Traditional Reflux Parameters and Not Impedance Monitoring Predict Outcome After Fundoplication in Extraesophageal Reflux

The Laryngoscope VC 2011 The American Laryngological, Rhinological and Otological Society, Inc. Traditional Reflux Parameters and Not Impedance Monitoring Predict Outcome After Fundoplication in Extraesophageal Reflux David O. Francis, MD, MS; Marion Goutte, BS; James C. Slaughter, DrPH; C. Gaelyn Garrett, MD; David Hagaman, MD; Michael D. Holzman, MD, MPH; Michael F. Vaezi, MD, PhD Objectives/Hypothesis: Fundoplication is considered in patients with refractory extraesophageal reflux symptoms. However, postoperative symptom resolution is inconsistent. This analysis investigates which presenting symptoms and preoperative objective parameters predict postoperative symptom improvement. Study Design: Retrospective cohort study. Methods: A total of 237 patients referred for extraesophageal reflux symptoms refractory to medical therapy underwent esophageal function testing. Fundoplication was performed in 27 patients with objective evidence of gastroesophageal reflux disease. Symptomatic improvement was assessed at postoperative intervals. Logistic regression determined which symptoms and objective parameters predicted improvement of the presenting extraesophageal reflux symptom. Results: Overall, 59% of patients reported at least partial improvement of their presenting extraesophageal symptom after fundoplication. Predictors of symptomatic improvement were the presence of heartburn with or without regurgitation concomitant to their primary presenting symptom (odds ratio [OR], 6.6; 95% confidence interval [CI], 0.97-44.9; P ¼.05) and ph < 4 more than 12% of a 24-hour period (OR, 10.5; 95% CI, 1.36-81.1; P ¼.02). Probability of postoperative extraesophageal reflux symptom improvement was 90% if both conditions were present. Conclusions: Both heartburn with or without regurgitation and esophageal ph < 4 more than 12% of a 24-hour period predicted postfundoplication resolution of the presenting extraesophageal reflux symptom. Key Words: Extraesophageal reflux, laryngopharyngeal reflux, gastroesophageal reflux disease, fundoplication, chronic cough, surgery. Level of Evidence: 2b. Laryngoscope, 121:1902 1909, 2011 INTRODUCTION Extraesophageal reflux (EER) is widely implicated in the etiology of laryngeal, pharyngeal, and pulmonary symptoms. 1 Despite significant attention to this condition, controversy continues regarding its diagnosis and management. Currently, most patients with signs and symptoms attributed to EER are empirically treated with proton pump inhibitors (PPIs). However, symptomatic improvement on a PPI is not as consistent in these patients compared to those with more classic gastroesophageal reflux disease (GERD). 2 Patients with presumed EER refractory to initial empiric medical therapy are often referred for testing to evaluate for the presence of underlying GERD and possible consideration for surgical fundoplication. From the Vanderbilt Voice Center, Department of Otolaryngology (D.O.F., C.G.G.); Division of Gastroenterology, Hepatology and Nutrition (M.G., M.F.V.); Department of Biostatistics (J.C.S.); Allergy, Sinus and Asthma Program (D.H.); and Department of Surgery (M.D.H.), Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A. Editor s Note: This Manuscript was accepted for publication March 24, 2011. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to David O. Francis, MD, MS, Vanderbilt Voice Center, Department of Otolaryngology, Bill Wilkerson Center, Vanderbilt University Medical Center, Medical Center East, South Tower, 1215 21st Avenue South, Suite 7302, Nashville, TN 37232-8783. E-mail: david.o.francis@vanderbilt.edu DOI: 10.1002/lary.21897 1902 Surgical fundoplication may be successful in improving reflux symptoms in more than 90% of patients with typical symptoms of GERD and, in a recent Cochrane review, was suggested to be more effective than medical treatment of GERD in the short to medium term. 3 Although, the relative effectiveness of medical to surgical management of GERD may be debatable, it is generally accepted that both are effective in reducing esophageal acid exposure and relieving patient symptoms. However, the role of antireflux surgery for EER symptoms refractory to aggressive acid suppressive therapy is unclear. In a systematic review by Iqbal et al., 15% to 95% of patients with EER symptoms improved after fundoplication. 