium bicarbonate).
  • 3% NaCl is an alternative approach, but note that substantial volumes will generally be required (e.g., a bolus of ~2 ml/kg or ~150 mL).
  • More on the use of hypertonic sodium for treatment of hyponatremia here.
• Sodium should be carefully followed subsequently (e.g., q4hr), with a target rise of ~6-8 mM over each successive day.
• More on the management of hyponatremia here.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Patients often have hypovolemia due to insensible losses (e.g., sweating), which may initially be masked by hypertension due to sympathomimetics. When treated with vasodilators, such patients may experience precipitous drops in blood pressure. This may seem paradoxical, but optimal treatment may require a combination of vasodilation plus volume resuscitation (in order to normalize both vascular tone and volume status).
• Avoid medications which may increase serotonin levels, as they could precipitate or aggravate a serotonin syndrome (e.g., fentanyl, meperidine, valproate, ondansetron, metoclopramide).
• Beware of acute hyponatremia in MDMA intoxication. Acute hyponatremia in young patients (especially women) can be life-threatening, even though the absolute sodium level isn't profoundly low.

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