Diseases of the Esophagus (2015) ••, ••–•• DOI: 10.1111/dote.12355
Original article
Incidence and impact of postoperative atrial fibrillation after minimally invasive esophagectomy R. W. Day,1 D. Jaroszewski,1 Y.-H. H. Chang,2 H. J. Ross,3 H. Paripati,3 J. B. Ashman,4 W. G. Rule,4 K. L. Harold5 Department of Surgery, Division of Cardiothoracic Surgery, Divisions of 2Health Sciences Research, Hematology and Oncology, 4Radiation Oncology and 5Minimally Invasive Surgery, Mayo Clinic Arizona, Phoenix, Arizona, USA 1
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SUMMARY. Atrial fibrillation (AF) following open esophagectomy has been associated with increased rates of pulmonary and anastomotic complications, and mortality. This study seeks to evaluate effects of AF after minimally invasive esophagectomy (MIE). A retrospective review of patients consecutively treated with MIE for esophageal carcinoma, dysplasia. and benign disease from November 2006 to November 2011 was performed. One hundred twenty-one patients underwent MIE. Median age was 65 years (range 26–88) with 85% being male. Thirty-eight (31.4%) patients developed AF postoperatively. Of these 38 patients, 7 (18.4%) had known AF preoperatively. Patients with postoperative AF were significantly older than those without postoperative AF (68.7 vs. 62.8 years, P = 0.008) and more likely to be male (94.7% vs. 80.7%, P = 0.04). Neoadjuvant chemoradiation showed a trend toward increased risk of AF (73.7% vs 56.6%, P = 0.07). Sixty-day mortality was 2 of 38 (5.3%) in patients with AF and 4 of 83 (6.0%) in the no AF cohort (P = 1.00). The group with AF had increased length of hospitalization (13.4 days vs. 10.6 days P = 0.02). No significant differences in rates of pneumonia (31.6% vs. 21.7% P = 0.24), stricture (13.2% vs. 26.5% P = 0.10), or leak requiring return to operating room (13.2% vs. 8.4% P = 0.51) were noted between groups. We did not find an increased rate of AF in our MIE cohort compared with prior reported rates in open esophagectomy populations. AF did result in an increased length of stay but was not a predictor of other short-term morbidities including anastomotic leak, pulmonary complications, stenosis, or 60-day mortality. KEY WORDS: atrial fibrillation, locally advanced esophageal carcinoma, minimally invasive esophagectomy, prophylaxis of atrial fibrillation.
INTRODUCTION The incidence of esophageal adenocarcinoma has increased significantly in the United States and many Western countries.1–3 Surgical resection, usually with neoadjuvant chemoradiotherapy, is the mainstay of treatment for localized and locally advanced patients.4 Open surgical approaches have reported morbidity up to 64%.5–7 The most common morbidities include pulmonary complications, anastomotic strictures and leaks, and atrial fibrillation (AF). MiniAddress correspondence to: Dr Dawn Jaroszewski, MD, Department of Surgery, Division of Cardiothoracic Surgery, Mayo Clinic Arizona, 3rd Floor, Mayo Clinic Specialty Building, 5777 E. Mayo Boulevard, Phoenix, AZ 85054, USA. Email:
[email protected] Financial disclosure: None. © 2015 International Society for Diseases of the Esophagus
mally invasive esophagectomy (MIE) has been shown to be a safe alternative to open techniques with similar 30-day mortality and possible benefits of lower blood loss, shorter hospital stay, and reduced respiratory complications.8,9 The incidence of AF after major non-cardiac thoracic surgery is reported to be 10–40%.10–15 Independent risk factors for development of postoperative AF include male gender, advanced age, preoperative heart rate greater than or equal to 72 beats per minute, and levels of brain natriuretic peptide.10,16 AF has been used as a surrogate marker of morbidity from other sources.10,11,15 This study reports the incidence and effects of AF after MIE including an analysis of the relationship to pulmonary and anastomotic complications, length of stay (LOS), and postoperative mortality. 1