4 This broad variability underscores our poor understanding of which patients with refractory EER symptoms might benefit from surgery. A concurrent control study in patients with chronic laryngeal symptoms refractory to PPI therapy did not find Nissen fundoplication to be of benefit. One year after surgery, only 10% of patients noted improvement in laryngeal symptoms, but signs of laryngopharyngeal reflux on laryngoscopy improved in 80% of patients. 5 Recent controversy surrounds the role of surgical fundoplication in patients with PPI-refractory symptoms who have abnormal nonacid reflux by impedance monitoring. In the only study assessing the role of fundoplication in patients with chronic cough refractory to PPI therapy, the authors suggested significant improvement of EER

in those with abnormal impedance monitoring when tested on therapy. 6 However, this finding is yet to be independently validated. Thus, the aims of this retrospective cohort study were to 1) assess symptomatic response to surgical fundoplication in patients with EER who were either partial or nonresponders to PPI therapy; and 2) to identify predictors for symptom response with fundoplication based on patient demographics and baseline esophageal physiologic tests including ph and impedance monitoring. MATERIALS AND METHODS The study was performed in accordance with the Declaration of Helsinki, good clinical practice and applicable regulatory requirements. The Vanderbilt University Institutional Review Board approved the study protocol (IRB#101219). Study Design and Patient Population The study population consisted of patients with chief complaint of EER refractory to PPI therapy referred for evaluation and treatment for possible reflux-associated symptoms. Refractory symptom was defined as less than 50% improvement in the chief complaint after at least 12 weeks of twice daily PPI therapy. The following information was collected for all participants: presence, severity and frequency of GERD (heartburn 6 regurgitation) and extraesophageal symptoms (cough, hoarseness, throat clearing, sore throat, globus sensation, postnasal drip symptoms, chest pain), current medication as well as information on subject demographics (age, sex, race, body mass index), history of alcohol and tobacco use, and presence of voice/laryngeal and nasal symptoms. Patients underwent esophagogastroduodenoscopy (EGD), wireless 48-hour ph monitoring and esophageal motility testing off acid suppression to assess the baseline esophageal motility and acid exposure. They also underwent 24-hour impedance/ph monitoring while on twice daily PPI therapy to determine the presence of nonacid reflux despite acid suppression. Symptom index (SI) and symptom association probability (SAP) were hand-calculated based on previously described methods for both wireless ph monitoring off therapy and impedance/ph monitoring on therapy. 7,8 Presence and size of hiatal hernia were determined at endoscopy, and severity of esophagitis was graded by Los Angeles Classification. 9 Patients with abnormal esophageal acid exposure at baseline (off PPI therapy) were offered laparoscopic surgical fundoplication. Inclusion criteria were age >18 years, chronic EER symptoms refractory to PPI therapy, and presence of abnormal baseline esophageal acid exposure. Patients were excluded from the study for the following reasons: Barrett s esophagus; history of alcoholism; prior ear, nose, and throat or gastrointestinal surgery; or unwillingness to participate in the study. Subjects who agreed to undergo fundoplication had a complete preoperative evaluation including chest X-ray, 12-lead electrocardiogram, blood testing (complete blood count, basic metabolic panel, and coagulation panel), and a consultation with the surgeon (M.D.H.) and an anesthesiologist. Postoperatively, patients were followed both in the Surgery and Esophageal Centers to assess response of EER symptoms to fundoplication and to identify any potential adverse outcome from the surgical intervention. All patient symptoms were assessed by using a standard