What is the association between milrinone (phosphodiesterase 3 inhibitor) use and cardiac arrhythmias in pediatric cardiac surgeries?

Association Between Milrinone Use and Cardiac Arrhythmias in Pediatric Cardiac Surgeries

Milrinone use in pediatric cardiac surgery is associated with a 2-4 fold increased risk of postoperative atrial fibrillation and is an independent risk factor for clinically significant tachyarrhythmias. 1, 2

Arrhythmia Risk with Milrinone

Evidence of Increased Arrhythmia Risk

• In patients undergoing elective cardiac surgery, perioperative milrinone was associated with a 2-4 fold increased risk of postoperative atrial fibrillation (58.2% vs. 26.1% in non-users) 1
• A multivariate analysis demonstrated that milrinone use on admission to cardiac intensive care unit was independently associated with increased odds of postoperative tachyarrhythmia requiring intervention (odds ratio 2.8,95% confidence interval 1.3 to 6.0) 2
• The FDA drug label for milrinone reports that ventricular arrhythmias were documented in 12.1% of patients receiving milrinone in clinical trials, including ventricular ectopic activity (8.5%), nonsustained ventricular tachycardia (2.8%), sustained ventricular tachycardia (1%), and ventricular fibrillation (0.2%) 3
• Holter recordings have demonstrated that milrinone injection can increase ventricular ectopy, including nonsustained ventricular tachycardia in some patients 3

Types of Arrhythmias Associated with Milrinone

• The most common arrhythmias observed in pediatric cardiac surgery patients receiving milrinone include:
  • Monomorphic ventricular tachycardia (12%) 2
  • Junctional ectopic tachycardia (10%) 2
  • Accelerated junctional rhythm (8%) 2
  • Atrial tachyarrhythmias including atrial fibrillation, atrial flutter, and ectopic or chaotic atrial tachycardia (8%) 2
• Supraventricular arrhythmias were reported in 3.8% of patients receiving milrinone 3
• Rare cases of "torsades de pointes" have been reported in post-marketing experience 3

Clinical Implications of Arrhythmias

• Patients who develop postoperative atrial fibrillation after receiving milrinone have:
  • Longer hospital stays (p < 0.001) 1
  • Higher likelihood of death (p = 0.02) 1
• Life-threatening arrhythmias, while infrequent, have been associated with:
  • Preexisting arrhythmias 3
  • Metabolic abnormalities (e.g., hypokalemia) 3
  • Abnormal digoxin levels 3
  • Catheter insertion 3

Comparative Arrhythmia Risk

• In patients with low cardiac output after cardiac surgery, dobutamine was associated with a higher incidence of atrial fibrillation than milrinone (18% vs 5%; p < 0.04) 1
• When comparing inotropes in adults, patients treated with norepinephrine had fewer arrhythmias than those treated with dopamine (12% versus 24%) 1

Benefits of Milrinone Despite Arrhythmia Risk

• Milrinone is effective in preventing low cardiac output syndrome (LCOS) in infants and children following biventricular cardiac repair 1
• High-dose milrinone (75 μg/kg bolus followed by 0.75 μg/kg/min infusion) significantly reduced the risk of LCOS compared to placebo, with a relative risk reduction of 55% (p=0.023) 4
• Children had better hemodynamic parameters and shorter ICU stays when receiving milrinone compared to low-dose epinephrine plus nitroglycerin for inotropic support following repair of tetralogy of Fallot 1
• Milrinone improved cardiac index in neonates with low cardiac output following cardiac surgery 1

Monitoring and Management Recommendations

• Patients receiving milrinone should be observed closely with continuous electrocardiographic monitoring to allow prompt detection and management of ventricular arrhythmias 3
• The FDA warns that milrinone use has been associated with increased frequency of ventricular arrhythmias, including nonsustained ventricular tachycardia 3
• Despite the occurrence of diverse arrhythmias in 10.3% of pediatric patients receiving milrinone for ≥3 days, modification of milrinone infusion to manage arrhythmia was required in only 0.4% of cases 5
• Dose reduction of milrinone due to hypotension occurred in only 0.5% of pediatric patients 5

Risk-Benefit Assessment

• The catecholamine dose for inotropic support in cardiogenic shock must be individually titrated due to wide variability in clinical response 1
• Milrinone may be beneficial for the prevention and treatment of low cardiac output following cardiac surgery, despite the arrhythmia risk 1
• In patients with single-ventricle physiology, milrinone can be used to reduce systemic vascular resistance and improve systemic blood flow and oxygen delivery 1
• A Cochrane review found insufficient evidence of the effectiveness of prophylactic milrinone in preventing death or LCOS in children undergoing surgery for congenital heart disease, compared to placebo 6

In conclusion, while milrinone is an effective agent for preventing and treating low cardiac output syndrome after pediatric cardiac surgery, clinicians should be aware of the significant association with postoperative arrhythmias and implement appropriate monitoring strategies to detect and manage these complications promptly.