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METHODS All patients undergoing a MIE at the Mayo Clinic Hospital in Phoenix, Arizona, from November 2006 to November 2011 were included in this retrospective review. Indications for MIE included both benign and malignant disease warranting an esophagectomy. Institutional review board approval was obtained. Patients with a neoplastic diagnosis underwent preoperative staging with cross-sectional imaging that including computed tomography with positron emission scanning and endoscopic ultrasound. Patients who were found to have advanced disease of T3, T4, or positive lymph nodes underwent preoperative chemoradiotherapy except for three patients who underwent only induction chemotherapy. Patients with T2 disease were evaluated by a multidisciplinary tumor board, and neoadjuvant therapy was undertaken as indicated. In more than 90% of patients, neoadjuvant chemotherapy consisted of platinum with a taxane plus/minus a fluoropyrimidine. Radiation was delivered to a median total dose of 5040 cGy with a range of 4500–6000 cGy. After neoadjuvant therapy, patients had a 4–6 week recovery period prior to surgical therapy. All patients that were referred for evaluation of esophagectomy to a single surgeon at this institution were planned for MIE; no cases were planned for open procedure. All cases were performed minimally invasively by a single surgical team as previously described.17 All cases utilized esophageal replacement with gastric conduit. Location of the tumor dictated the site of the anastomosis as cervical or thoracic. Feeding jejunostomy tubes were placed intraoperatively for all patients who did not have one prior to surgery. Twenty-three individuals who had lost more than 20% of their body weight prior to surgery underwent a preoperative feeding jejunostomy tube placement in order to optimize their nutrition prior to surgery. Patients who underwent neoadjuvant therapy were reviewed by a multidisciplinary tumor board, and patients with celiac nodal disease who were suspected to have a limited response based on imaging and repeat endoscopic ultrasound were referred for intraoperative radiation therapy to enhance locoregional control. In the four patients selected for intraoperative radiation, the initial portion of the procedure including laparoscopic gastric tube formation and mobilization was undertaken and then a 4–5-cm laparotomy incision carried out in order to facilitate a radiation cone incorporating the celiac artery and diaphragmatic crus. A mobile linear accelerator (Mobetron, IntraOp Medical Corporation, Sunnyvale, CA, USA) was used to deliver 1250 cGy with 9 MeV electrons in each case. Patients continued all anti-arrhytmic medications up until the time of surgery. They were resumed
immediately in the postoperative period via feeding jejunostomy tube. New onset AF in the postoperative index hospitalization was treated with intravenous amiodarone bolus of 150 mg over 10 minutes followed by 1 mg/min for 6 hours and then 0.5 mg for 18 hours and then converted to oral amiodarone. If they did not respond to this initial treatment, a second bolus of 150 mg of amiodarone was given. Patients who remained in rapid ventricular response were initiated on a diltiazem drip at 10 mg/hour that was titrated up to 20 mg/hour to accommodate heart rate and blood pressure. Recorded clinical parameters included patient demographics, surgical approach, date of surgery, preoperative body mass index (BMI), neoadjuvant radiation, neoadjuvant chemotherapy, adjuvant radiation, adjuvant chemotherapy, type of adjuvant chemotherapy, and hospital LOS. Morbidities recorded included postoperative AF, pneumonia, acute respiratory distress syndrome requiring reintubation and respiratory support, dysphagia, stricture, anastomotic leak of any degree including clinically asymptomatic, return to operating room within 30 days of surgery for procedure related to a complication, and other complications. Information pertaining to follow-up dates, mortality dates, and cause of mortality were also recorded. Clinical endpoints included postoperative AF, morbidities, 30-day in-hospital mortality, 60-day overall mortality, and hospital LOS. Postoperative AF was defined as an irregularly irregular rhythm without discernible P waves in at least three leads on electrocardiogram tracing occurring at least 10 minutes within 30 days of MIE. All patients had telemetry monitoring for a minimum of 5 days postoperatively. Anastomotic leak was defined as any radiographic evaluation with evidence of contrast extravasation or clinical