questionnaire at follow-up. The patients were asked to give percentage improvement of their primary symptoms on a Likert scale. Greater than 50% improvement compared to baseline differentiated responders from nonresponders. Resolved symptoms were defined as complete resolution of the primary chief complaint, and improvement was defined as greater than 50% symptom improvement compared to baseline. Predictors of treatment success were determined based on presurgical demographic and esophageal physiologic testing on and off PPI therapy. Wireless ph Monitoring Ambulatory ph monitoring was performed for 48 hours using a wireless monitoring device (Given Imaging, Inc., Duluth, GA). Study patients were instructed to stop taking all PPIs and H2-receptor antagonists for at least 14 days before undergoing evaluation. Wireless capsules were calibrated by submersion in buffer solutions at ph 7.0 and ph 1.0 and then activated by magnet removal. Patients underwent EGD with conscious intravenous sedation for visual anatomic inspection and distance measurements from the incisors to the squamocolumnar junction. Capsules were then placed using the manufacturer s delivery system at 6 cm above the squamocolumnar junction and attached with vacuum suction of 600 mm Hg. Capsule placement was confirmed at endoscopy. After successful placement, patients were given wireless ph recorders to wear about their waists or to keep within 3 to 5 feet at all times. Recording devices receive ph data sampling transmitted by the capsule at 433 Hz with 6-second sampling intervals. Patients were instructed to perform their normal daily activities and dietary practices. Distal esophageal ph recording was conducted for a total of 48 hours. During this time, patients kept diaries of meal times, symptoms, and supine position. After completion of the 48-hour study, data were downloaded from recording devices to dedicated computers using Datalink software (Sandhill Scientific, Inc., Highlands Ranch, CO). Patient diary information was manually entered into the computer-based record. Measurements of the total, upright, and supine percentages of time when esophageal ph was below 4 were determined for day 1 and day 2 of the wireless study. Acid exposure time (% total time ph < 4) greater than 4.2% per day was considered abnormal. 10 Esophageal Motility Testing High-resolution manometry (Sierra Scientific Instruments, Inc., Los Angeles, CA) was used to measure the location of the lower esophageal sphincter (LES) before placement of the impedance ph. A solid-state assembly with 36 circumferential sensors spaced at 1-cm intervals (outside diameter, 4.2 mm) was used. This device detects pressure over a length of 2.5 mm in each of the 12 radially dispersed sectors of the 36 pressuresensing elements. The sector pressures are averaged, making the sensors a circumferential pressure detector. Before recording, the transducers were calibrated at 0 and 100 mm Hg using externally applied pressure. Using this device, LES was measured and the proximal location noted for placement of the impedance -ph catheter. Combined Impedance-pH Monitoring Patients underwent impedance-ph monitoring while on at least twice daily PPI therapy for 1 month before evaluation. They were instructed to fast for 4 hours before testing. Each patient s primary symptom complaint was recorded as part of the preprocedure evaluation. Patients were given diaries to record time of start and end of meals, position changes (upright or recumbent) and occurrence of symptoms during 24-hour impedance and ph monitoring. Impedance testing was performed by using a combined impedance-ph monitoring device (Sandhill Scientific, Inc., Highlands Ranch, CO) comprising a data recorder (Sleuth System; Sandhill Scientific, Inc.) and a 2.1-mm-diameter polyvinyl 1903

