Ann Thorac Surg 2002;73:381-385
© 2002 The Society of Thoracic Surgeons
Original article: general thoracic
Effects of antireflux procedures on respiratory symptoms1
Kevin L. Greason, CDR, MC, USNRa,
Daniel L. Miller, MD*b,
Claude Deschamps, MDb,
Mark S. Allen, MDb,
Francis C. Nichols, III, MDb,
Victor F. Trastek, MDc,
Peter C. Pairolero, MDb
a Division of Cardiothoracic Surgery, Naval Medical Center, San Diego, California, USA
b Division of General Thoracic Surgery, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
c Division of General Thoracic Surgery, Mayo Clinic and Mayo Foundation, Scottsdale, Arizona, USA
* Address reprint requests to Dr Miller, Division of General Thoracic Surgery, Mayo Clinic and Mayo Foundation, 200 First Street, SW, Rochester, MN 55905, USA
e-mail: miller.danielmd{at}mayo.edu
Presented at the Forty-seventh Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 9–11, 2000.
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Abstract
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Background. Antireflux surgery can reduce respiratory symptoms associated with gastroesophageal reflux. However, there is a paucity of data on the durability of this benefit. To evaluate the long-term effects of antireflux surgery on respiratory complaints associated with gastroesophageal reflux, we reviewed our experience.
Methods. Retrospective review of 2,123 antireflux procedures completed between 1986 and 1998 identified 65 patients (3.1%) with associated respiratory symptoms. There were 32 men and 33 women, ranging in age from 20 to 80 years (median 59 years). Respiratory symptoms included wheezing in 43 patients, sputum production in 37, cough in 30, choking episodes in 24, and hoarseness in 17. Preoperative medication use included steroids in 23 patients and bronchodilators in 18.
Results. Antireflux operations included the uncut Collis-Nissen fundoplication in 29 patients, Belsy Mark IV repair in 13, open Nissen fundoplication in 13, and laparoscopic Nissen fundoplication in 10. Perioperative complications occurred in 19 patients who underwent open procedures and in none who had laparoscopic procedures. There was one death in the open-operation group and none in the laparoscopic group. Median follow-up was 65 months (range 1 to 174 months) and was complete in 62 patients (96.9%). Improvement in respiratory symptoms (83%) and reduction in respiratory medication use (78%) were significant as compared to a calculated 33% placebo-effect improvement (p < 0.05).
Conclusions. Antireflux operations significantly reduce respiratory complaints associated with gastroesophageal reflux. This benefit appears to be long term.
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Introduction
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Gastroesophageal reflux disease is a common disorder of the esophagus, with more than 40% of Americans experiencing heartburn or acid regurgitation on a regular basis [1, 2] Antireflux surgery effectively reduces these symptoms [3]. Less commonly recognized complications of gastroesophageal reflux disease include respiratory complaints of wheezing, choking episodes, cough, and recurrent pneumonia [4, 5]. The midterm outcome of antireflux surgery in treating these respiratory problems is variable, with reported improvement rates ranging from 50% to 100% [4–7]. There is a paucity of data on the durable benefits of antireflux surgery for respiratory symptoms. Our study evaluates the long-term effects of antireflux surgery on respiratory complaints associated with gastroesophageal reflux.
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Material and methods
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We retrospectively reviewed the records of 2,123 patients treated with an antireflux procedure for gastroesophageal reflux between 1986 and 1998 at the Mayo Clinic in Rochester, Minnesota. A total of 65 patients (3.1%) reported respiratory complaints on their admission review of systems; these patients form the basis for this review. Preoperative information was obtained from the medical records. Follow-up information came from direct patient contact or by telephone or mail, using a standardized questionnaire. Data collection included patient demographics, preoperative symptoms and medication use, diagnostic studies, surgical procedures, hospital course, and follow-up symptoms and medication use.
We coded preoperative respiratory symptoms as either present or not present, and follow-up symptoms as improved or not improved. We coded preoperative and follow-up medication use as present or not present. The definition of asthma requires the demonstration of altered airway responsiveness [8]. Because of the retrospective nature of the study, we were unable to document this adequately in all patients who presented with a subjective history of asthma. As such, we limited our follow-up analysis of respiratory complaints to symptoms that included wheezing, sputum production, cough, choking episodes, hoarseness, and pneumonia. Operative mortality was considered to have occurred when patients died within the first 30 days after operation or during the same hospitalization but at a later date.
