Cardiovascular drug poisoning

Cardiovascular drug poisoning can occur as a result of attempted self-harm, inadvertent medication error, or changes in drug clearance, e.g., if renal insufficiency develops. Hypotension, arrhythmias, and/or neurologic changes commonly occur at toxic levels of these medications. Management often requires a clinical diagnosis to be made based on medication history and ECG changes, and the patient is treated symptomatically until the offending agent is identified. Initial symptomatic treatment may include GI decontamination, IV fluids for hypotension, atropine for bradycardia, and benzodiazepines for seizures. Definitive therapy may include a drug class-specific antidote, e.g., high-dose euglycemic insulin therapy for calcium channel blocker poisoning or digoxin immune Fab (DigiFab) for digoxin poisoning.

Cardiovascular drug poisoning often manifests with cardiogenic shock that may require judicious IV fluid resuscitation with vasopressors and inotropes PLUS substance-specific antidotes.

Nonspecific features common to most cases of cardiovascular drug poisoning include: ^[2]

• Cardiovascular features
  • Hypotension
  • Bradycardia
  • Heart blocks
  • Reflex tachycardia
  • Tachyarrhythmias
  • Sudden cardiac death
• Neurologic features
  • Somnolence
  • Unconsciousness
  • Seizures
• Other features: nausea and vomiting

Patients with severe cardiovascular drug poisoning can present with cardiogenic shock or cardiac arrest.

Initial management ^[2][5]

• Initiate cardiac monitoring and pulse oximetry.
• Perform a toxicological risk assessment including clinical and diagnostic evaluation.
• Determine the need for GI decontamination.
• Call the local poison control center: In the US, the Poison Help line is 1-800-222-1222.
• Begin symptom-specific management until an offending agent is identified.
• Obtain POCUS or echocardiography to assess volume status and contractility and guide resuscitation.
• Begin specific management once the substance is identified (e.g., beta blocker poisoning, CCB poisoning, digoxin poisoning).
• Administer antidotes as indicated by the substance (see “Antidotes and dosages”).

Management of poisoning by multiple classes of cardiovascular drugs is complex; Consult a medical toxicologist and critical care specialist.

Diagnostic evaluation

Cardiovascular (CV) drug poisoning is primarily diagnosed clinically. Serum drug levels, when available, can support the diagnosis and, in some cases, help guide management.

• Ensure the following are included in the toxicological history and physical examination:
  • CV drug ingestion details (e.g., witnesses, time, quantity, access, availability)
  • Co-ingested hemodynamically active medications or substances
  • Conditions affecting CV drug metabolism, e.g., worsening renal failure
• Consult a toxicologist to determine individual risk as toxic dose thresholds for CV drugs can vary by poison center. ^[6][7]
• Obtain ECG, CMP, and drug levels (e.g., serum digoxin). ^[5][8]
• See “Toxicological risk assessment” for details.

A single pill of a cardiovascular drug formulated for adults may contain a toxic or even fatal dose for a child. ^[7]

GI decontamination

• Consider single-dose activated charcoal if: ^[2][9]
  • Ingestion was < 1–2 hours ago (or longer if drug was sustained release)
  • Ingested drug was taken in massive quantities or has high toxicity, e.g., CCBs
  • No effective antidote is available
• Consider whole bowel irrigation on an individual basis for ingestions of sustained-release or enteric-coated drugs. ^{[10][11][12][13]}

Do not perform whole bowel irrigation if the patient is hemodynamically unstable, has clinical signs of bowel obstruction, and/or their airway is not protected. ^[13]

Symptom-specific management ^[2]

Hypotension

• Immediate hemodynamic support: 20–40 mL/kg normal saline bolus followed by norepinephrine infusion titrated to MAP ≥ 65 mm Hg
• Obtain POCUS or echocardiogram early to guide resuscitation. ^[2][5]
  • Normal contractility: Give IV fluid bolus.
  • ↓ Contractility: Options depend on the ingested drug and include calcium for drug OD, high-dose glucagon, norepinephrine infusion, and/or high-dose euglycemic insulin. ^[5]
  • ↑ Contractility and normal preload: implies ↓ vascular resistance, consider norepinephrine infusion ^[14][15]
• Consult ICU.
• Consider venoarterial extracorporeal membrane oxygenation (VA-ECMO) for refractory shock.