catheter embedded by one ph and six impedance sensors at predefined positions. The ph sensors were calibrated before placement by using standardized buffer solutions at ph 4.0 and 7.0 as recommended by the manufacturer. The catheter was placed intranasally so that the esophageal ph sensor was positioned 5 cm above the manometrically defined upper border of the LES. Intraluminal impedance was measured at 3, 5, 7, 9, 15, and 17 cm above the LES. Data sampling frequency for both impedance and ph sensors was 50 Hz. Studies were performed for 18 to 24 hours, after which patients returned to the lab for catheter removal and data review. Data were downloaded from the recorder and analyzed using BioView Analysis software (Sandhill Scientific, Inc.). Reflux episodes were identified by computerized detection (Autoscan; Sandhill Scientific, Inc.) of proximally directed decreases in impedance. Tracings were also manually reviewed by an experienced investigator (M.F.V.) to confirm accuracy and correct any errors. Total, upright, and supine reflux events were recorded. Acid reflux events were defined as those occurring with ph less than or equal to 4, and nonacid reflux events were defined as those occurring at ph greater than 4. For impedance parameters, total number of reflux events greater than 48 was considered abnormal. 11 14 Surgical Fundoplication Patients with objective evidence of GERD on wireless ph and/or endoscopy were counseled about treatment options including continued medical management and fundoplication surgery. Medical management involved continued twice-daily PPI. All patients opting for surgery were evaluated and had surgical fundoplication performed by the same surgeon (M.D.H.). The procedure was performed on an elective basis, agreed upon by the subject and the surgeon. A standard 360 (Nissen) laparoscopic fundoplication was performed in all subjects. None of the patients required conversion to an open procedure. Surgical technique used the standard five-port laparoscopic abdominal setup. The procedure consisted of abdominal insufflation with carbon dioxide gas, retraction of the left lobe of the liver, dissection and identification of the right and left diaphragmatic crura, and takedown of the short gastric vessels using a harmonic scalpel. After the diaphragmatic crura were reapproximated using two to three interrupted nonabsorbable sutures, the posterior fundus of the stomach was passed through the retroesophageal window to create the fundoplication. A bougie was utilized in all cases to assist in calibration of the fundoplication. All patients then received routine postoperative care. Statistical Analysis Data were collected and stored at the secure web-based Vanderbilt Digestive Disease Center REDCap (Research Electronic Data Capture; 1 UL1 RR024975 NCRR/NIH). REDCap is an application designed to support data capture for research studies providing 1) an intuitive interface for validating data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources. There was strict control and supervision of the data entry and access for this study. Both primary presenting extraesophageal symptoms and secondary concomitant presence of heartburn with or without regurgitation were surveyed at the initial consultation and postoperatively. Primary presenting symptoms were categorized into cough, asthma/wheezing, or other. Other included throat clearing, shortness of breath/pneumonia, hoarseness/lar- 1904 Fig. 1. Study flow diagram. EER ¼ extraesophageal reflux; PPI ¼ proton pump inhibitor. yngitis, and postnasal drip. Resolution was graded by the patients as none, partial, or complete and dichotomized for analysis into responders (50% improvement) or nonresponders (<50% symptom improvement). Patient demographics and presurgery esophageal physiologic test parameters were compared for those with and without symptom improvement based on 1-year postoperative response. All statistical tests were performed using Stata/SE 10 (Stata Corporation, College Station, TX). Univariate comparisons were performed with v 2 and Wilcoxon rank sum tests. Analysis of variance or covariance was used where appropriate and adjusted for multiple comparisons. Multivariable logistic regression was used to estimate the effect of covariates on the probability of presenting EER symptom improvement. RESULTS Patient Population A total of 335 patients were referred to Vanderbilt Swallowing and Esophageal Disorders Clinic with refractory extraesophageal symptoms between 2005 and 2010 (Fig. 1), of which 237 underwent physiologic testing for GERD. In this group, 182 (77%) had objective evidence of GERD based on abnormal esophageal acid exposure off PPI therapy of which 27 (14.8%) underwent laparoscopic surgical fundoplication; median age (interquartile range [IQR]): 56 (49 66), BMI: 30.9 (27 34.3), 100% caucasian, 78% female. Overall, cough (44%, 12/27) and asthma/wheezing (22%, 6/27) were the most common presenting EER symptoms among patients who chose to undergo surgery (Table I). Hiatal hernia was present in 63% and esophagitis in 8% of patients. Median (IQR) LES pressure (LESp) was 10.8 mm Hg (0.0 16.2), and