There is a significant placebo effect noted in asthma trials; in one study it resulted in a 33% improvement [9]. To account for this effect, we compared the observed improvement of a variable against an expected 33% placebo improvement using the 
2 test. The observed improvement equaled the number of improved patients divided by the total number of patients with the preoperative variable. Statistical analysis of the categorical data used either Fisher’s exact or McNemar’s test, with significance defined as a p value less than 0.05 [10].
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Results
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There were 32 men and 33 women, with ages that ranged from 20 to 80 years (median 59 years) at the time of operation. Review of the medical records identified a history of pneumonia in 34 patients, Barrett’s esophagus in 26, and esophagitis in 25. Respiratory complaints included wheezing in 43 patients, sputum production in 37, cough in 30, choking episodes in 24, and hoarseness in 17. In all, 56 patients (86.2%) reported two or more complaints. A total of 31 patients (47.7%) used preoperative respiratory medications, including steroids (oral or inhaled) in 23 cases and bronchodilators (oral or inhaled) in 18. Thirteen patients used both steroids and bronchodilators.
Abnormal pulmonary function was present in 43 of 55 patients (78.2%) tested and included an FEV1/FVC ratio less than 80% (n = 43), a positive bronchodilator response with an increase in FEV1 of more than 12% and 200 mL (n = 11), or a positive methacholine response with a decrease in FEV1 of more than 20% (n = 2). Chest radiography identified pulmonary infiltrates or fibrosis in 33 patients.
Gastroesophageal reflux symptoms were present in 60 patients and included dyspepsia in 54, regurgitation in 47, and dysphagia in 23. A total of 49 patients (75.3%) used preoperative antireflux medications including histamine-2 (H2)–blockers in 29 patients, proton pump inhibitors in 21, and antacids in 8. Fourteen patients used a combination of two or more antireflux medications.
The diagnosis of gastroesophageal reflux was clinically based on symptom presentation and was supplemented with objective evidence of gastroesophageal reflux; the modality of diagnostic evaluation was at the discretion of the treating physician and surgeon. Table 1
contains results of preoperative diagnostic studies.
All patients underwent evaluation for gastroesophageal reflux; diagnostic studies included esophagogastroduodenoscopy (n = 62), esophageal manometry (n = 49), upper gastrointestinal series (n = 49), or pH study (n = 16). A total of 53 patients had objective findings of gastroesophageal reflux. In 3 patients, respiratory symptoms were correlated with episodes of gastroesophageal reflux on pH study; results of pH study did not quantify the level of the esophagus to which gastroesophageal reflux occurred. The 12 patients without gastroesophageal reflux on diagnostic evaluation underwent operation for symptomatic intrathoracic stomach.
Antireflux procedures included the transthoracic uncut Collis-Nissen fundoplication in 29 patients, Belsy Mark IV repair in 13, laparoscopic Nissen fundoplication in 10, transthoracic Nissen fundoplication in 7, and open transabdominal Nissen fundoplication in 6. The operating surgeon determined the type of operative procedure. Nine patients (13.8%) had a history of a prior antireflux operation. The time period from the original operation to the repeat operation ranged from 6 months to 39 years (median 11 years). It is unknown whether respiratory complaints preceded the previous antireflux operation.
Complications occurred in 19 patients who underwent open procedures, including pneumonia in 5 patients, atrial fibrillation in 4, wound infection in 4, bleeding in 3, and chylothorax in 1. Esophageal perforation occurred in 2 patients: in 1 patient after a Belsy Mark IV repair, and in the other after a redo fundoplication (uncut Collis-Nissen). Median hospital stay was 7 days (range 1 to 25 days). One patient died on postoperative day 22 from multisystem organ failure secondary to one of the perforations. No complications or operative deaths occurred in the laparoscopic treatment group. Complications were significantly greater in the patients who underwent open procedures compared with patients who underwent laparoscopy (p = 0.03)
Follow-up was complete in 62 patients (96.9%) at a median of 65 months (range 1 to 175 months). Respiratory symptoms significantly improved in 54 of 65 patients (83.1%); wheezing improved in 21 patients, sputum production in 21, cough in 18, choking episodes in 21, and hoarseness in 11. Only 3 of 34 patients (8.8%) were reported to have episodes of recurrent pneumonia. Medication use for respiratory symptoms improved in 32 of 41 patients (78.1%); steroid use improved in 18 patients and bronchodilator use in 14.