symptoms consistent with anastomotic leak. Anastomotic stricture was defined as any radiographic or endoscopic anastomotic evaluation demonstrating less than 1.5 cm diameter anastomosis. Descriptive statistics were used to summarize the data. The comparison between patients with and without AF was performed using the Wilcoxon rank sum test, chi-square test, or Fisher’s exact test. Overall survival was estimated using Kaplan–Meier methods and compared by the logrank test. The time to death was also evaluated by the Cox proportional hazard model. All tests were two sided, and a P-value < 0.05 was considered statistically significant. The analysis was conducted using SAS 9.2 (SAS Institute, Cary, NC, USA). RESULTS One hundred twenty-one patients underwent MIE from November 2006 to November 2011. © 2015 International Society for Diseases of the Esophagus
AF minimally invasive esophagectomy Table 1 Patient characteristics N = 121 Age ≥70 70 Gender Male Female Diagnosis Benign Dysplasia Squamous cell carcinoma Adenocarcinoma Metastatic breast Anastomosis Cervical Thoracic Preoperative therapy None Chemoradiation Chemotherapy alone
Percentage (%)
47 74
38.8 61.2
103 18
85.1 14.9
2 8 8 102 1
1.7 6.6 6.6 84.3 0.8
14 107
11.6 88.4
46 72 3
38.0 59.5 2.5
Demographics are reviewed in Table 1. The median age of patients was 65 years (range of 26–88), and 103 (85%) were male. Fourteen patients underwent threefield MIE with cervical anastomoses, and 107 patients underwent transthoracic MIE with thoracic anastomosis. Two conversions to laparotomy occurred. There were no conversions to open thoracotomy. After MIE, 38 patients (31.4%) developed postoperative AF. In the population that developed postoperative AF, 7 of the 38 patients (18.4%) had a prior history of AF. The total number of patients with new-onset postoperative AF was 31 of 121 (25.6%). Seventeen of the 38 patients (44.7%) had onset of the arrhythmia on or prior to postoperative day number 2. None of the patients with postoperative AF were
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found to have had a myocardial infarction at the time of diagnosis. Patients with postoperative AF were significantly older than those without postoperative AF (68.7 ± 8.2 vs. 62.8 ± 12.0 years, P = 0.008; Table 2). Prior history of AF was one of the strongest predictors of postoperative AF (18.4% vs. 2.4%, P = 0.002). Additionally, neoadjuvant chemoradiation showed a trend to increased risk of postoperative AF (73.7% vs. 56.6%, P = 0.07). BMI was not a prognostic factor for AF. AF was significantly associated with increased hospital LOS (13.4 ± 10.0 vs. 10.6 ± 7.4; P = 0.02). The most common postoperative morbidities for patients undergoing MIE were pneumonia (30.0%), anastomotic stricture (22.3%), and anastomotic leak (9.9%). None of these were significantly related to AF (Table 3). In patients with cancer, AF trended as more common in higher stage patients, most of whom underwent chemoradiation. This study cannot determine whether the increased trend to AF in the more advanced stage group is related to chemoradiotherapy or to stage of cancer. The 30-day in-hospital mortality (2.6% vs. 3.6%; P = 1.0) and the 60-day overall mortality (5.3% vs. 6.0%; P = 1.0) were not different between patients with and without AF. Patients were monitored for all-cause mortality from the date of surgery until March 2013 with a median follow-up time of 18.8 months. Patients with AF had a shorter overall survival compared with patients without AF (P = 0.01; Fig. 1). The overall survival was also evaluated by the multivariable Cox proportional model including AF, age, and gender. Based on our data, age and gender were not potential confounders.
Table 2 Characteristics of postoperative AF group versus those without postoperative AF
Age (mean ± SD, median) Gender (male) BMI (mean ± SD, median) Prior history of AF Neoadjuvant chemoradiation Neoadjuvant chemotherapy
AF group n = 38
Non-AF group n = 83
P-value
68.7 ± 8.2, 70.0 36 (94.7%) 27.7 ± 5.9, 26.0 7 (18.4%) 27 (71.1%) 28 (73.7%)
62.8 ± 12.0, 63.0 67 (80.7%) 28.4 ± 4.8, 27.6 2 (2.4%) 45 (54.2%) 47 (56.6%)
0.008* 0.04** 0.23* 0.02** 0.08** 0.07**
*Wilcoxon rank sum test. **Chi-square test. AF, atrial fibrillation; BMI, body mass index; SD, standard deviation.