TABLE I. Demographic and Physiologic Parameters of Surgery Versus Continued Medical Therapy. Surgery (N ¼ 27) Medication (N ¼ 155) P Demographics Age* 56 (49 66) 54 (42 61).20 Caucasian, % 100 91.11 Female, % 78 69.36 BMI* 30.9 (27 34.3) 28.4 (25.2 32.6).09 1 symptom, % Cough 44.4 30.2.01 Asthma/wheezing 22.2 7.3 Other 33.3 62.4 EGD Hiatal hernia, % 63 33.04 Hernia size (cm)* 3.5 (2 5) 3 (2 4).39 Hernia size >4 cm, % 26.7 20.57 Esophagitis, % 8 22.12 Wireless ph (% off therapy) Total time ph < 4* 12.8 (6.2 15.7) 8.6 (5.8 12.6).09 Upright time ph < 4 16.1 (9.5 23.8) 11.3 (7.6 17.4).05 Supine time ph < 4 1.8 (0.5 11.6) 2.5 (0 8.2).48 Abnormal SI, %* 7.7 20.8.26 Abnormal SAP, %* 38.5 35.0.80 Impedance (on therapy) No. of reflux episodes (acid þ nonacid)* 59.5 (45 86) 36 (16 48) <.01 No. acid reflux episodes* 8 (3 26) 6 (2 15).40 No. nonacid reflux episodes* 43.5 (26 56) 24 (9 43) <.01 Abnormal SI, % 40.9 16.7.03 Abnormal SAP, % 36.4 20.8.17 *Median (interquartile range). Throat clearing, shortness of breath, hoarseness, laryngitis, postnasal drip. Values represent mean of the 2-day monitoring period. BMI ¼ body mass index; EGD ¼ esophagogastroduodenoscopy; SI ¼ symptom index; SAP ¼ symptom association probability. percentage of time ph was less than 4 was 12.1% (8.5% 15.6%). Compared to patients who continued medical management (n ¼ 155), the surgery group had a higher rate of hiatal hernia (63% vs. 33%, P ¼.04) and upright percentage time ph < 4 (16.1% vs. 11.3%, P ¼.05; Table I). Patients in the surgery group also had more total reflux episodes (59.5 vs. 36, P <.01) and nonacid reflux episodes (43.5 vs. 24, P <.01) as well as higher percentage abnormal SI and SAP. Demographic and physiologic parameters for the two groups were otherwise similar. Outcome and Predictors of Response Postfundoplication patients were followed for a median (IQR) of 33 months (14 40). Response to surgery was assessed at each visit and on an interval basis based on clinic-visit symptom report. Initial visit was defined as the first postoperative visit and occurred a median (IQR) of 1 month after surgery (1 1). Last visit/contact was the patient s follow-up furthest from the surgery date (median [IQR], 33 months [14 40]). Incremental postoperative symptom improvement is shown in Figure 2. The percentage of patients reporting improvement at initial, 1-year, and last visit/contact were 81%, 59%, and 56%, respectively (Fig. 2). Predictive model analyses were performed based on response at 1-year after fundoplication because report of patient improvement stabilized by this time point. At 1-year follow-up, 16 of 27 (59%) patients reported improvement in their chief presenting symptom (48% complete resolution, 11% partial resolution). There was no difference in length of follow-up between patients with and without symptomatic improvement (median months of follow-up [IQR]: responders, 27.5 (15 39) vs. nonresponders, 38 [14 40]; P ¼.60). There was no difference in response to surgery based on primary presenting EER symptom (analysis of variance, P ¼.78; Table II) or patient demographics, EGD, ph, impedance, or SI/SAP parameters between responders and nonresponders postfundoplication (Table II). Manometry measurements were also not different between groups (median LES pressure [IQR]: responders, 11.8 mm Hg [0 20] vs. nonresponders, 5.4 mm Hg [0 16]; P ¼.56, median mean esophageal amplitude [IQR]: responders, 83.5 [56 102] vs. nonresponders, 71.5 [53 102]; P ¼.95). However, among patients with postfundoplication symptom improvement, 85% had concomitant baseline heartburn with or without regurgitation 1905