Regurgitation improved in 42 of 47 patients (89.4%). Reflux medication use improved in 88% of patients: antacid use in 8 patients, H2-blocker use in 28, and proton pump inhibitor use in 15. Table 2
compares preoperative respiratory complaints and use of medication (respiratory and reflux) with follow-up symptoms and medication use. The magnitude of improvement was significantly greater than the calculated expected placebo improvement of 33% for all categories (p < 0.05).
Table 3
reports the probability of abnormal pH study or pulmonary function being predictive of variable improvement. Abnormal pH study was the only predictor of improvement in any variable. Improvements in sputum production and steroid use were significant (p < 0.05). For no other variables were abnormal pH study or pulmonary function predictive of improvement. Follow-up pulmonary function was available in 26 patients. The time to repeat pulmonary function test ranged from 5 to 173 months (median 38 months). The change in FEV1/FVC ranged from a decrease of 0.121 to an increase of 0.133 L (median 0.001; p = ns) Neither previous antireflux operation nor type of operation performed affected outcome (p = ns).
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Comment
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The occurrence of respiratory symptoms with gastroesophageal reflux is variable. The reported prevalence ranges from 9% to 50% [1, 5]. In this retrospective 13-year review, we identified respiratory symptoms in only 3% of more than 2,100 patients who had undergone operation for gastroesophageal reflux disease. Five accepted antireflux operative procedures produced a statistically significant improvement in respiratory complaints. There was a similar significant reduction in respiratory medication use. Findings did not vary as to the type of operation performed; however, the laparoscopic technique had significantly fewer postoperative complications. Improvement in respiratory complaints and medication use appear to be durable with a median follow-up of 65 months.
The relationship between asthma and gastroesophageal reflux disease is not completely understood. Several theories exist as to how gastroesophageal reflux might exacerbate asthma: esophagobronchial reflex, heightened bronchial reactivity, direct alterations in ventilation, or microaspiration [11]. Evidence supports the esophagobronchial reflex theory based on decreased expiratory airflow and increased airway resistance in response to esophageal acid infusion [12]. Atropine, vagotomy, and inhibitors of substance P block the variations in airflow and resistance. Findings such as these suggest the esophagobronchial reflex involves both vagal fibers and neurogenic inflammation. Data also support heightened bronchial reactivity [13, 14]. Esophageal acid exposure increases bronchial reactivity to other stimuli such as isocapnic hyperventilation and methacholine; furthermore, patients with asthma and gastroesophageal reflux disease show evidence of autonomic dysfunction with hypervagal responsiveness.
Nonasthmatic patients develop increased minute ventilation and respiratory rate with esophageal acid infusion. The alteration in ventilation and respiratory rate occurs without associated changes in other measured variables noted on routine pulmonary function tests [12]. Findings such as these suggest that gastroesophageal reflux increases minute ventilation directly without affecting lung function [15, 16]. This might explain the paradox of medical treatment improving asthma symptoms but not pulmonary function. Tracheal acidification results in a greater increase in airway resistance than does esophageal acidification alone. Although microaspiration appears to be a strong inducer of bronchial reactivity, it does not seem to be the primary pathologic mechanism of reflux-induced respiratory symptoms in the majority of patients [11].
Several reports support our results demonstrating beneficial effects of antireflux surgery on respiratory symptoms and medication use. Field and colleagues [7] published a review that included 417 patients collected from 24 reports in the literature; asthma symptoms improved in 79% of patients (range 50% to 100%) and medication use requirements improved in 88% (range 35% to 100%). Bowrey and coworkers [17] reviewed data in 19 surgical series; they indicated that almost 90% of children and 70% of adults noted improvement in respiratory symptoms after operation. Spivak and associates [18] reported data from a prospective study on the effectiveness of fundoplication in gastroesophageal reflux–associated asthma; they found statistically significant improvement in asthma exacerbations, cough/wheezing, and oral steroid medication use. In our series, 83% of patients had improvement of their respiratory symptoms and 78% had a reduction in the use of respiratory medications.