Consider initiating VA-ECMO early in severely unstable patients. ^[2][5]

Bradycardia ^[5]

• Follow the “Adult unstable bradycardia algorithm.”
• Administer IV atropine .
• Prepare for temporary cardiac pacing.

Atropine is seldom effective for medication-induced bradycardia. Temporary cardiac pacing and antidotes (e.g., high-dose glucagon) are often required. ^[16]

Arrhythmias ^[17]

• Correct electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia) promptly.
• Undifferentiated tachycardia: Follow “Approach to tachycardia.”
• Ventricular tachycardia: See “Initial management of ventricular tachycardia.”

Avoid Class IA and Class IC antidysrhythmic medications, as they may worsen the proarrhythmic state of the myocardium. ^[2][17]

Seizures ^[5]

• Correct hypoglycemia, if present.
• Administer benzodiazepines: See “Toxic seizures.”

Calcium therapy for drug poisoning ^[2][16][18]

• Indications: CCB poisoning, beta blocker poisoning
• Administration: calcium chloride or calcium gluconate ^[2][5][16]
• Monitoring: Check ionized calcium levels every 30 minutes initially; the goal is 1.5–2 times normal value. ^[2][18]
• Safety with digoxin use: unclear; consult medical toxicologist. ^[5][19][20]

Calcium chloride is usually administered through a central line, unless the patient is hemodynamically unstable. ^[2]

High-dose euglycemic insulin therapy ^[2][16][18]

• Indications: CCB poisoning, beta blocker poisoning
• Administration: Titrate infusion upward every 10–15 minutes until reaching a heart rate ≥ 50/min and systolic blood pressure ≥ 90 mm Hg. ^[21]
  • Regular insulin ^[2][5][16]
  • PLUS dextrose ^[2][5][22]
• Monitoring
  • Check blood glucose every 15–30 minutes until stable; the goal is euglycemia.
  • Check potassium every 60 minutes until stable; maintain levels of at least 2.8–3.2 mEq/L. ^[5]

High-dose glucagon ^{[2][5][16][18][23]}

• Indications: beta blocker poisoning, CCB poisoning ^[16]
• Administration: Titrate glucagon to response, then start glucagon infusion at response dose per hour. ^[5][16]
• Monitoring: frequent blood glucose

Intravenous lipid emulsion therapy (ILE) ^[2][24]

• Indications: CCB poisoning, beta blocker poisoning, sodium channel blocker poisoning
• Administration: See “Intravenous lipid emulsion therapy” for dosages.

Only use intravenous lipid therapy when symptoms of toxicity are refractory to more conventional therapy, e.g., if at least three vasopressors to correct hypotension. ^[2][24]

Methylene blue for drug poisoning ^[2][5][25]

• Indications: CCB poisoning, methemoglobinemia from nitrate poisoning
• Administration: methylene blue (off-label for hypotension) ^[25][26]

The following are expert-recommended best practices. Follow local protocols and consult a toxicologist to help determine individual disposition. ^{[2][3][5][27][28]}

• Transfer unstable patients to the ICU.
• Admit patients to a monitored bed in the following cases:
  • New arrhythmias or conduction abnormalities
  • Chronic digoxin poisoning regardless of symptoms
  • Ingestion of drugs with extended release formulations or delayed toxicity, e.g., sotalol
  • Signs or symptoms of toxicity that do not reverse in the observation period.
• Observe stable patients based on the half-life of the ingested medication(s) and the amount ingested.
• Consult psychiatry if the overdose was intentional.

Potentially toxic doses ^[7]

Discuss risk with poison control; the lowest reported toxic dose is typically higher than the maximum recommended therapeutic dose but can overlap in drugs with a narrow therapeutic index.