Fig. 2. Incremental postoperative symptomatic improvement during follow-up period: 1-month, 12-month, and 33-month postoperative symptom report from surgery date. compared to 55% who had no improvement (P ¼.04). Similarly, 44% of the responders had a hiatal hernia > 4 cm compared with 0% in nonresponders (P ¼.06). Distribution of baseline percent time ph < 4 for the group is shown in Figure 3. Threshold of 12% for percentage time ph < 4 identified a significant difference between responders and nonresponders. Specifically, acid exposure greater than 12% was higher in the responder (75%) compared with nonresponder (22%) group (P ¼.02). Patients with greater than 12% baseline acid reflux had 10.5-fold increased odds of improvement (odds ratio [OR], 10.5; 95% confidence interval [CI], 1.36-81.1; P ¼.02), and those with concomitant heartburn with or without regurgitation had 6.6-times increased odds of postoperative symptomatic improvement (OR, 6.60; 95% CI, 0.97-44.9; P ¼.05). Based on multivariable logistic regression the probability of the primary EER symptom improvement postfundoplication increased significantly from 8.5% in those without heartburn/regurgitation or acid exposure greater than 12% (95% CI, 0.6-58.2) to 90.7% if patients experienced both conditions (95% CI, 53.3-98.8; P ¼.01) (Fig. 4). DISCUSSION In this study, we sought to quantify the effectiveness of surgical fundoplication among patients with both medication-refractory EER symptoms and physiologic evidence of GERD and, further, to identify what preoperative parameters enhance the probability of surgical success at treating EER symptoms. Overall, 59% of patients experienced postoperative symptom 1906 improvement. We also found that patients with concomitant classical GERD signs and symptoms were more likely to experience EER symptom improvement postfundoplication than those with silent reflux. Preoperative heartburn with or without regurgitation and esophageal acid exposure of greater than 12% at baseline were significant predictors of response of the primary EER symptom to antireflux surgery. In fact, there was a 90% probability of symptom improvement if both were present. Impedance-pH parameters performed on therapy were not predictive of EER symptom improvement postfundoplication. Our data provide unique and important insights into the effectiveness of fundoplication surgery in a select population of patients with medication-refractory EER and objective GERD. To date, no study has applied such strict inclusion criteria and has performed both impedance-ph on and wireless ph monitoring off therapy with the goal of predicting what physiologic esophageal parameters predispose to postoperative EER symptomatic improvement. Creating a predictive model to identify who will benefit from surgical intervention for EER symptoms is critical. Patients presenting with chronic cough, refractory asthma, and other atypical reflux symptoms are often desperate for a magic bullet to resolve their condition. We need to be educated and realistic about surgery s effectiveness and better understand who might benefit before exposing them to associated risks. The role of surgical fundoplication in treating EER patients refractory to PPI therapy remains nebulous. 15,16 Reported effectiveness of fundoplication for EER symptoms varies from 15% to 95% 4 and is largely attributable to disparate study design, patient selection, and outcome metrics. In our population limited to subjects with refractory reflux symptoms and objective evidence of GERD, 59% had EER symptom improvement after surgery. Other studies have used similar inclusion criteria. 6,17 For example, Iqbal et al. identified 50 patients meeting the same inclusion criteria and found that, at a median follow-up of 41 weeks, 85% reported their result as satisfactory with a mean reflux SI (RSI) 18 decrement of 10 points. 17 Although these results are subject to recall bias due to retrospective outcome assessment, it is interesting that 85% of patients had baseline concomitant heartburn with or without regurgitation and that most of these patients (84%) had improved EER symptoms after fundoplication. This relationship is consistent with our findings and those of previous studies. 16,19 Mainie et al. 6 used similar patient selection but did not limit to patients with EER symptoms. Instead, their 19 subjects were heterogeneous: nine with typical (i.e., heartburn, regurgitation) and 10 with atypical presenting reflux symptoms (i.e., cough, asthma, throat clearing). Power limitations prevented separate analysis of these groups. Although 94% of subjects were asymptomatic at a mean of 14 months postoperatively, patient heterogeneity restricts the ability to extrapolate their findings to all patients with refractory EER symptoms. Other studies differed in both patient selection and outcome metrics. Westcott et al. identified 41 patients