Table 3 Comparison of morbidity and mortality in patients with postoperative AF and those without postoperative AF
Pneumonia Anastomotic stricture Anastomotic leak Hospital LOS (mean ± SD, median) 60-day mortality
AF group n = 38
Non-AF group n = 83
P-value
12 (31.6%) 5 (13.2%) 5 (13.2%) 13.4 ± 10.0, 9.0 2 (5.3%)
18 (21.7%) 22 (26.5%) 7 (8.4%) 10.6 ± 7.4, 8.0 5 (6.0%)
0.24* 0.10* 0.51** 0.02*** 1.00**
*Chi-square test. **Fisher’s exact test. ***Wilcoxon rank sum test. AF, atrial fibrillation; LOS, length of stay; SD, standard deviation. © 2015 International Society for Diseases of the Esophagus
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Fig. 1 Overall survival among patients with or without postoperative atrial fibrillation.
DISCUSSION AF is a common postoperative complication of thoracic surgery.10–15,18 It has been associated with prolonged hospitalization and substantially increased postoperative costs for anticoagulation and monitoring. Our rate of 31.4% postoperative AF is consistent with the incidence in open esophagectomy reported at 10–40%.10–15 Other studies have noted a comparable rate of AF in the MIE cohorts as compared with open esophagectomy.11 In our cohort, postoperative AF had no statistically significant relationship with other acute postoperative complications including postoperative pneumonia, anastomotic leaks or perioperative mortality. Individuals who developed postoperative AF had an increased LOS. The increased LOS may be attributed to treatment of AF alone; however, 22 of 38 patients (58%) experienced a major complication that could also contribute to an increased LOS. Long-term complications, including anastomotic stricture, were not increased in patients having AF, although overall survival was decreased in the AF group. These results are similar to the previously published preliminary data from a smaller cohort at our same institution.19 Our data support the previously identified risk factors for development of postoperative AF after thoracic surgery including advanced age, male
gender, prior history of AF, and the use of neoadjuvant chemoradiotherapy. Neoadjuvant chemoradiotherapy appears to be an important risk factor for AF, despite only showing a trend toward significance in this cohort. The association among age, advanced stage neoplasm, and the use of neoadjuvant chemoradiotherapy in the development of AF and subsequent long-term survival is somewhat unclear because in this cohort the overwhelming majority of advanced staged patients had preoperative chemoradiotherapy, which also implicates advanced stage neoplasms. Published data differ among patients undergoing open esophagectomy versus MIE as to whether AF is a marker of shortterm postoperative morbidity and mortality.11,12,15 AF after open esophagectomy has been specifically associated with increased 30-day in-hospital mortality, anastomotic leak, and pulmonary complications; AF usually preceded these findings by a period of 1–8 days in previous analyses.11,12,15 Our data do not show a significant relationship between AF and 30-day in-hospital mortality. However, patients with postoperative AF did have shorter overall survival, although these patients also tended to be male and of advanced age, which could also contribute to their decreased long-term survival. Compared with open esophagectomy, morbidity and mortality after MIE were not affected by AF in this patient cohort. These results can be attributed to © 2015 International Society for Diseases of the Esophagus
AF minimally invasive esophagectomy
our small cohort size but can also be hypothesized to be associated with rapid intervention and treatment of AF to prevent prolonged periods of hypotension, which could preserve blood flow to anastomotic microvascular arcades. Additionally, MIE could contribute less vascular damage than open esophagectomy as MIE has been shown to have less blood loss during the operation.20,21 Others have also documented decreased immunologic response and energy expenditure after MIE that may counteract some of the impetus for and detrimental effects of AF.22,23 AF prophylaxis in high-risk patient populations may be indicated in order to prevent increased LOS, increased cost, and the morbidity associated with anticoagulation. However, complications such as hypotension as a consequence of treating with beta blocking or calcium channel blocking medications may eliminate benefits. Several methods of chemoprophylaxis for postoperative AF have been described, although not specifically in the setting of MIE.14,24,25 The benefits of preventing AF versus the risks of complication relating to prophylaxis are unknown in the MIE population. Beta-blockers or amiodarone are routinely used as primary prophylaxis in patients undergoing cardiac surgery.26,27 In patients undergoing pneumonectomy, published studies support the use of diltiazem, bupivacaine epidurals, and magnesium for AF prophylaxis.27–30 Amiodarone prophylaxis has been shown to decrease the rates of AF after thoracic esophagectomy.14 Additional studies are needed to guide the selection of prophylaxis in the specific population of patients undergoing MIE. This study has several limitations. The retrospective, single-center nature of data collection as well as the use of only one surgical team limit the generalizability of the results and conclusions. In order to further ascertain the associations between AF and MIE, a prospective multicenter study with prophylaxis and no-prophylaxis cohorts could be designed.