Bisoprolol toxicity may not follow a clear dose-response relationship. Similar toxic effects have been seen at low and high doses of exposure. ^[31]

A few drops of ophthalmic beta blockers (e.g., timolol) can cause significant systemic effects. ^[32]

Clinical features ^[2][5][27]

Onset

• Life-threatening symptoms: possible as early as 30 minutes after ingestion ^[5]
• Most symptoms: within the first 6 hours ^[5]
• Sotalol poisoning: can cause delayed and prolonged symptoms

Signs and symptoms

• Clinical features of CV drug poisoning: typically bradycardia, hypotension, and CNS depression
• Other features
  • Delirium
  • Respiratory depression
  • Seizures (typically seen with propranolol) ^[31]
  • Bronchospasm (rare)
  • Adverse effects of beta blockers
  • Clinical features of hyperkalemia
  • Clinical features of hypoglycemia

Sotalol poisoning can manifest with CNS depression and vomiting. ^[31]

Diagnostics ^[2][5][27]

• Laboratory studies
  • BMP: hypoglycemia, hyperkalemia
  • Blood gas: metabolic acidosis
  • Drug levels: test not generally available
• ECG
  • Sinus bradycardia
  • AV block
  • Junctional bradycardia
  • Prolonged QRS
• Additional studies
  • CXR if the patient is at risk of congestive heart failure
  • Digoxin levels if the patient is known to have had access to digoxin
  • Additional bradycardia workup based on clinical suspicion

Management ^{[2][14][16][27][33]}

If the patient is unstable, begin interventions simultaneously rather than sequentially.

Initial management

• Begin initial management of CV drug poisoning.
• Hypotension: IV fluid bolus 20–40 mL/kg
• Symptomatic bradycardia: atropine , temporary cardiac pacing
• Sodium bicarbonate (off label) if all of the following are present: ^[2]
  • Poisoning with a membrane-stabilizing agent: e.g., propranolol, pindolol, labetalol, oxprenolol, acebutolol
  • Acute QRS prolongation > 120 ms
  • Clinical signs of shock

Persistent instability after initial management

• High-dose glucagon therapy
• Calcium for drug poisoning; may be unsafe if there is concurrent digoxin poisoning ^[5][19][20]
• High-dose euglycemic insulin therapy

Glucagon can be used as an antidote for beta blocker poisoning. ^[2][5]

Sustained instability after secondary interventions

• Norepinephrine infusion (first line)
• Vasopressin infusion
• Additional inotrope or vasopressor, e.g., epinephrine infusion for decreased contractility

Refractory instability

• Intravenous lipid emulsion therapy
• Consider hemodialysis for atenolol or sotalol poisoning in patients with renal impairment AND refractory bradycardia, hypotension, or torsades de pointes. ^[34]
• VA-ECMO

Potentially toxic doses ^[6]

Discuss risk with poison control; the lowest reported toxic dose is typically higher than the maximum recommended therapeutic dose but can overlap in drugs with a narrow therapeutic index.

Clinical features ^[2][5][27]

Onset

• Immediate release CCBs: within 6 hours ^[35]
• Sustained-release CCBs: within 12–24 hours ^[35]
• Patients who present early or have only consumed a small quantity of CCBs may be asymptomatic.

Signs and symptoms

Most clinical features of CV drug overdose can occur. Specific features depend on the agent and poisoning severity.

• Mild or moderate dihydropyridine CCB poisoning
  • Distributive shock features may predominate.
  • Reflex tachycardia ^[5]
• Mild or moderate nondihydropyridine CCB poisoning: Clinical features of acute heart failure (e.g., pulmonary edema) may predominate. ^[5]
• All severe poisoning: bradycardia and cardiogenic shock ^[5]
• Other features
  • Respiratory depression (including apnea), pulmonary edema
  • Hyperglycemia

CCB poisoning more often results in life-threatening symptoms (e.g., profound hypotension and bradycardia) than beta blocker poisoning. ^[2]

Diagnostics ^[2][12][27]

• Laboratory testing
  • BMP: typically shows mild hyperglycemia and hyperkalemia
  • Blood gas: metabolic acidosis
  • Drug levels: test not generally available
• ECG ^[16]
  • AV block
  • AV dissociation
  • Junctional rhythm
  • Sinus bradycardia , sinus arrest
  • Tachycardia
• Additional studies
  • CXR if the patient is at risk of congestive heart failure
  • Serum levels of suspected co-ingestions (e.g., digoxin)
  • Additional bradycardia workup based on clinical suspicion

Management ^[33][36][37]

If the patient is unstable, begin interventions simultaneously rather than sequentially.