TABLE II. Demographic and Physiologic Parameters of Responders Versus Nonresponders After Fundoplication. Responders (n ¼ 16) Nonresponders (n ¼ 11) P Demographics Age* 58 (52 67) 53 (40 62).21 Caucasian, % 100 100 1.00 Female, % 77 81.8.77 BMI* 30.9 (27 34) 30.7 (27 35).64 1 symptoms, % Cough 56.3 45.5.78 Asthma/wheezing 25.0 27.3 Other 18.8 27.3 Baseline heartburn 6 regurgitation, % 85 55.04 EGD Hiatal hernia, % 58.3 66.7.74 Hernia size (cm)* 3.5 (3 5) 3 (2 4).28 Hernia size > 4 cm, % 44.4 0.06 Esophagitis, % 13.3 0.26 Wireless ph (off therapy) Total time ph < 4, %* 14.8 (11.4 17.3) 8 (6 10.6).13 Upright time ph < 4, % 19.4 (15.2 23.9) 11.8 (8.4 19).24 Supine time ph < 4, % 1.6 (0.9 10.4) 2 (0 12.7).65 Abnormal SI, % 0 20.19 Abnormal SAP, % 50 20.28 Impedance (on therapy) No. reflux episodes (acid þ nonacid)* 53 (45 82) 65.5 (37 100).60 No. acid reflux episodes* 7 (1 32.5) 9 (4 14).77 No. nonacid reflux episodes* 43.5 (25 52) 46 (36 71).60 Abnormal SI, % 41.7 40.0.94 Abnormal SAP, % 33.3 40.0.75 *Median (interquartile range). Throat clearing, shortness of breath, hoarseness, laryngitis, postnasal drip. Values represent mean of the 2-day monitoring period. BMI ¼ body mass index; EGD ¼ esophagogastroduodenoscopy; SI ¼ symptom index; SAP ¼ symptom association probability. Fig. 3. Distribution of preoperative percentage time ph > 4 based on primary extraesophageal reflux symptom response to surgical fundoplication. Solid lines mark medians (responders 14.8% vs. nonresponders 8%) and dotted line represents 12% threshold. who underwent fundoplication: 27% for presumed EER signs (i.e., subglottic stenosis, laryngeal leukoplakia/cancer) and 73% for medication-refractory EER symptoms. 20 Of these, less than half had preoperative evidence of GERD on physiologic testing. The primary outcome measure was change in RSI. 18 Defined a priori as a reduction in RSI of 5 points, 84% had symptom improvement. Interestingly, preoperative PPI therapy provided at least partial symptomatic improvement for 86% of responders to fundoplication compared with only 12% of nonresponders. The findings of theirs and other studies 15 suggest that patients with EER who respond to medical therapy have a greater likelihood of symptomatic improvement from antireflux surgery. PPI therapy is more consistently effective in patients with typical GERD 2 ; therefore, many argue that patients with preoperative symptom response to PPI may have undiagnosed underlying GERD responsible for the EER symptoms/ manifestations. To eliminate potential confounding, our analysis was limited to patients with medication-refractory EER and objectively diagnosed GERD. Efforts to identify preoperative predictors of symptomatic improvement of EER symptoms from 1907

Fig. 4. Probability of primary extraesophageal reflux symptom improvement 1 year postoperatively based on presence or absence of concomitant baseline heartburn/regurgitation and acid exposure greater than 12%. fundoplication surgery have been similarly hampered by inconsistent methodology. Consistent with prior studies 16,21 we found concomitant baseline heartburn with or without regurgitation to be predictive of postoperative EER symptom improvement. Heartburn with or without regurgitation is the quintessential symptom of typical GERD but is considered a less prominent symptom of EER. 22 It is, however, included in the RSI, which grades patient complaints from 0 to 5 on several different domains. 18 It is unclear from studies that have used RSI as the metric for effectiveness of fundoplication whether the demonstrated improvement was primarily due to resolution/improvement of this classic symptom or some combination of other domains. We also found patients experiencing ph < 4 for more than 12% over 24 hours had higher likelihood of postoperative EER symptom improvement. Longer duration of ph < 4 is an indicator of higher GERD severity. Our findings corroborate those of previous studies demonstrating the effectiveness of fundoplication in treatment of EER symptoms in patients who also have typical signs and symptoms of reflux. 