Can intravenous (IV) diphenhydramine (Benadryl) cause QT interval prolongation in patients, particularly those with underlying cardiovascular disease?

IV Diphenhydramine and QT Prolongation

Yes, intravenous diphenhydramine can cause QT interval prolongation, particularly in overdose situations or in patients with multiple risk factors, though it is not classified among the high-risk QT-prolonging medications that require routine monitoring at therapeutic doses. 1, 2

Evidence Classification

Diphenhydramine is notably absent from major cardiology society lists of medications requiring mandatory hospitalization monitoring during initiation, unlike Class IA/III antiarrhythmics, macrolides, and certain antipsychotics that appear prominently in these guidelines. 3, 4 The ACC/AHA/ESC guidelines on ventricular arrhythmias do not include first-generation antihistamines in their tables of frequent or less-frequent QT-prolonging drugs, which list agents like quinidine, sotalol, erythromycin, haloperidol, and methadone. 3

Mechanism and Dose-Dependency

The QT prolongation from diphenhydramine occurs through:

• Inhibition of fast sodium channels at therapeutic concentrations 1
• Blockade of repolarizing potassium channels at higher concentrations, leading to action potential prolongation 1
• Critical toxicity threshold of 1.0 gram, with most documented cases involving doses >500 mg 1, 2

At therapeutic doses, diphenhydramine produces moderate QT prolongation (mean QTc 453 ± 43 ms in overdose patients vs 416 ± 35 ms in controls), but importantly, no cases of torsades de pointes were observed even in patients with apparent QTc prolongation in the largest case series of 126 overdose patients. 2

High-Risk Patient Populations Requiring Monitoring

Monitor QTc if the patient has multiple risk factors for torsades de pointes, even with lower-risk medications like diphenhydramine: 4

• Baseline QTc ≥500 ms (or ≥550 ms with wide QRS) 4
• Female sex (inherently higher baseline risk) 3, 4
• Severe electrolyte abnormalities: hypokalemia (target K+ 4.5-5.0 mEq/L), hypomagnesemia, hypocalcemia 3, 4
• Bradycardia or heart block 3, 4
• Structural heart disease: left ventricular hypertrophy, heart failure with reduced ejection fraction, recent conversion from atrial fibrillation 3, 4
• Concomitant QT-prolonging drugs: Class IA/III antiarrhythmics, macrolides, fluoroquinolones, ondansetron, metoclopramide, haloperidol, phenothiazines, methadone 3, 4
• End-stage renal disease patients (particularly vulnerable population) 1
• Congenital long QT syndrome or family history of sudden cardiac death 3, 4

Monitoring Protocol When Indicated

For patients with ≥2 risk factors receiving IV diphenhydramine: 4

• Baseline 12-lead ECG before administration 4
• Repeat QTc every 8-12 hours after drug initiation 4
• Use consistent ECG lead (preferably lead II or V3) for serial measurements 4
• Calculate QTc using Bazett's formula: QTc = QT/√RR interval 4

Critical Action Thresholds

QTc ≥500 ms OR increase ≥60 ms from baseline: 4

• Consider discontinuing diphenhydramine
• Correct electrolytes immediately (IV magnesium 2g, potassium repletion to 4.5-5.0 mEq/L) 3, 4
• Increase monitoring frequency
• Review and discontinue other QT-prolonging medications 3, 4

QTc >500 ms with polymorphic ventricular beats or T-wave alternans: 4

• Immediate intervention required
• Continuous telemetry monitoring
• IV magnesium sulfate (even if serum magnesium normal) 3
• Temporary pacing if recurrent torsades de pointes despite electrolyte repletion 3

Common Clinical Pitfalls

The most dangerous error is combining diphenhydramine with other QT-prolonging medications without recognizing cumulative risk, particularly in the ICU setting where patients frequently receive ondansetron, fluoroquinolones, or macrolides. 3, 4, 5 The risk of rapid IV administration is specifically highlighted as a risk factor for drug-induced torsades de pointes. 3

In dialysis patients, diphenhydramine is commonly used for pruritus, but this population has multiple compounding risk factors (electrolyte shifts, structural heart disease, bradycardia) that substantially increase arrhythmic risk. 1

Contrast with Routine Practice

Unlike high-risk agents (amiodarone, sotalol, dofetilide) that require hospitalization for monitoring during initiation, diphenhydramine at therapeutic IV doses in patients without risk factors does not require routine QTc monitoring. 3, 4 However, overdose situations (>500 mg) warrant ECG monitoring regardless of baseline risk factors. 4, 2, 6