What causes a prolonged QTc (corrected QT) interval in a patient?

Causes of High QTc

QTc prolongation results from medications, electrolyte abnormalities, structural heart disease, congenital channelopathies, and bradyarrhythmias, with drug-induced causes being the most common and preventable etiology in clinical practice. 1

Medication-Induced QTc Prolongation

Drug-induced QTc prolongation is the most frequent acquired cause and requires vigilant monitoring, particularly in the ICU setting where polypharmacy is common. 1, 2

High-Risk Antiarrhythmic Drugs

• Class IA agents (quinidine, procainamide, disopyramide) carry a 1-10% incidence of torsades de pointes and require monitoring. 1, 3
• Class III agents (sotalol, dofetilide, ibutilide) also carry a 1-10% incidence and require monitoring particularly 4-5 hours post-administration. 1, 3
• Amiodarone causes QTc prolongation but has a lower risk of torsades compared to other Class III agents. 3, 2

Non-Cardiac Medications

• Macrolide antibiotics (clarithromycin, erythromycin) and fluoroquinolones (sparfloxacin) prolong QTc. 1, 3, 2
• Antipsychotics including haloperidol, thioridazine, pimozide, chlorpromazine, and mesoridazine cause QTc prolongation, with higher-than-recommended doses associated with increased risk of QT-prolongation and torsades de pointes. 1, 3, 4
• Methadone causes significant dose-dependent QTc prolongation, with both baseline QT and dosage predicting prolongation; baseline and follow-up ECGs are recommended when daily dosage exceeds 100 mg. 1, 3, 5
• Chemotherapy agents (arsenic trioxide, vandetanib) cause QTc prolongation with an incidence of 26-93% for arsenic trioxide. 1
• Antiemetics (ondansetron, domperidone, droperidol) are frequently associated with QTc prolongation in ICU patients. 3, 2

Electrolyte Abnormalities

Electrolyte disturbances are critical correctable risk factors that must be aggressively addressed. 6, 1

• Hypokalemia (potassium <4 mEq/L) is a significant risk factor, particularly in women, and decreases T wave amplitude while increasing U wave amplitude. 1, 3, 5
• Hypomagnesemia contributes to QTc prolongation, particularly when severe. 1, 3
• Hypocalcemia potentiates drug-induced QT prolongation and is associated with prolonged QTc in men. 1, 7
• Diuretic-induced hypokalemia from heart disease treatment creates compounded arrhythmia risk requiring vigilant electrolyte monitoring. 1

Cardiac Structural Disease

Structural heart abnormalities create substrate for both QTc prolongation and arrhythmia development. 1

• Left ventricular hypertrophy is a recognized risk factor for QTc prolongation. 1
• Heart failure with reduced ejection fraction contributes to QTc prolongation. 1, 5
• Myocardial ischemia (both acute and chronic, including previous myocardial infarcts) prolongs QT and predisposes to sudden cardiac death, with ischemic heart disease attributable to 15% of all deaths. 1, 7
• Inherited cardiomyopathies (hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy) increase sudden cardiac death risk. 1

Bradyarrhythmias

• Bradycardia including sinus bradycardia and heart block prolongs QTc and predisposes to torsades de pointes. 6, 3
• Recent conversion from atrial fibrillation is associated with QTc prolongation. 3

Congenital Long QT Syndrome

• Congenital LQTS has a prevalence of 1 in 2,500-5,000 live births, with the most common mutation being KCNQ1 (LQT1) affecting IKs current. 1, 5
• De novo mutations account for 30% of cases with unaffected parents. 1, 5
• Autoimmune-related cases can occur in neonates born to mothers with anti-Ro/SSA antibodies. 1, 5

Patient-Specific Risk Factors

Certain patient characteristics independently increase risk for QTc prolongation. 1

• Female sex is a significant risk factor, with women having inherently longer QT intervals post-puberty. 1, 3, 7
• Advanced age increases risk for drug-associated QT effects, particularly in hospitalized elderly patients. 1, 3, 7
• History of thyroid disease and hypothyroidism are associated with prolonged QTc. 4, 7

Drug Interactions and High-Risk Scenarios

• Concomitant use of multiple QT-prolonging drugs significantly increases risk even when individual drugs pose minimal risk. 1, 3
• Combination with metabolic inhibitors (e.g., CYP3A4 inhibitors like verapamil) increases QTc prolongation risk. 1, 4
• High drug concentrations from impaired metabolism or rapid IV administration increase risk. 3

Critical ECG Warning Signs

When QTc is prolonged, specific ECG features signal imminent torsades de pointes risk. 1

• Enhanced U waves and QT-U prolongation, especially after pauses. 1, 3
• T-wave alternans (macroscopic). 1, 3
• Polymorphic ventricular premature beats or couplets. 1, 3
• Nonsustained polymorphic ventricular tachycardia. 1
• Short-long-short R-R cycle pattern before torsades onset. 3
• QTc ≥500 ms or increase ≥25% from baseline mandates immediate discontinuation of offending agents and continuous monitoring until washout occurs. 1, 3

Common Pitfalls

• ICU patients are particularly vulnerable due to concurrent illness, electrolyte disorders, IV drug administration, and polypharmacy exposure. 2
• The individual risk and potential of a pharmacologic substance to prolong QTc are not always predictable, requiring repeated ECG controls during therapy, especially when drug doses are changed or additional drugs are prescribed. 8
• Avoid AV nodal blocking agents (adenosine, calcium channel blockers, digoxin, beta-blockers) in pre-excited atrial fibrillation as these may paradoxically increase ventricular response. 6