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Page 8 of 12 Waterford et al. Vessel Plus 2022;6:28 https://dx.doi.org/10.20517/2574-1209.2021.115

Protocols for use of amiodarone to prevent postoperative atrial fibrillation
The various trials reviewed use different doses and durations of amiodarone, and many protocols are
effective. Some protocols use oral amiodarone before surgery, while others start amiodarone on the day of
surgery. Of note, low-dose protocols using a total of 2 g of amiodarone given over the first two
postoperative days have shown none to low reduction in POAF [46,47] . Therefore, amiodarone must be started
preoperatively to have the greatest benefit. Rates of 10% for POAF have been achieved in trials with
adequate prophylactic regimens that involve the administration of a large enough amount of amiodarone.
These amounts are well tolerated, with very low rates of bradyarrthythmias in all trials.

Amongst the authors of the current paper, protocols are as follows. Many use a 2 to 3-day course of oral
amiodarone at a dose of 400 mg twice daily before surgery. This is followed by a longer course of 8 days
postoperatively, ranging from 200 mg to 400 mg daily. Another protocol is a 5 to 7-day course of oral
amiodarone at a dose of 200 mg daily before surgery. This is followed by 400 mg daily until discharge. If
POAF develops, a load of 400 mg three times daily is given, followed by a 4-week taper. To summarize, it is
important to select a regimen that provides enough preoperative amiodarone to provide a measurable
reduction in POAF.

Knowledge gaps and future directions
There are several gaps in our current understanding of amiodarone use for POAF. While the
pharmacokinetics of intravenous amiodarone are well described, the clinical efficacy of intravenous
amiodarone boluses for POAF, compared to oral administration of amiodarone, have not been studied in a
trial setting. It also remains unclear how many boluses to give an individual patient. The safety of
intravenous amiodarone boluses is also a point of contention. Intravenous amiodarone is dissolved in
polysorbate 80, a solvent that is a known vasodilator and a negative inotrope . The negative inotrope
[54]
properties of polysorbate 80, also known as Tween 80, were reported in dogs in 1982, where severe declines
[54]
in left ventricular dP/dt for over 30 min after administration were observed . It is known that
vasodilatation occurs from an intrinsic vasorelaxant effect, as well as histamine release triggered by
[55]
[55]
polysorbate 80 . These effects may be decreased by lowering the rate of infusion . Evidence for the role of
polysorbate 80 has recently been provided by a study that compared blood pressure in patients after
administration of amiodarone dissolved in polysorbate 80 (120 patients), to blood pressure in patients after
administration of amiodarone dissolved in a new solvent cyclodextrin (40 patients) . Patients received
[56]
these formulations based on a rate of amiodarone of 1 mg/min for 6 h, followed by 0.5 mg/min for 18 h
There was both a significant decrease in blood pressure as well as increased requirement for fluid boluses to
treat hypotension in the polysorbate 80 group. These findings were also reported in dog studies in which
amiodarone in polysorbate 80 decreased aortic pressure, cardiac output, and cardiac contractility . These
[57]
findings were also noted after administration of polysorbate 80 alone, but not after administration of the
cyclodextrin solvent. This helps to explain why 15% to 26% of patients receiving intravenous amiodarone
have hypotension . These studies explain the common observation of hypotension with intravenous
[57]
amiodarone boluses, but the overall safety of these boluses, as well as which patients should be receiving
them, remains unknown. Further, it is not established whether or not amiodarone drips are more
efficacious than oral amiodarone dosing for the management of POAF.

These gaps in understanding provide avenues for further study. We would propose a randomized trial in
which patients are randomized to intravenous amiodarone drips or oral amiodarone regimens for new-
onset POAF. We would propose a further study in which patients are randomized to various amounts of
150 mg boluses of amiodarone for POAF, with outcomes to be studied including not only duration of the
atrial fibrillation episode, but also other parameters such as hypotension and requirement for cessation of
intravenous infusion. A more widely available formulation of amiodarone dissolved in cyclodextrin could