Intrapericardial Delivery of Amiodarone and Sotalol: Atrial Transmural Drug Distribution and Electrophysiological Effects

Abstract

Amiodarone and sotalol are frequently used in the treatment of atrial fibrillation. However, oral and intravenous (IV) therapy with these drugs has suboptimal efficacy and is associated with serious extracardiac side effects. We hypothesized that intrapericardial (IPC) delivery produces antiarrhythmic effects at lower plasma drug concentrations than IV delivery. Goats (n = 27) were randomised into 5 groups receiving either IPC vehicle, amiodarone (IV or IPC) or dl-sotalol (IV or IPC). Epicardial and endocardial atrial effective refractory period and atrial response to burst pacing (rapid atrial response, RAR) were assessed before and after 3 hours of drug infusion at 2 mg.kg.h. IPC delivery produced steeply decreasing drug concentrations from epicardium to endocardium in both atria and ventricles. Plasma drug concentrations were significantly lower in IPC than in IV groups. IPC amiodarone and sotalol reduced epicardial RAR inducibility (-74% +/- 20% and -66% +/- 30%, respectively) compared with IV delivery (-11% +/- 17% and -17% +/- 28%, respectively; P < 0.05). Endocardial RAR inducibility was only reduced in the IPC amiodarone group (-70% +/- 17%, P < 0.05). In conclusion, IPC delivery of amiodarone and sotalol increases atrial drug concentration and antiarrhythmic effects at reduced plasma drug concentrations. These potential benefits are particularly prominent for IPC delivered amiodarone.

Clinical efficacy of epicardial application of drug-releasing hydrogels to prevent postoperative atrial fibrillation

“…To improve the effectiveness of drugs and minimize their systemic toxicity, 3 alternative applications for epicardial amiodarone delivery have been developed: IPC-infused amiodarone solutions, epicardially sprayed in situ amiodarone releasing adhesive hydrogels, and epicardially sutured amiodarone-eluting bilayered patches or disc. [19][20][21] A number of studies have investigated local drug delivery of antiarrhythmic agents, including lidocaine, digoxin, amiodarone, beta-blockers, procainamide, ibutilide, sotalol, and flecainide. 17,21,22 Pharmacokinetic advantages and significant effects on atrial electrophysiologic parameters were invariably demonstrated.…”

Epicardial application of an amiodarone-releasing hydrogel to suppress atrial tachyarrhythmias

“…1-2 orders of magnitude lower than levels normally present during intravenous or chronic oral amiodarone therapy. In a recent study in our laboratory, we showed that transmural drug concentration gradients during intrapericardial delivery of amiodarone were not only present in ventricles, but also in atria [9]. Although epicardial and endocardial atrial ERPs were both prolonged, the absolute difference between them (transmural dispersion of refractoriness) did not increase.…”

“…Measurements were performed during the surgical procedure and 1, 2, 3,4,7,9,11,14,16,18,21,23,25 and 28 days after the surgical procedure. An electrophysiology monitoring system with an integrated amplifier/stimulator (EPTracer 38, CardioTek, Maastricht-Airport, The Netherlands) was used to simultaneously record limb-lead ECG and six bipolar electrograms from the 3 silicone patches sutured to the right atrial lateral wall.…”

“…At days 1, 2, 3,4,7,9,11,14,16,18,21,23, 25 and 28 after hydrogel application, blood samples were drawn from a peripheral vein of the hind limb via a venflon cannula and collected in EDTA-containing vacutainer tubes (Becton-Dickinson, Franklin Lakes, New Jersey, USA). After centrifugation, the plasma was stored at − 80°C.…”

“…The concept of local amiodarone delivery to the myocardium has been investigated in several animal studies by short-term (≤ 3 h) intrapericardial infusion of amiodarone solutions [7][8][9]. Although results are encouraging, most arrhythmias require a longer duration of treatment, but long-term catheter-based intrapericardial infusion may increase risks of infections and fibrosis [10,11].…”