We did not compare our surgical results with those of a medical treatment group. Other investigators, however, report superior results with antireflux surgery compared with medical therapy [17]. Wetscher and colleagues [5] reported a group of 21 patients with severe pulmonary symptoms and proven gastroesophageal reflux. There was a significant decrease in the need for respiratory medication use after antireflux surgery. Furthermore, respiratory symptoms improved in 86% of surgically treated patients versus in only 14% of the medically treated patients; the difference was significant. Larrain and coworkers [19] reported 81 patients with asthma prospectively randomized to placebo, H2-blockers, or antireflux surgery. After 6 months, the surgical group had the best outcome. Although the individual studies vary is size and outcomes, the collective data demonstrate that antireflux surgery improves asthma symptoms and use of respiratory medications.
We found that the beneficial effects of antireflux surgery on respiratory symptoms occurred no matter what procedure was performed. There was no difference in benefit between the patients who had open procedures versus those who had laparoscopic procedures in our series. However, only 10 of our patients underwent laparoscopic procedures. Similar beneficial results are found in larger laparoscopic series. Rothenberg and colleagues [20] reported 56 pediatric patients with severe steroid-dependent asthma and reflux. All patients had successful laparoscopic fundoplication and 52 noted symptomatic improvement at a mean follow-up of 17 months. Another group of investigators correlated improvement of preoperative respiratory symptoms with omeprazole or H2-blockers with improvement after laparoscopic operation [21]. Reduced operative pain and morbidity are significant benefits of the laparoscopic technique [22–24].
Our study has several limitations. Quantitative symptom and medication frequency scores are useful tools in the evaluation of gastroesophageal reflux treatment [18]; in addition, response to medical treatment scores is predictive of improvement after antireflux surgery [21]. The retrospective nature of our study, however, made quantitative assessment of symptoms, medication use, and response to treatment difficult. We believed that it was unreasonable to expect patients to report accurate symptoms, medication frequency scores, or improvement periodically over the long follow-up period, which reached a maximum of 175 months in 1 patient. To minimize bias in this area, we simply recorded respiratory symptoms and medication use data in a nominal fashion.
We did not have complete preoperative diagnostic evaluations for all patients because of the retrospective design of the study. We believe that the lack of data with respect to pulmonary function is of minor issue, as several investigations do not support a general relationship between gastroesophageal reflux and pulmonary function [7, 25]. Abnormal pH study, on the other hand, identifies patients who are most likely to benefit from antireflux surgery [24, 26]. Only 16 patients underwent preoperative pH study in our series. In this group, however, abnormal pH study was predictive of improvement in both sputum production and steroid medication use. In only 3 of these 16 patients did respiratory symptoms correlate with gastroesophageal reflux, a correlation that provides additional predictive value on the beneficial effects of surgical treatment [26]. The small number of patients in our series prevented further analysis of this relationship.
We did not obtain postoperative pH study as a marker of operation success in preventing gastroesophageal reflux. Compliance with follow-up pH study is not good; rates for postoperative study range from 28% to 53% [21, 24]. An accepted surrogate measure of success is improvement in dyspepsia or regurgitation. The standard for relief of symptoms after antireflux operation is approximately 90% [21, 27]. We did not collect data on follow-up dyspepsia, but did note an 89% improvement in regurgitation. Also, our patients had a significant 88% reduction in the use of reflux medication. Based on these data, we believe that our patients achieved excellent long-term surgical treatment of their gastroesophageal reflux.
In conclusion, several theories support a relationship between gastroesophageal reflux and respiratory symptoms. The key question to the surgeon is which patients are best served with operative management. A practical approach would aim to establish a response to medical treatment. Further diagnostic evaluation with a pH study correlating respiratory symptoms with gastroesophageal reflux is strong evidence of a cause–effect relationship. These patients should be considered for antireflux operations, with expected long-term clinical improvement and decreased medication requirements. However, there are a number of patients who do not have a good correlation with reflux diagnostic studies and respiratory symptoms. Every effort should be made to determine whether respiratory symptoms could be caused by conditions other than gastroesophageal reflux. Because laparoscopic techniques offer the benefit of antireflux surgery with reduced morbidity, this modality may be the treatment of choice in the future. Long-term follow-up is warranted for this less invasive procedure in this select group of patients.
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Footnotes
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1 The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy or the United States Government. 
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Abstract
Introduction