Initial management

• Begin initial management of CV drug poisoning.
• Hypotension: IV fluid bolus 20–40 mL/kg
• Bradycardia (symptomatic): atropine (rarely effective), temporary cardiac pacing

Consider GI decontamination for sustained-release CCB poisoning. ^[5]

Persistent instability after initial management

• Calcium for drug poisoning; may be unsafe if there is concurrent digoxin poisoning ^[5][19][20]
• High-dose euglycemic insulin therapy (preferred over vasopressor infusion)
• Consider high-dose glucagon.

Where possible, use high-dose euglycemic insulin therapy rather than vasopressor infusions for severe CCB poisoning. ^[5]

Sustained instability after secondary interventions

The effectiveness of these agents is inconsistent.

• Norepinephrine infusion (first-line therapy)
• Vasopressin infusion
• Additional inotrope or vasopressor, e.g., epinephrine infusion for decreased contractility

Refractory instability

• Intravenous lipid emulsion therapy
• Methylene blue for drug poisoning ^[2][5][27]
• VA-ECMO

Non-ECMO extracorporeal therapy (e.g., hemodialysis) is discouraged for severe poisoning with amlodipine, diltiazem, and verapamil as these substances are not dialyzable. ^[38]

Poisoning may result from acute digoxin overdose, reduced clearance of chronically administered digoxin, or ingestion of plants containing cardiac glycosides.

Risk factors ^[2][5]

• Electrolyte imbalances
  • Hypokalemia: digoxin competes with K⁺ for binding to Na⁺/K⁺-ATPase
  • Others: hyperkalemia, hypernatremia, hypomagnesemia, hypercalcemia, alkalosis
• Medical conditions
  • Renal failure (reduced digoxin excretion)
  • Volume depletion (e.g., treatment with diuretics)
  • Hypothyroidism
• Drug interactions
  • Treatment with verapamil, diltiazem, amiodarone, and/or quinidine: These drugs may displace digoxin from tissue binding sites and decrease renal elimination.
  • Co-ingestion with other cardiovascular drugs (e.g., beta blockers) or sympathomimetic drugs (e.g., cocaine)

Digoxin has a narrow therapeutic index. Serum concentrations of cardiac glycosides must be monitored closely because overdoses can have severe consequences.

Clinical features ^{[2][5][8][39]}

The symptoms and signs of chronic digoxin poisoning are nonspecific, with significant overlap between acute and chronic toxicity.

• Acute poisoning: Nonspecific clinical features of CV drug poisoning can occur.
• Acute and chronic poisoning: Symptoms are less obvious in chronic poisoning.
  • Vagal symptoms: nausea, vomiting, diarrhea, abdominal pain, anorexia
  • Arrhythmia symptoms: palpitations, syncope, and presyncope
• Chronic poisoning
  • Confusion, fatigue, lethargy, weakness, and disorientation
  • Visual disturbances
    • Blurred vision, halos, scotomas, diplopia
    • Photophobia
    • Xanthopsia (yellow-tinted vision)

Potentially fatal bradyarrhythmias and/or tachyarrhythmias may occur in digoxin poisoning.

Diagnostics ^[2][5]

ECG ^[40]

Any dysrhythmia or conduction block may occur; bradyarrhythmias are as common as tachyarrhythmias.

