David Amar

Metformin has been associated with a reduced incidence of atrial fibrillation in the general population, potentially by means of anti-inflammatory mechanisms, but its effects on atrial fibrillation occurring after noncardiac thoracic surgery are unknown.

Summary StatementRecent changes in perioperative care have led to new perspectives and important advances that have helped to improve outcomes among patients treated with esophagectomy for esophageal cancer.

We thank Dr. Hoftman and Dr. Umar for their comments1 and their interest in our focused review.2 In their letter to the editor, they refer to their interesting work on the utility of vital capacity to estimate tidal volume in contrast to the widely used predicted body weight in patients undergoing thoracic surgery. Their work did not report on clinical outcomes.3 As these authors acknowledge, their data were derived from a small retrospective dataset, and their results are exploratory. Large clinical trials should be conducted before revising clinical care pathways.1,3 In the continuously enhanced world of personalized medicine, dogma most certainly should be challenged. Our review presented clinical outcome data that showed conflicting results on the association of not only tidal volume but also other parameters of protective lung ventilation bundles and morbidity in patients undergoing lung resection. We stressed the importance of proven risk factors for postoperative pulmonary complications after lung resection, such as decrements in forced expiratory volume in 1 s or diffusion capacity of the lung for carbon monoxide and greater fluid administration during surgery, to be considered when interpreting observational data or in the design of future studies.The expert in mechanical ventilation will stylize many factors including the inspiratory pressures and time, positive end-expiratory pressure, lung compliance, and respiratory rate to optimize breath delivery, which can change hour by hour during surgery. Promoting novices to experts certainly depends on education and experience. Algorithms and consultations with experts can improve critical care delivery. Designing ventilators with machine learning computers could potentially further personalize care.The authors declare no competing interests.

We thank Dr. Kinoshita and Dr. Kawashima,1 and Dr. Wen, Dr. Huang, and Dr. Li2 for their comments and their interest in our work. In the comments from Kinoshita and Kawashima,1 they speculate that exposing our patients to a high fraction of inspired oxygen during one-lung ventilation negated the potential antioxidant effects of N-acetylcysteine during the 48 h after surgery. In our study, N-acetylcysteine was started only 1 to 2 h after the patient arrived at the postanesthesia care unit, where they had been receiving oxygen, by nasal cannula in most cases and occasionally by face mask, with varying degrees of inspired oxygen (typically in the range of 30 to 40%). 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.Dr. Wen, Dr. Huang, and Dr. Li suggest the performance of a subgroup analysis by surgical modailty.2 However, because of the small number of patients within the groups and the lack of power to do so, we did not perform a secondary subgroup analysis of the incidence of atrial fibrillation by type of surgery, whether open or minimally invasive. We have previously shown that the extent of lung resection affects the incidence of atrial fibrillation, and it is for this reason that we included patients who underwent anatomical lung or esophageal resection.4 However, on the basis of our work—and the recommendations from the American Association for Thoracic Surgery task force on this topic—we disagree that the side of surgery affects the incidence of atrial fibrillation.5,6 We also disagree with the authors’ assertion that our finding of a lack of effect for N-acetylcysteine on inflammatory or oxidative stress markers is attributable to a lack of power. First, the number of patients in each of the randomized groups in our study was not small, and both groups were well balanced in terms of demographic and surgical characteristics. Second, all patients participated in an institutional enhanced recovery pathway and received similar intraoperative and postoperative opioid analgesics. Finally, the inflammatory and oxidative marker data were well distributed and did not require log transformation before statistical analysis. Considering that our use of N-acetylcysteine or placebo was intravenous over the course of 48 h and was started in the postanesthesia care unit long after intraoperative drugs, such as dexmedetomidine, were used, we do not believe that these pharmacologic agents influenced our findings.Support was provided solely from institutional and/or departmental sources.Dr. Jones serves as a consultant for AstraZeneca (Cambridge, United Kingdom) and on a Clinical Trial Steering Committee for Merck (Kenilworth, New Jersey). The other authors declare no competing interests.

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Background: Postoperative atrial fibrillation may identify patients at risk of subsequent atrial fibrillation, with its greater risk of stroke. This study hypothesized that N-acetylcysteine mitigates inflammation and oxidative stress to reduce the incidence of postoperative atrial fibrillation. Methods: In this double-blind, placebo-controlled trial, patients at high risk of postoperative atrial fibrillation 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 intravenous bolus (50 mg/kg) and then continuous infusion (100 mg/kg over the course of 48 h) was administered plus intravenous amiodarone (bolus of 150 mg and then continuous infusion of 2 g over the course of 48 h). The primary outcome was sustained atrial fibrillation longer than 30 s by telemetry (first 72 h) or symptoms requiring intervention and confirmed by electrocardiography 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 F_2α; isofuran) were assessed immediately after surgery and on postoperative day 2. Patients were telephoned monthly to assess the occurrence of atrial fibrillation in the first year. Results: Among 154 patients included, postoperative atrial fibrillation occurred in 15 of 78 who received N-acetylcysteine (19%) and 13 of 76 who received placebo (17%; odds ratio, 1.24; 95.1% CI, 0.53 to 2.88; P = 0.615). The trial was stopped at the interim analysis because of futility. Of the 28 patients with postoperative atrial fibrillation, 3 (11%) were discharged in atrial fibrillation. Regardless of treatment at 1 yr, 7 of 28 patients with postoperative atrial fibrillation (25%) had recurrent episodes of atrial fibrillation. Inflammatory and oxidative stress markers were similar between groups. Conclusions: Dual therapy comprising N-acetylcysteine plus amiodarone did not reduce the incidence of postoperative atrial fibrillation or markers of inflammation and oxidative stress early after major thoracic surgery, compared with amiodarone alone. Recurrent atrial fibrillation episodes are common among patients with postoperative atrial fibrillation within 1 yr of major thoracic surgery. Editor’s Perspective: What We Already Know about This Topic: What This Article Tells Us That Is New:

Vasopressor use during esophagectomy has been reported to increase the risk of postoperative anastomotic leak and associated morbidity. We sought to assess the association between vasopressor use and fluid (crystalloid and colloid) administration and anastomotic leak following open esophagectomy. Patients who underwent open Ivor Lewis esophagectomy were identified from a prospective institutional database. The primary outcome was postoperative anastomotic leak (any grade) and analyzed using logistic regression models. Postoperative anastomotic leak developed in 52 of 327 consecutive patients (16%) and was not significantly associated with vasopressor use or fluid administered in either univariable or multivariable analyses. Increasing body mass index was the only significant characteristic of both univariable (P = 0.004) and multivariable analyses associated with anastomotic leak (odds ratio, 1.05; 95% confidence interval, 1.01–1.09; P = 0.007). Of the 52 patients that developed an anastomotic leak, 12 (23%) were grade 1, 21 (40%) were grade 2 and 19 (37%) were grade 3. In our cohort, only body mass index, and not intraoperative vasopressor use and fluid administration, was significantly associated with increased odds of postoperative anastomotic leak following open Ivor Lewis esophagectomy.