CONCLUSIONS AF is a common complication following esophagectomy. We did not find an increased rate of AF in our MIE cohort compared with prior reported rates in open esophagectomy populations. In our MIE cohort, AF did result in an increased LOS but was not a predictor of other short-term morbidities including anastomotic leak, pulmonary complications, stenosis, or 60-day mortality. Overall survival was shorter in the AF group. Additional studies should be considered to identify patients at high risk for postoperative AF that would benefit from pro© 2015 International Society for Diseases of the Esophagus
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phylaxis, as well as to identify and quantify the risk and benefits to prophylaxis in high-risk patients. References 1 Enzinger P C, Mayer R J. Esophageal cancer. N Engl J Med 2003; 349: 2241–52. 2 Simard E P, Ward E M, Siegel R, Jemal A. Cancers with increasing incidence trends in the United States: 1999 through 2008. CA Cancer J Clin 2012; 62: 118–28. 3 Thrift A P, Whiteman D C. The incidence of esophageal adenocarcinoma continues to rise: analysis of period and birth cohort effects on recent trends. Ann Oncol 2012; 23: 3155–62. 4 Pennathur A, Luketich J D. Resection for esophageal cancer: strategies for optimal management. Ann Thorac Surg 2008; 85: S751–6. 5 Chang A C, Ji H, Birkmeyer N J, Orringer M B, Birkmeyer J D. Outcomes after transhiatal and transthoracic esophagectomy for cancer. Ann Thorac Surg 2008; 85: 424–9. 6 Birkmeyer J D, Siewers A E, Finlayson E V et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002; 346: 1128–37. 7 Atkins B Z, Shah A S, Hutcheson K A et al. Reducing hospital morbidity and mortality following esophagectomy. Ann Thorac Surg 2004; 78: 1170–6. 8 Nagpal K, Ahmed K, Vats A et al. Is minimally invasive surgery beneficial for the management of esophageal cancer? A meta-analysis. Surg Endosc 2010; 24: 1621–9. 9 Luketich J D, Pennathur A, Awais O et al. Outcomes after minimally invasive esophagectomy: review of over 1000 patients. Ann Surg 2012; 256: 95–103. 10 Passman R S, Gingold D S, Amar D et al. Prediction rule for atrial fibrillation after major noncardiac thoracic surgery. Ann Thorac Surg 2005; 79: 1698–703. 11 Stawicki S P, Prosciak M P, Gerlach A T et al. Atrial fibrillation after esophagectomy: an indicator of postoperative morbidity. Gen Thorac Cardiovasc Surg 2011; 59: 399–405. 12 Murthy S C, Law S, Whooley B P, Alexandrou A, Chu K M, Wong J. Atrial fibrillation after esophagectomy is a marker of postoperative morbidity and mortality. J Thorac Cardiovasc Surg 2003; 126: 1162–7. 13 Amar D, Burt M E, Bains M S, Leung D H. Symptomatic tachydysrhythmias after esophagectomy: incidence and outcome measures. Ann Thorac Surg 1996; 61: 1506–9. 14 Tisdale J E, Wroblewski H A, Wall D S et al. A randomized controlled study of amiodarone for prevention of atrial fibrillation after transthoracic esophagectomy. J Thorac Cardiovasc Surg 2010; 140: 45–51. 