• Premature ventricular beats (most common)
• Reentry or enhanced automaticity: Vtach or Vfib, atrial tachycardia with AV block, Afib or atrial flutter
• Depressed conduction (vagal effect): sinoatrial arrest, sinoatrial block, AV block
• Digitalis effect: waveform changes that occur in the presence of digoxin but do not necessarily indicate digoxin toxicity ^[5][19][41]
  • T-wave inversion or flattening
  • Deformed ST segment: scooping or sagging
  • ↓ QT interval
  • ↑ PR interval

There is no characteristic arrhythmia associated with digoxin poisoning; a wide range of arrhythmias can occur. ^[2]

Laboratory studies ^[42]

• Serum digoxin concentration: Measure 6 hours after ingestion to avoid overtreatment unless the patient is severely symptomatic. ^[2][5][42]
  • 0.7–1.1 ng/mL: therapeutic range ^[2][5]
  • 1.1–3 ng/mL: indeterminate range; arrhythmias possible
  • ≥ 2.5 ng/mL: incidence of arrhythmia > 50%
• Serum electrolytes
  • Potassium: hyperkalemia (associated with poor prognosis)
  • Creatinine and blood urea nitrogen to evaluate renal function
  • Other abnormalities that may have triggered digoxin poisoning: See “Risk factors.”

Management ^{[2][5][40][43][44]}

DigiFab is the antidote for significant acute and chronic poisoning. ^[2][44]

• Initial management
  • Begin initial management of CV drug poisoning.
  • Administer activated charcoal even if ingestion was not recent. ^[45]
  • Administer digoxin immune Fab (DigiFab), if indicated.
• Electrolyte abnormalities
  • Treat hyperkalemia > 5.0 mEq/L with DigiFab; calcium may be unsafe. ^[5][19][20]
  • Correct hypokalemia slowly: K⁺ levels may rise rapidly hours after digoxin ingestion. ^[2]
  • Correct magnesium level cautiously. ^[2]
• Arrhythmia treatment
  • DigiFab therapy is preferred over pacing or antiarrhythmic drugs. ^[2]
  • Supraventricular bradyarrhythmias and/or high-degree AV block : atropine , consider temporary cardiac pacing ^[40]
  • ECG changes in hyperkalemia : sodium bicarbonate (off-label)
  • Ventricular arrhythmias or irritability
    • Phenytoin (preferred; off-label) ^[2][5]
    • If phenytoin is contraindicated or maximum phenytoin dose has been reached: lidocaine ^[2][5]

In severe digoxin poisoning, interventions such as cardiac pacing or cardioversion can trigger asystole or Vfib, as cardiac tissue may be hypersensitive to electrical and/or mechanical stimulation. ^[2]

Avoid class IA antiarrhythmics, e.g., quinidine, procainamide, and disopyramide. ^[5]

Digoxin immune Fab (DigiFab) ^[2][5][43]

• Fragments of immunoglobulins with a Fab region that binds free digoxin in the serum ^[46]
• The definitive treatment for digoxin poisoning

Indications ^[2][5][43]

Known or suspected digoxin poisoning in patients with any of the following:

• Cardiac arrest ^[5]
• Any life-threatening or potentially life-threatening arrhythmia ^[5]
• Serum potassium rapidly rising or > 5.0 mEq/L (attributable to digoxin) ^[2]
• Acute ingestion > 4 mg (or > 0.1 mg/kg) in a healthy child or 10 mg in a healthy adult ^[5]
• Serum digoxin concentrations > 10 ng/mL soon after acute ingestion or > 6 ng/mL steady state ^[2][5]
• Serum digoxin concentration > 1.6 ng/mL AND signs or symptoms of severe digoxin toxicity ^[43]
• Co-ingestion of other cardiovascular drugs

There are no absolute contraindications to DigiFab. ^[46]

Dosage and administration ^[46]

Several strategies can be used to determine the initial dose of DigiFab. Expect a clinical response in most patients within 1 hour of infusion completion. ^[5]

• Unknown ingested quantity: empiric administration
  • Acute ingestion
  • Chronic ingestion
• Known ingested quantity: ingested digoxin in mg x 2 = vials of DigiFab ^[2][5][46]
• Known serum digoxin concentration: (concentration in ng/mL x patient weight in kg)/100 = vials of DigiFab

Adverse effects of Digifab include hypokalemia, loss of therapeutic effects of digoxin (e.g., rebound rapid A-fib), and occasionally, allergic reactions. ^[46]

Monitor for recurrence of toxicity; repeat dosing of DigiFab is occasionally required. ^[2]

Class I antiarrhythmic poisoning ^[5][8]

