A patient on isosorbide mononitrate (ISMN) develops symptomatic bradycardia (heart rate <50 bpm with dizziness, syncope, or fatigue); what is the likely cause and how should it be managed?

ISMN and Bradycardia: Cause and Management

Isosorbide mononitrate (ISMN) can cause symptomatic bradycardia through vasodilation-induced hypotension that triggers vagal reflexes, and management requires immediate ISMN discontinuation, identification of hemodynamic compromise, and treatment of reversible causes before considering permanent pacing.

Mechanism of ISMN-Induced Bradycardia

• ISMN causes marked venous pooling and reduced left ventricular end-diastolic volume (LVEDV) and pressure (LVEDP), which triggers vagal reflexes that produce severe, reversible bradycardia in susceptible patients. 1
• The FDA label confirms that ISMN overdose produces bradycardia and heart block as part of its hemodynamic toxicity profile, resulting from excessive vasodilatation and venous pooling with reduced cardiac output. 2
• This bradycardia is typically accompanied by hypotension, syncope (especially upright), vertigo, palpitations, diaphoresis, and confusion—all manifestations of reduced cardiac output and cerebral hypoperfusion. 2

Immediate Assessment

• Document the rhythm with a 12-lead ECG to confirm bradycardia (HR <50 bpm), assess for conduction abnormalities (PR interval, QRS duration, AV block), and determine whether symptoms correlate directly with the low heart rate. 3
• Assess for cardinal symptoms of hemodynamic compromise: syncope or presyncope, altered mental status (confusion, decreased responsiveness), ischemic chest pain, hypotension (systolic BP <90 mmHg), or signs of acute heart failure (dyspnea, pulmonary edema). 3
• If the patient is asymptomatic despite HR <50 bpm, no treatment or monitoring is required—asymptomatic bradycardia is benign regardless of the absolute heart rate. 3, 4

Acute Management of Symptomatic Bradycardia

First-Line Pharmacologic Therapy

• Administer atropine 0.5–1 mg IV bolus, repeatable every 3–5 minutes up to a total of 3 mg, as first-line therapy for symptomatic bradycardia. 3
• Never give atropine doses <0.5 mg, as they may paradoxically worsen bradycardia. 3
• Absolute contraindication: Do not administer atropine to heart-transplant recipients without autonomic re-innervation, as it can precipitate high-grade AV block. 3

Volume Resuscitation for ISMN-Induced Hypotension

• Because ISMN-induced bradycardia results from venodilatation and arterial hypovolemia, therapy should prioritize central fluid volume expansion: passive leg elevation may suffice, but IV normal saline infusion is often necessary. 2
• Avoid epinephrine or other arterial vasoconstrictors in ISMN overdose, as they are likely to cause more harm than good. 2
• In patients with renal disease or congestive heart failure, volume expansion carries risk and may require invasive hemodynamic monitoring. 2

Second-Line Catecholamine Infusions (if Atropine Fails)

• If atropine is ineffective and the patient has low coronary-ischemia risk, initiate dopamine 5–20 µg/kg/min IV (titrate by 5 µg/kg/min every 2 min) for combined chronotropic and inotropic support. 3
• Alternatively, use epinephrine 2–10 µg/min IV or isoproterenol 1–20 µg/min IV, titrated to target heart rate. 3
• Avoid catecholamines in patients at high risk for coronary ischemia. 3

Temporary Pacing (Bridge Therapy)

• Transcutaneous pacing is indicated for severe symptoms or hemodynamic compromise unresponsive to atropine and catecholamines, serving only as a bridge to transvenous or permanent pacing. 3
• Transvenous pacing is reserved for persistent hemodynamic instability refractory to medical therapy, with a complication rate of 14–40% (venous thrombosis, pulmonary emboli, arrhythmias, perforation). 3

Definitive Management: ISMN Discontinuation

• Immediately discontinue ISMN in any patient who develops symptomatic bradycardia—this is the single most important reversible cause in this scenario. 3, 4
• Review all other negative chronotropic medications (beta-blockers, non-dihydropyridine calcium-channel blockers, digoxin, amiodarone, sotalol, ivabradine) and discontinue or reduce doses of non-essential agents. 3, 4

Evaluation for Other Reversible Causes (Class I Priority)

Reversible Cause	Evaluation	Treatment
Medications (β-blockers, CCBs, digoxin, antiarrhythmics)	Review drug list	Discontinue or reduce dose [3,4]
Hypothyroidism	TSH, free T4	Initiate levothyroxine [3,4]
Electrolyte abnormalities	Serum K⁺, Mg²⁺	Correct hypo-/hyperkalemia, hypomagnesemia [3,4]
Acute inferior MI	Cardiac biomarkers, ECG	Treat ischemia; bradycardia often resolves [3]
Obstructive sleep apnea	Clinical suspicion, sleep study	Initiate CPAP [3]
Elevated intracranial pressure	Neuroimaging	Neurosurgical consultation [3]

Indications for Permanent Pacemaker (Only After ISMN Withdrawal)

• Permanent pacing is indicated (Class I) only if symptomatic bradycardia persists after ISMN has been discontinued and all other reversible causes have been excluded or adequately treated. 3
• High-grade AV block (Mobitz II or third-degree) with symptoms also warrants permanent pacing. 3
• Do not implant a permanent pacemaker before fully evaluating and correcting reversible causes—this is a critical pitfall. 3, 4

Diagnostic Monitoring for Intermittent Symptoms

• If symptoms are intermittent, establish rhythm-symptom correlation before any permanent intervention: 3
  • Daily symptoms: 24–72 hour Holter monitor 3
  • Weekly symptoms: 7–30 day event recorder 3
  • Monthly or less frequent: Implantable loop recorder (diagnostic yield ≈43–50% at 2 years, ≈80% at 4 years) 3

Common Pitfalls to Avoid

• Do not treat asymptomatic bradycardia based solely on heart-rate numbers—even rates of 37–40 bpm require no intervention if the patient is asymptomatic. 3, 4
• Do not fail to identify ISMN as the reversible cause before considering permanent pacing—medication review is the highest priority. 3, 4
• Do not administer atropine doses <0.5 mg (may worsen bradycardia) or to heart-transplant patients (risk of high-grade AV block). 3
• Do not use arterial vasoconstrictors (epinephrine) in ISMN-induced hypotension—volume expansion is the correct approach. 2

Prognosis After ISMN Withdrawal

• Asymptomatic sinus bradycardia has a benign prognosis and does not affect survival. 3
• ISMN-induced bradycardia is typically reversible once the drug is discontinued and hemodynamic status is restored with volume resuscitation. 2, 1
• If bradycardia persists despite ISMN withdrawal and correction of other reversible factors, permanent pacing becomes appropriate. 3