15 Kassis E S, Kosinski A S, Ross P Jr, Koppes K E, Donahue J M, Daniel V C. Predictors of anastomotic leak after esophagectomy: an analysis of the society of thoracic surgeons general thoracic database. Ann Thorac Surg 2013; 96: 1919–26. 16 Hou J L, Gao K, Li M et al. Increased N-terminal pro-brain natriuretic peptide level predicts atrial fibrillation after surgery for esophageal carcinoma. World J Gastroenterol 2008; 14: 2582–5. 17 Laxa B U, Harold K L, Jaroszewski D E. Minimally invasive esophagectomy: esophagogastric anastomosis using the transoral orvil for the end-to-side Ivor-Lewis technique. Innovations (Phila) 2009; 4: 319–25. 18 Vaporciyan A A, Correa A M, Rice D C et al. Risk factors associated with atrial fibrillation after noncardiac thoracic surgery analysis of 2588 patients. J Thorac Cardiovasc Surg 2004; 127: 779–86. 19 Carpenter S G, Jaroszewski D E, Stucky C C et al. Incidence and impact of post-operative atrial fibrillation after minimally invasive esophagectomy. J Am Coll Surg 2012; 215: S60. 20 Xie M R, Liu C Q, Guo M F, Mei X Y, Sun X H, Xu M Q. Short-term outcomes of minimally invasive Ivor-Lewis esophagectomy for esophageal cancer. Ann Thorac Surg 2014; 87: 1721–7. 21 Dolan J P, Kaur T, Diggs B S et al. Impact of comorbidity on outcomes and overall survival after open and minimally invasive esophagectomy for locally advanced esophageal cancer. Surg Endosc 2013; 27: 4094–103.
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22 Maas K W, Biere S S, van Hoogstraten I M, van der Peet D L, Cuesta M A. Immunological changes after minimally invasive or conventional esophageal resection for cancer: a randomized trial. World J Surg 2014; 38: 131–7. 23 Yatabe T, Kitagawa H, Yamashita K, Hanazaki K, Yokoyama M. Energy expenditure measured using indirect calorimeter after minimally invasive esophagectomy in ventilated postoperative patients. Asia Pac J Clin Nutr 2014; 23: 555–9. 24 Stroobandt R, Stiels B, Hoebrechts R. Propafenone for conversion and prophylaxis of atrial fibrillation. Am J Cardiol 1997; 79: 418–23. 25 Daoud E G, Strickberger S A, Man K C et al. Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery. N Engl J Med 1997; 337: 1785–91. 26 Crystal E, Connolly S J, Sleik K, Ginger T J, Yusuf S. Interventions on prevention of postoperative atrial fibrillation in
27
28 29 30
patients undergoing heart surgery: a meta-analysis. Circulation 2002; 106: 75–80. Dunning J, Treasure T, Versteegh M, Nashef S A. Guidelines on the prevention and management of de novo atrial fibrillation after cardiac and thoracic surgery. Eur J Cardiothorac Surg 2006; 30: 852–72. Amar D, Roistacher N, Burt M E et al. Effects of diltiazem versus digoxin on dysrhythmias and cardiac function after pneumonectomy. Ann Thorac Surg 1997; 63: 1374–81. Oka T, Ozawa Y, Ohkubo Y. Thoracic epidural bupivacaine attenuates supraventricular tachyarrhythmias after pulmonary resection. Anesth Analg 2001; 93: 253–9. Terzi A, Furlan G, Chiavacci P, Dal Corso B, Luzzani A, Dalla Volta S. Prevention of atrial tachyarrhythmias after noncardiac thoracic surgery by infusion of magnesium sulfate. Cardiovasc Surg 1996; 44: 300–3.
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