• Background ^[47]
  • All Class I antiarrhythmics are sodium channel blockers along with tricyclic antidepressants (TCAs), antiepileptics, and local anesthetics
  • Mechanism of action: depress rate of depolarization, slow conduction
  • Adverse effects (can begin even at therapeutic doses): reduced inotropy, proarrhythmic effects
  • Effects in overdose: Neurological effects may also occur, e.g., seizures, coma, respiratory depression.
• Clinical features: Symptoms often resemble those of TCA poisoning and local anesthetic systemic toxicity.
  • All classes: clinical features of CV drug poisoning
  • Class IA: CHF
  • Class IB and Class IC: seizures
• Diagnostics
  • ECG: wide QRS can occur with all sodium channel blockers and indicates an increased risk of arrhythmia and seizures.
    • Class IA: torsade de pointes, QT prolongation
    • Class IB: AV block
    • Class IC: Vfib, Vtach, QT prolongation
    • Other features resembling ECG findings of TCA poisoning may be present. ^[48]
  • Serum electrolytes: Abnormalities may increase the risk of arrhythmias.
  • Drug levels (if offending agent known) ^[8]
• Management ^[5]
  • All patients: Begin initial management of CV drug poisoning and treat symptomatically.
  • Specific treatments include:
    • Sodium bicarbonate for prolonged QRS, bradyarrhythmias, and hypotension in class IA and IC toxicity
    • Benzodiazepines for toxic seizures

Amiodarone poisoning ^[5][8]

Acute overdose is rare and experience with acute amiodarone poisoning is limited; see “Adverse effects of amiodarone” for side effects of long-term therapeutic use. ^[8]

• Clinical features: bradyarrhythmias, hypotension, asystole
• Management
  • Follow the general management of CV drug poisoning.
  • Consider intravenous lipid emulsion therapy and VA-ECMO for refractory arrhythmias.

Clonidine poisoning ^[2][5]

Clinical features

• Onset: symptoms occur within 30–60 minutes, peak effect occurs 2–3 hours after ingestion ^[2][5]
• Signs and symptoms: may be similar to clinical features of CV drug poisoning and/or opioid poisoning
  • Lethargy, somnolence, obtundation (most common symptom)
  • Hypotension
  • Bradycardia
  • Respiratory depression
  • Hypothermia
  • Miosis

Diagnostics

• ECG: bradycardia (common), heart block
• Glucose: to rule out hypoglycemia

Management

• Begin initial management of CV drug poisoning and treat symptomatically.
• Initiate respiratory monitoring: pulse oximetry, end-tidal CO₂
• Treat hypotension
  • Initial: IV fluid bolus 20–60 mL/kg
  • Persistent hypotension: norepinephrine infusion
• Symptomatic bradycardia: Administer atropine .
• Consider naloxone for CNS or respiratory depression (see “Naloxone for opioid overdose” for dosage). ^[2][5]

Nitrate poisoning ^[2]

Toxicity from nitrates may result from vasodilation and/or methemoglobinemia.

• Clinical features
  • Hypotension (common)
  • Reflex tachycardia
  • Headache
  • Methemoglobinemia
• Management: Begin initial management of CV drug poisoning and treat symptomatically.
  • If patient is on nitrate infusion : Review therapeutic indication and discontinue the treatment, if possible. ^[2]
  • Hypotension: supine position, IV fluids, norepinephrine infusion
  • Methemoglobinemia: supplemental oxygen, methylene blue

If the nitrates were initiated for acute coronary syndrome, use vasopressors cautiously. ^[2]

ACEI and ARB poisoning ^[5]

Toxicity is rarely life-threatening in isolated ACEI or ARB overdose.

• Clinical features
  • Both: hypotension, syncope, cardiac ischemia
  • ARBs: palpitations, diaphoresis, dizziness, lethargy, confusion
• Management: mostly supportive; follow the general management of CV drug poisoning.
  • Angioedema: Administer treatment for bradykinin-mediated angioedema.
  • Hypotension: IV fluid boluses, norepinephrine infusion, naloxone (in opioid-naive patients; under specialist supervision)

Check for co-ingestion with other antihypertensives, e.g., beta blockers or CCBs.