Amiodarone with or without N-Acetylcysteine for the Prevention of Atrial Fibrillation after Thoracic Surgery: A Double-blind, Randomized Trial

Abstract

Background Postoperative atrial fibrillation (AF) may identify patients at risk of subsequent AF, with its greater risk of stroke. We hypothesized that N-acetylcysteine mitigates inflammation and oxidative stress to reduce the incidence of postoperative AF. Methods In this double-blind, placebo-controlled trial, patients at high risk of postoperative AF scheduled to undergo major thoracic surgery were randomized to N-acetylcysteine plus amiodarone or placebo plus amiodarone. On arrival to the postanesthesia care unit, N-acetylcysteine or placebo bolus (intravenous 50 mg/kg then 50 mg/kg/24 h x 48 h) was administered plus amiodarone (intravenous 150 mg then 1 g/24 h x 48 h). The primary outcome was sustained AF >30 s by telemetry (first 72 h) or symptoms requiring intervention and confirmed by ECG within 7 days of surgery. Systemic markers of inflammation (interleukin-6, interleukin-8, tumor necrosis factor–α, C-reactive protein) and oxidative stress (F2-isoprostane prostaglandin PGF2α [8-iso-PGF2α], isofuran) were assessed immediately after surgery and on postoperative day 2. Patients were phoned monthly to assess the occurrence of AF in year 1. Results Among 154 patients included, postoperative AF occurred in 15 of 78 who received N-acetylcysteine (19%) and 13 of 76 who received placebo (17%) (odds ratio, 1.24; 95.1% confidence interval, 0.53-2.88; p=0.615). The trial was stopped at the interim analysis because of futility. Three of the 28 patients with postoperative AF (11%) were discharged in AF. Regardless of treatment at 1 year, 7 of 28 patients with postoperative AF (25%) had recurrent episodes of AF. Inflammatory and oxidative stress markers were similar between groups. Conclusions Dual therapy comprising N-acetylcysteine plus amiodarone did not reduce the incidence of postoperative AF or markers of inflammation and oxidative stress early after major thoracic surgery, compared with amiodarone alone. Recurrent AF episodes are common among patients with postoperative AF within 1 year of major thoracic surgery.

Inflammatory Responses to Surgery and Postoperative Atrial Fibrillation

“…In conclusion, the work of Amar et al 1 demonstrates the feasibility and safety of N -acetylcysteine administration in this patient population. However, the study, which was stopped early at the interim analysis because of futility, discovered no additional benefit for the prevention of postoperative atrial fibrillation and its complications when compared to a conventional approach.…”

“…In this issue of Anesthesiology , Amar et al 1 studied the effect of N -acetylcysteine, a known antioxidant and free radical scavenger, as a prophylactic measure for postoperative atrial fibrillation after thoracic noncardiac surgery. The authors conducted a double-blind trial to compare amiodarone and the combination of amiodarone and N -acetylcysteine on the incidence of postoperative atrial fibrillation and postoperative stroke.…”

N-Acetylcysteine and Postoperative Atrial Fibrillation: Comment

“…2 However, we have additional potential explanations for why there was no significant difference in the occurrence of postoperative atrial fibrillation in patients who did and did not receive perioperative N-acetylcysteine in the study of Amar et al 1 N-Acetylcysteine is an l-cysteine prodrug and glutathione precursor that, via l-cysteine conversion, helps scavenge oxygen-derived free radicals and binds metal ions into complexes, resulting in oxidative stress reduction. 3 However, as we showed in a previous study, which was done in rats and focused on the mesenteric artery, l-cysteine induces an oxygen-derived free radical, superoxide production mediated by NADPH oxidase in a high 95% oxygen condition. 4 In contrast, it does not cause redox derangement in a 50% oxygen mixture.…”

N-Acetylcysteine and Postoperative Atrial Fibrillation: Reply

“…In our practice, oxygen administration is usually titrated off as long as the patient is able to maintain an oxygen saturation measured by pulse oximetry greater than 94% on room air. Most lung-resection patients at our center are ambulating the day after surgery; among the patients in our study, 3 some were discharged from the hospital upon completion of 48 h of N -acetylcysteine or placebo infusions. Although Dr. Kinoshita’s and Dr. Kawashima’s work in experimental animals is very interesting, it cannot be assumed that these findings apply to humans, nor is it warranted to speculate on which of the mechanisms that they identify apply to postoperative patients.…”