16,23 Preoperative presence of a large hiatal hernia (> 4 cm) was associated, albeit not significantly, with symptomatic improvement after fundoplication. In our population, approximately two thirds of both responders and nonresponders to surgery had a hiatal hernia. Among those, 44% of hiatal hernias in the responder were > 4 cm compared with 0% in the nonresponder group. Owing to power limitations, this relationship did not achieve statistical significance (P ¼.06). However, it is worth mention. Previous studies have found that patients with larger hiatal hernias were more likely to have abnormal findings on ph monitoring. 24,25 Hiatal hernia is a known risk factor for GERD as it effectively impairs or eliminates the native high-pressure zone at the distal esophagus and lower esophageal sphincter. This association further supports our assertion that patients with medication-refractory EER symptoms who have coexistent objective GERD (more likely in presence of a large hiatal hernia) have greater likelihood of symptom improvement postoperatively. 1908 We did not find any relationship between preoperative impedance-ph parameters on therapy and postoperative symptomatic improvement. Such a relationship had previously been proposed by Mainie et al. 6 They concluded that detection of GERD could be done independent of ph by recording electrical stimulation within the esophagus, thereby contending that impedance ph is ideal for evaluating patients with residual symptoms while on acid-suppression therapy. This is an attractive possibility because weakly acidic and nonacidic reflux is often implicated as the explanation for why standard ph testing does not identify all patients presumed to have EER. 26 However, our results are unable to substantiate their findings. Our study has some limitations, which need mention. Inherent to any retrospective study is possible selection bias. Patients with refractory EER and objective evidence of GERD were counseled about treatment options including continued medical therapy and fundoplication. Randomization to surgery was not possible; however, a comparison of the demographic and physiologic parameters of those who underwent fundoplication versus those who continued on medical therapy showed similar findings. Power limitation secondary to sample size may have restricted our ability to identify other less robust predictors. Thus our analysis focused on only large effect sizes. Therefore, the presence of heartburn with or without regurgitation and ph < 4 for 12% over 24 hours should be considered strong predictors of postoperative EER symptom improvement. Larger prospective multicenter trials will be required to confirm these findings and better define which patients might benefit from surgery. CONCLUSION This study aimed to quantify response of patients with refractory EER to surgical fundoplication and to identify predictors of response to surgery. We found that 59% of patients with refractory EER symptoms experienced symptom improvement postsurgery. Those with concomitant classical GERD signs and symptoms were more likely to experience EER symptom improvement postoperatively compared with those with silent reflux. We could not confirm that impedance-ph parameter performed on therapy is predictive of symptom response postfundoplication, as previously suggested. Based on our findings, we recommend surgical fundoplication be considered judiciously in EER patients refractory to PPI therapy. BIBLIOGRAPHY 1. Frye JW, Vaezi MF. Extraesophageal GERD. Gastroenterol Clin North Am 2008;37:845 858, ix. 2. Qadeer MA, Phillips CO, Lopez AR, et al. Proton pump inhibitor therapy for suspected GERD-related chronic laryngitis: a meta-analysis of randomized controlled trials. Am J Gastroenterol 2006;101:2646 2654. 3. Wileman SM, McCann S, Grant AM, Krukowski ZH, Bruce J. Medical versus surgical management for gastro-oesophageal reflux disease (GORD) in adults. Cochrane Database Syst Rev 2010;(3):CD003243. 4. 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